A summary of some notable key multiple myeloma research from June-July 2026  

Scope and Methodology   
This week’s blog summarizes key multiple myeloma research published in several peer-reviewed publications and medical journals from June-July  2026. Content was developed by the International Myeloma Foundation medical editorial team using various medical abstracts on new guidelines, recommendations, reviews, letters to the editor, correspondence, and the latest results of ongoing clinical trials. It is intended for patients, care partners, and oncology professionals. This blog article was medically reviewed by Joseph Mikhael, MD, MEd, FRCPC, FACP, FASCO, on July 29, 2026. The blog reflects medical guidance available at the time of review and is not routinely updated.  

Clinical Updates  

POEMS Syndrome: 2026 Update on Diagnosis, Risk-Stratification, and Management — American Journal of Hematology (July 2026)

What is the purpose of the clinical update? 
To summarize the current evidence on the diagnosis, risk stratification, treatment, monitoring, and outcomes of POEMS syndrome, a multisystem disorder associated with an underlying clonal plasma cell neoplasm. It outlines current diagnostic criteria, prognostic factors, and management approaches based on the available clinical evidence.

Summary  
POEMS syndrome is diagnosed by the presence of three major criteria, including both polyneuropathy and a clonal plasma cell disorder, together with at least one minor criterion. Diagnosis relies on clinical assessment supported by radiographic evaluation, vascular endothelial growth factor (VEGF) measurement, and bone marrow examination, while treatment is guided by disease extent: radiation therapy is recommended for patients with a dominant plasmacytoma, whereas systemic therapy is recommended for patients with diffuse bone lesions or disseminated bone marrow involvement. Reported prognostic factors include serum albumin, age, pleural effusion, pulmonary hypertension, reduced estimated glomerular filtration rate (eGFR), treatment response, and selected clinical features, with supportive care remaining an important component of management.

Key points

Disease characteristics 
• POEMS syndrome is a life-threatening syndrome caused by an underlying clonal plasma cell neoplasm. 
• Major diagnostic criteria include polyneuropathy, clonal plasma cell disorder, sclerotic bone lesions, elevated VEGF, Castleman disease 
• Minor features include organomegaly, endocrinopathy, characteristic skin changes, papilledema, extravascular volume overload, and thrombocytosis.

Diagnosis 
• Diagnosis requires three major criteria (including polyneuropathy and clonal plasma cell disorder) plus at least one minor criterion. 
• Recommended evaluation includes: 
   - Radiographic assessment of bone lesions 
   - VEGF measurement 
   - Bone marrow biopsy

• Reported VEGF diagnostic cutoffs: 
   - Plasma VEGF ≥200 pg/mL: specificity 95%, sensitivity 68% 
   - Serum VEGF ≥1920 pg/mL: specificity 98%, sensitivity 73%

• N-terminal propeptide of type I collagen ≥70 ng/mL was reported as a potential diagnostic marker with specificity 91.5% and sensitivity 80%.

• Mandatory VEGF testing for acquired demyelinating neuropathy was reported in one cost-effectiveness analysis to reduce misdiagnosis, healthcare costs, and delayed diagnosis.

Risk stratification 
• No established molecular or genetic prognostic markers are currently available. 
• Reported adverse prognostic factors include: 
   - Low serum albumin 
   - Older age 
   - Pleural effusion 
   - Pulmonary hypertension 
   - Reduced eGFR 
   - Elevated IL-6 
   - Extravascular volume overload 
   - Respiratory symptoms 
   - Impaired diffusing capacity (DLCO) 
   - Papilledema 
   - Coexisting Castleman disease

• Better outcomes were associated with complete hematologic response and higher serum albumin.

Treatment 
• Radiation therapy is recommended for patients with isolated plasmacytoma or limited bone lesions and may be curative. 
• Systemic therapy is recommended for disseminated bone marrow involvement or diffuse skeletal disease. 
• Corticosteroids may provide temporary symptom control. 
• Alkylating agents and lenalidomide are described as main systemic treatment options. 
• Thalidomide and bortezomib have reported activity but require consideration of peripheral neuropathy risk. 
• Daratumumab-containing combinations have shown promising findings in case series. 
• Treatment is directed primarily at the underlying plasma cell disorder rather than VEGF inhibition alone.

Clinical outcomes 
• Overall survival has improved over time, with reported 10-year survival increasing from 55% (before 2003) to 79% (after 2003). 
• Modern therapies were associated with overall 6-year progression-free survival (PFS) exceeding 50%. 
• Patients achieving complete hematologic response had a reported 5-year PFS of 88%. 
• Radiation therapy for localized disease was associated in one Mayo Clinic series with: 
  - 4-year overall survival of 97% 
  - 4-year failure-free survival of 52% 
  - Updated cohorts reported 10-year overall survival of 70% and 6-year PFS of 62%.

Monitoring 
• Patients should undergo regular follow-up with assessment of clinical status relative to baseline. 
• VEGF trends may assist monitoring but may not consistently correlate with disease activity. 
• Hematologic markers and M-protein measurements have limitations because plasma cell burden is often small. 
• Suggested response assessment includes hematologic response, VEGF response, FDG-PET response, and organ-specific clinical evaluation.

Supportive care 
Recommended supportive measures include physical therapy, ankle-foot orthotics, CPAP or bilevel positive airway pressure when indicated, treatment of neuropathic pain, and depression screening.

Strengths  
• Integrates current evidence on diagnosis, prognosis, treatment, supportive care, and response assessment for POEMS syndrome. 
• Includes long-term outcome data and summarizes available observational evidence.

Limitations  
• There is a paucity of published randomized clinical trials in POEMS syndrome. 
• Treatment recommendations are based primarily on limited clinical trial data, retrospective studies, case series, and anecdotal experience. 
• Some reported treatment outcomes derive from retrospective series.

Why this clinical update matters 
POEMS syndrome requires diagnosis using defined clinical criteria supported by imaging, VEGF measurement, and bone marrow evaluation. Management is based on the extent of plasma cell involvement, with radiation therapy recommended for localized disease and systemic therapy for disseminated disease, alongside supportive care and ongoing monitoring. The review notes that current treatment recommendations are limited by the scarcity of randomized clinical trials and are based largely on observational evidence and case series.

Reference: 
A. Dispenzieri, “POEMS Syndrome: 2026 Update on Diagnosis, Risk-Stratification, and Management,” American Journal of Hematology (2026): 1–20, https://doi.org/10.1002/ajh.70438. 

Review

Management of Bispecific Antibody Toxicities: A Focus on Multiple Myeloma — ASCO Educational Book (June 2026)

What is the purpose of the review? 
This review describes toxicities associated with bispecific antibodies (BsAbs) used in T-cell–redirecting therapy for advanced malignancies, including their timing, clinical features, and management. It also summarizes infection risk, prophylaxis recommendations, and less common acute and late toxicities.

Summary  
Bispecific antibodies (BsAbs) used in advanced malignancies are associated with toxicities including cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome (ICANS), infections, infusion-related reactions, and tumor flare reactions. CRS occurs in up to two thirds of patients, is usually low-grade, and is primarily observed during step-up dosing and the first full dose, while ICANS is rare and may occur in association with CRS. Infection risk persists throughout therapy and is a leading cause of nonrelapse mortality, particularly with B-cell maturation antigen (BCMA)–targeting BsAbs due to B-cell and plasma cell depletion resulting in near-universal hypogammaglobulinemia, with additional contributions from cytopenias including neutropenia and lymphopenia. 

Key points 
• CRS occurs in up to two thirds of patients, is generally low-grade, and is mainly observed during step-up dosing and the first full dose. 
• ICANS is rare and may be associated with CRS. 
• Infection risk persists throughout BsAb therapy and is a leading cause of nonrelapse mortality, particularly with BCMA-targeting BsAbs due to B-cell and plasma cell depletion and resulting hypogammaglobulinemia. 
• Neutropenia and lymphopenia occur during the first 6 months and contribute to infection risk. 
• Recommended prophylaxis includes herpes simplex virus, varicella zoster virus, and Pneumocystis jirovecii pneumonia prophylaxis, with intravenous immunoglobulin strongly recommended for BCMA-targeting BsAbs. 
• Additional toxicities include infusion-related reactions (typically within <6 hours of infusion), tumor flare reactions (usually during the first cycle), and GPRC5D-targeting toxicities such as taste alteration, weight loss, rash, and skin and nail changes. 
• Rare late complications include progressive multifocal leukoencephalopathy and second primary malignancies. 
• No strengths or limitations are explicitly stated in the abstract.

Why this review matters 
Bispecific antibodies used in advanced malignancies are associated with acute toxicities including CRS, ICANS, infusion-related reactions, tumor flare, and infection risk, as well as less common late complications. CRS is generally low-grade and occurs mainly early in treatment, while infection risk persists throughout therapy and is particularly significant in BCMA-targeting BsAbs due to hypogammaglobulinemia. The abstract emphasizes prophylaxis strategies and ongoing vigilance for early and late toxicities as BsAb use continues to expand.

Reference: 
Eden Biltibo et al. Management of Bispecific Antibody Toxicities: A Focus on Multiple Myeloma. Am Soc Clin Oncol Educ Book 46, e517460(2026). DOI:10.1200/EDBK-26-517460

Safety profile of chimeric antigen receptor T-cell therapy in relapsed/refractory multiple myeloma: A systematic review and meta-analysis of proportions from clinical trials — British Journal of Haematology (June 2026)

What is the purpose of the review? 
This meta-analysis evaluates the safety profile of chimeric antigen receptor (CAR) T-cell therapies in patients with relapsed or refractory multiple myeloma (RRMM) by pooling data from clinical trials and examining the incidence of adverse events and factors associated with toxicity outcomes.

Summary 
This systematic review and meta-analysis included 32 clinical trials of CAR T-cell therapies for RRMM. The pooled incidence of any-grade cytokine release syndrome (CRS) was 84%, while grade ≥3 CRS occurred in 5% of patients. Any-grade neurotoxicity occurred in 13% of patients, immune effector cell-associated neurotoxicity syndrome (ICANS) in 8%, and severe infections in 21%.

Reported rates of grade ≥3 hematologic toxicities included neutropenia (86%), leukopenia (75%), anemia (52%), lymphopenia (52%), and thrombocytopenia (50%). Meta-regression analyses identified associations between toxicity outcomes and factors including prior lines of treatment (LoT), prior autologous hematopoietic stem cell transplantation (AHSCT), patient age, high-risk cytogenetic abnormalities (HRCAs), and study region. Safety outcomes were reported as comparable between the two currently approved CAR T-cell therapies based on five trials involving 749 patients.

Key points 
• 32 clinical trials of CAR T-cell therapies for RRMM were included. 
• Any-grade CRS occurred in 84% of patients; grade ≥3 CRS occurred in 5%. 
• Any-grade hemophagocytic lymphohistiocytosis (HLH) occurred in 3%. 
• Any-grade neurotoxicity occurred in 13% of patients. 
• Any-grade ICANS occurred in 8% of patients. 
• Grade ≥3 neurotoxicity occurred in 4% of patients. 
• Grade ≥3 ICANS occurred in 3% of patients. 
• Reported rates of grade ≥3 hematologic toxicities included: 
   - Neutropenia: 86% 
   - Leukopenia: 75% 
   - Anemia: 52% 
   - Lymphopenia: 52% 
   - Thrombocytopenia: 50%

• Any-grade infections occurred in 53% of patients; grade ≥3 infections occurred in 21%. 
• Higher numbers of prior LoT were associated with increased incidences of grade ≥3 CRS and grade ≥3 ICANS. 
• Higher percentages of prior AHSCT were associated with increased incidences of any-grade neurotoxicity, any-grade ICANS, and grade ≥3 neurotoxicity. 
• Older age was associated with higher incidences of grade ≥3 anemia and any-grade ICANS. 
• A higher burden of HRCAs was associated with increased incidence of grade ≥3 neutropenia. 
• Safety outcomes were comparable between the two currently approved CAR T-cell therapies in five trials involving 749 patients.

Strengths 
• The authors described this as one of the most comprehensive pooled analyses of CAR T-cell toxicities in RRMM. 
• Included meta-regression and subgroup analyses to identify factors associated with toxicity outcomes.

Limitations 
• Most included studies lacked control groups, limiting the ability to distinguish treatment-related adverse events from events related to the underlying disease or disease course. 
• Significant interstudy heterogeneity was observed for several outcomes. 
• Limited long-term follow-up may have reduced detection of rare late complications and delayed toxicities. 
• Lack of standardized definitions for non-ICANS neurotoxicity across trials. 
• Limited reporting of late-onset movement and neurocognitive treatment-emergent events (MNTs).

Why this review matters 
In this meta-analysis of 32 clinical trials of CAR T-cell therapy in RRMM, any-grade CRS occurred in 84% of patients, while grade ≥3 CRS, ICANS, and neurotoxicity occurred in 5%, 3%, and 4% of patients, respectively. Reported rates of grade ≥3 hematologic toxicities included neutropenia (86%), leukopenia (75%), anemia (52%), lymphopenia (52%), and thrombocytopenia (50%). Meta-regression analyses identified associations between toxicity outcomes and factors including prior lines of treatment, prior AHSCT, age, and HRCAs.

Reference: 
Filippatos, C., Ntanasis-Stathopoulos, I., Voulomenou, A., Malandrakis, P., Kastritis, E., Gavriatopoulou, M., Dimopoulos, M.-A. and Terpos, E. (2026), Safety profile of chimeric antigen receptor T-cell therapy in relapsed/refractory multiple myeloma: A systematic review and meta-analysis of proportions from clinical trials. Br J Haematol. https://doi.org/10.1111/bjh.70624 

The Changing Landscape of Maintenance Therapy in Newly Diagnosed Multiple Myeloma: A Systematic Review With Network Meta-Analysis of the European Myeloma Network (EMN) — American Journal of Hematology (June 2026)

What is the purpose of the review? 
To evaluate the effectiveness of maintenance therapies in multiple myeloma (MM), focusing on progression-free survival (PFS) and overall survival (OS).

Summary 
Lenalidomide, proteasome inhibitors, and CD38 antibodies were associated with improved PFS in maintenance therapy for MM. OS benefit was observed mainly with lenalidomide in transplant-eligible (TE) patients, while CD38-directed therapies showed a non-significant trend toward improved OS and proteasome inhibitors did not show OS benefit. In network meta-analysis compared with observation, daratumumab–lenalidomide (DR) showed the greatest PFS reduction, followed by carfilzomib–lenalidomide–dexamethasone (KRd), KR in TE patients, and DRd in transplant-ineligible patients; OS prolongation in TE patients was observed with KR, DR, and lenalidomide alone.

Key points
• PFS improvement: Lenalidomide, proteasome inhibitors, and CD38 antibodies improved progression-free survival. 
• OS findings: OS benefit was observed with lenalidomide in TE patients; KR, DR, and lenalidomide alone reduced mortality risk in TE patients. 
• Network meta-analysis ranking (PFS): DR showed the greatest PFS benefit (~80% reduction in progression risk), followed by KRd, DRd, KR, and Isa-Rd. 
• CD38 antibodies: Showed PFS benefit and a non-significant trend toward OS improvement (pooled HR for mortality 0.79, 95% CI 0.59–1.05). 
• Subgroup findings: Similar patterns across subgroups; DR and Dara-Rd identified as top regimens in TE and transplant-ineligible populations respectively. 
• High-risk cytogenetics: Limited data; DR and KR improved PFS (74% and 66% reduction in progression risk). 
• Maintenance duration: Evidence was insufficient to determine superiority of continued vs limited-duration maintenance.

Strengths
• Network meta-analysis enabled indirect comparisons and regimen ranking
• Robustness supported by subgroup analyse (digitized vs published data and risk-of-bias stratification)

Limitations
• Heterogeneity across trials, assumptions in landmark analysis
• Immature/incomplete survival data
• Unclear separation of induction vs maintenance phases
• Lack of post-progression therapy data

Why this critical review matters 
Maintenance therapies with lenalidomide, proteasome inhibitors, and CD38 antibodies improved progression-free survival, with OS benefits primarily observed for lenalidomide and selected combination regimens in transplant-eligible patients. Network meta-analysis identified daratumumab–lenalidomide-based combinations and carfilzomib-based regimens as providing the greatest reductions in progression risk. However, interpretation is limited by heterogeneity, incomplete reporting, and immature survival data across studies.

Reference: 
H. Ludwig, E. Terpos, F. Gay, et al., “The Changing Landscape of Maintenance Therapy in Newly Diagnosed Multiple Myeloma: A Systematic Review With Network Meta-Analysis of the European Myeloma Network (EMN),” American Journal of Hematology (2026): 1–18, https://doi.org/10.1002/ajh.70397. 

Toxicities of CAR-T, Bispecific Antibodies, and Antibody–Drug Conjugates in Multiple Myeloma: A Practical Approach to Risk Mitigation and Management — Cancers (June 2026) 
 

What is the purpose of the review? 
This narrative review summarizes the published evidence on the toxicities of approved and investigational B-cell maturation antigen (BCMA)- and G protein-coupled receptor class C group 5 member D (GPRC5D)-directed immunotherapies for relapsed/refractory multiple myeloma (MM). It also outlines practical approaches to toxicity recognition, risk stratification, management, and the infrastructure needed to safely deliver these therapies in community and smaller healthcare centers.

Summary 
This review examined evidence from pivotal clinical trials, real-world cohorts, pharmacovigilance studies, retrospective studies, case series, case reports, and consensus recommendations regarding toxicities associated with chimeric antigen receptor T-cell (CAR-T) therapies, bispecific T-cell engagers (BsAbs), and antibody–drug conjugates (ADCs) targeting BCMA or GPRC5D. Toxicities were categorized by timing into acute (including cytokine release syndrome [CRS], immune effector cell-associated neurotoxicity syndrome [ICANS], infections, ocular and mucocutaneous toxicities), subacute (including cranial nerve palsies, parkinsonism, myelitis, peripheral neuropathies, immune effector cell-associated enterocolitis [IEC-associated enterocolitis], and cardiovascular events), and long-term complications (including prolonged cytopenias and second primary malignancies).

The review highlights the use of validated risk stratification tools, including the CAR-HEMATOTOX score, Endothelial Activation and Stress (EASIX) index, and multidisciplinary geriatric assessment, to support individualized treatment planning. Among patients with relapsed/refractory MM, a high CAR-HEMATOTOX score (≥2) was associated with severe ICANS (16% vs. 0% in low-score patients; p<0.001), severe infections (adjusted odds ratio 4.9; p=0.03), and longer hospitalization (13 vs. 8 days). The review also describes the clinical infrastructure recommended for community centers, including acute monitoring capabilities, multidisciplinary specialist access, structured referral pathways, and long-term surveillance.

Key points 
• Study type: Narrative review of published literature on BCMA- and GPRC5D-directed immunotherapies for multiple myeloma. 
• Reviewed therapies included: 
  - CAR-T cell therapies 
  - Bispecific T-cell engagers (BsAbs) 
  - Antibody–drug conjugates (ADCs)

• Toxicities were organized by timing: 
  - Acute: CRS, ICANS, infections, ocular toxicities, mucocutaneous toxicities. 
  - Subacute: Cranial nerve palsies, parkinsonism, myelitis, peripheral neuropathies, IEC-associated enterocolitis, cardiovascular events. 
   - Long-term: Prolonged cytopenias and second primary malignancies.

• Risk stratification tools discussed: 
   - CAR-HEMATOTOX score 
   - EASIX index 
   - Multidisciplinary geriatric assessment

• Reported findings for a high CAR-HEMATOTOX score (≥2): 
   - Severe ICANS: 16% vs. 0% in low-score patients (p<0.001). 
   - Severe infections: adjusted odds ratio 4.9 (p=0.03). 
   - Longer hospitalization: 13 vs. 8 days.

• Frailty assessments were described as useful for individualized risk stratification and treatment planning rather than automatic exclusion from intensive therapy.

• The review recommends community treatment centers have: 
  - Continuous acute monitoring capability. 
  - Access to critical care and multidisciplinary specialists (neurology, ophthalmology, infectious diseases). 
  - Structured referral pathways. 
  - Long-term follow-up for delayed toxicities, prolonged cytopenias, cardiovascular events, and second primary malignancies.

Strengths  
• Integrates evidence from pivotal trials, real-world cohorts, pharmacovigilance studies, and consensus management recommendations. 
• Provides a practical framework for recognizing, mitigating, and managing toxicities in both specialist and community care settings.

Limitations  
• Narrative review without a formal systematic review methodology, making it susceptible to selection bias. 
• Evidence for many uncommon toxicities is based primarily on retrospective studies, pharmacovigilance reports, small case series, and case reports. 
• Focuses mainly on currently approved BCMA- and GPRC5D-directed therapies. 
• Toxicity profiles of emerging therapies (including dual-target CAR-T, trispecific antibodies, combination bispecifics, sequential immune redirection strategies, and CAR-NKT therapies) remain incompletely characterized. 
• Some recommendations are based on the best available evidence and expert consensus rather than prospective comparative studies.

Why this review matters 
This narrative review summarizes the range of acute, subacute, and long-term toxicities associated with BCMA- and GPRC5D-directed immunotherapies for relapsed/refractory multiple myeloma and reviews published evidence supporting their recognition and management. It highlights validated risk stratification tools, including the CAR-HEMATOTOX score, EASIX index, and multidisciplinary geriatric assessment, as components of individualized treatment planning, and describes the infrastructure and long-term surveillance considered necessary for safe delivery of these therapies in community practice.

Reference: 
Hej-Ali, S., Banwell, K., Mohamed, H., Cervi, A., Dass, A., Gupta, R., Hamm, C., Kanjeekal, S., Strange Seguel, I., Szalay, M., & Khan, S. (2026). Toxicities of CAR-T, Bispecific Antibodies, and Antibody–Drug Conjugates in Multiple Myeloma: A Practical Approach to Risk Mitigation and Management. Cancers, 18(13), 2083. https://doi.org/10.3390/cancers18132083 

Multiple myeloma: A tale of deregulated transcription factors — HemaSphere (July 2026)

What is the purpose of the review? 
This review examines the roles of transcription factors (TFs) in the development, progression, and biology of multiple myeloma (MM). It also reviews their potential use as prognostic biomarkers and discusses emerging therapeutic strategies designed to target TF activity.

Summary  
The review describes the physiological functions of TFs in lymphoid lineage commitment and plasma cell differentiation, and explains how dysregulation of TFs, including IRF4 and PRDM1, contributes to MM pathogenesis through genetic and epigenetic alterations. It summarizes established and emerging TF families involved in MM, their potential value for patient stratification and risk assessment, and recent therapeutic approaches such as siRNA-loaded lipid nanoparticles and Proteolysis-Targeting Chimeras (PROTACs) that aim to modulate TF activity. The review concludes that integrating physiological and pathological knowledge of TFs may support precision medicine approaches in MM.

Key points 
• Transcription factors (TFs) regulate normal lymphoid lineage commitment and terminal B-cell differentiation into plasma cells. 
• Dysregulation of TF activity through genetic or epigenetic alterations contributes to the initiation and progression of multiple myeloma (MM). 
• TFs influence malignant plasma cell survival, proliferation, migration, invasion, and transcriptional dependencies. 
• Key TFs discussed include IRF4 and PRDM1, along with other established and emerging TF families relevant to MM. 
• Aberrant expression of specific TFs has been associated with adverse clinical outcomes. 
• Incorporating TF expression patterns into molecular risk models has improved patient stratification compared with conventional cytogenetic classifications. 
• Several TFs are highlighted as potential prognostic biomarkers and therapeutic targets. 
• Emerging therapeutic strategies discussed include siRNA-loaded lipid nanoparticles, Proteolysis-Targeting Chimeras (PROTACs), RNA-based therapies, and targeted protein degradation technologies aimed at modulating TF function. 
• The review emphasizes continued investigation of TF regulatory networks and next-generation targeting strategies to support future clinical translation.

Strengths  
• Integrates physiological and pathological insights into TF function in MM. 
• Reviews both well-established and emerging TFs with potential clinical relevance. 
• Discusses recent advances in therapeutic strategies targeting TFs.

Why this review matters 
This review identifies transcription factors as central regulators of normal plasma cell biology and important contributors to multiple myeloma pathogenesis when their activity becomes dysregulated. It highlights evidence supporting their use as prognostic biomarkers and summarizes emerging therapeutic approaches, including RNA-based therapies and PROTACs, that aim to target TF function. The authors state that further investigation of TF regulatory networks and next-generation targeting strategies will be important for translating these findings into clinical practice.

Reference: 
Gómez-Echarte, N., San José-Enériz, E., Urizar-Compains, E., Rodriguez-Otero, P., Prósper, F. and Agirre, X. (2026), Multiple myeloma: A tale of deregulated transcription factors. HemaSphere, 10: e70411. https://doi.org/10.1002/hem3.70411 

Molecular determinants of Bortezomib sensitivity and resistance in multiple myeloma — Cancer Treatment and Research Communications (July 2026)

What is the purpose of the review? 
To synthesize current evidence on the molecular mechanisms that influence sensitivity and resistance to bortezomib (BTZ) in multiple myeloma (MM). It focuses on the roles of p53, Ras signaling, mTOR, Wee1 kinase, and long non-coding RNAs (lncRNAs), and discusses their potential relevance to biomarker development and therapeutic strategies.

Summary  
This review describes how intrinsic and acquired resistance to bortezomib arises from interconnected molecular pathways involving tumor suppressor function, oncogenic signaling, metabolic regulation, cell-cycle control, and lncRNA-mediated gene regulation. The evidence reviewed indicates that alterations in p53, Ras, mTOR, Wee1, and lncRNAs contribute to cellular adaptation, stress tolerance, and reduced response to proteasome inhibition in multiple myeloma. The review also summarizes emerging approaches under investigation, including RNA-based therapies, multi-omics profiling, biomarker development, and combination treatment strategies.

Key points 
• Bortezomib (BTZ) has substantially improved the treatment of multiple myeloma (MM), but both intrinsic and acquired resistance limit long-term effectiveness. 
• BTZ resistance is described as a coordinated, multilayered process involving stress response, survival signaling, metabolic adaptation, cell-cycle regulation, and transcriptomic regulation. 
• p53 is a central mediator of BTZ-induced apoptosis; loss of function through TP53 mutations or 17p deletion reduces pro-apoptotic signaling and decreases BTZ sensitivity. 
• Ras signaling promotes cell survival by activating MAPK/ERK and PI3K/AKT/mTOR pathways, increasing anti-apoptotic proteins and supporting proteostasis and metabolic adaptation. 
• mTOR signaling supports protein synthesis, antioxidant responses, proteasome recovery, and metabolic compensation during proteasome inhibition, and hyperactive mTOR signaling is associated with reduced BTZ sensitivity. 
• Wee1 kinase maintains the G₂/M checkpoint, allowing myeloma cells additional time to repair DNA damage and tolerate proteotoxic stress; Wee1 inhibition enhances BTZ-induced apoptosis in experimental studies. 
• lncRNAs, including NEAT1, MALAT1, MIAT, and ANRIL, regulate BTZ resistance through effects on apoptosis, cell-cycle checkpoints, chromatin remodeling, metabolism, and exosome-mediated intercellular communication. 
• The review discusses potential future strategies, including combinations of BTZ with MDM2, MEK, AKT/mTOR, or Wee1 inhibitors, as well as lncRNA-targeted therapies, multi-omics profiling, and biomarker development.

Strengths  
• Integrates multiple molecular pathways into a systems-level framework to describe BTZ response and resistance. 
• Synthesizes current evidence on molecular determinants of BTZ sensitivity and resistance while discussing emerging therapeutic and biomarker approaches.

Why this review matters 
This review concludes that resistance to bortezomib in multiple myeloma results from the interaction of multiple molecular mechanisms, including p53 dysfunction, Ras and mTOR signaling, Wee1-dependent cell-cycle regulation, and lncRNA-mediated regulatory networks. According to the reviewed evidence, understanding these interconnected pathways provides a basis for investigating biomarkers and mechanism-guided combination therapies aimed at overcoming resistance to proteasome inhibition.

Reference: 
Jahir Hossain, Debopriya Choudhury, Soham Bhattacharyya, Brahmachari Vedeshachaitanya, Pushkar Malakar, Molecular determinants of Bortezomib sensitivity and resistance in multiple myeloma, Cancer Treatment and Research Communications, Volume 48, 2026, 101303, ISSN 2468-2942, https://doi.org/10.1016/j.ctarc.2026.101303. 

Light Chain Monoclonal Gammopathy of Undetermined Significance: Diagnosis, Biology, and Clinical Management — European Journal of Haematology (July 2026)

What is the purpose of the review? 
To review current evidence on the diagnosis, risk stratification, clinical evaluation, and follow-up of light chain monoclonal gammopathy of undetermined significance (LC-MGUS). It focuses on improving diagnostic accuracy through revised serum free light chain (FLC) reference intervals and outlines a clinical approach that separately evaluates the risks of progression to light chain multiple myeloma (LC-MM) and AL amyloidosis.

Summary 
LC-MGUS is defined by an abnormal serum FLC ratio with elevated involved light chain, no detectable immunoglobulin heavy chain on immunofixation, and no end-organ damage attributable to a plasma cell disorder. The review reports that standard FLC reference intervals overdiagnose LC-MGUS because of age-related physiological FLC elevation, chronic kidney disease, and ancestry-related differences in individuals of African descent; revised age-, kidney function-, and ancestry-adjusted reference intervals reduced LC-MGUS prevalence by 82%, with no observed progression among reclassified individuals during a median follow-up of 4.6 years, and these intervals were validated in multiple independent international cohorts. The authors recommend confirming the diagnosis with appropriate reference intervals, independently assessing the risks of LC-MM and AL amyloidosis, and monitoring patients longitudinally without treatment unless progression to smoldering myeloma, multiple myeloma, or AL amyloidosis occurs.

Key points 
• LC-MGUS definition 
 - Abnormal serum FLC ratio and elevated involved light chain. 
 - No detectable immunoglobulin heavy chain on immunofixation. 
 - No end-organ damage attributable to a plasma cell disorder.

• Diagnostic considerations 
 - Standard FLC reference intervals may overdiagnose LC-MGUS because of: 
   • Age-related physiological FLC elevation. 
   • Reduced renal clearance in chronic kidney disease. 
   • Ancestry-related differences in individuals of African descent.

 - Revised age-stratified and kidney function-adjusted reference intervals reduced LC-MGUS prevalence by 82%. 
 - No observed progression occurred among individuals reclassified by the revised reference intervals during 4.6 years of available follow-up. 
 - The revised reference intervals were validated across multiple independent international cohorts. 
 - Ancestry-adjusted reference intervals are recommended for individuals of African ancestry with normal renal function.

• Disease progression 
 - LC-MGUS may progress through two distinct biological pathways: 
   • Clonal expansion to light chain multiple myeloma (LC-MM). 
   • Amyloidogenic transformation to AL amyloidosis. 
 - Risk models developed for myeloma progression do not fully capture the risk of AL amyloidosis. 
 - AL amyloidosis may develop despite a low plasma cell burden and only modest FLC abnormalities.

• Clinical evaluation 
 - Diagnosis should be confirmed using age-, kidney function-, and ancestry-adjusted FLC reference intervals where appropriate, with repeat testing for borderline or unexpected results. 
 - Bone marrow plasma cell burden may be estimated using the externally validated iStopMM prediction model. 
 - Evaluation for AL amyloidosis should be performed independently of marrow risk assessment. 
 - Baseline assessment should include NT-proBNP, high-sensitivity troponin, quantitative urine protein, creatinine with estimated glomerular filtration rate (eGFR), complete blood count, calcium, and serum and urine immunofixation. 
 - Tissue biopsy should not be delayed when clinical suspicion for AL amyloidosis is present.

• Management and follow-up 
 - No treatment is recommended unless progression to smoldering myeloma, multiple myeloma, or AL amyloidosis is confirmed. 
 - Laboratory reassessment is recommended at 6 months using the same FLC assay platform. 
 - Stable lower-risk patients may undergo annual follow-up with laboratory monitoring and assessment for symptoms or signs of organ involvement. 
 - Population screening for LC-MGUS is not currently recommended outside clinical trials; the iStopMM randomized controlled trial is evaluating whether systematic screening improves overall survival.

Strengths  
• Revised reference intervals were validated across multiple independent international cohorts. 
• The iStopMM multivariable prediction model was externally validated in ethnically diverse populations.

Limitations  
• The long-term safety of revised reference intervals remains an unresolved question. 
• Cross-platform harmonization of FLC measurements is still needed. 
• The biological determinants of the different progression pathways remain uncertain. 
• Results from the iStopMM randomized controlled trial evaluating population screening are still pending.

Why this review matters 
Accurate diagnosis of LC-MGUS depends on appropriate interpretation of serum FLC measurements using age-, kidney function-, and, where applicable, ancestry-adjusted reference intervals. Clinical evaluation and follow-up should independently assess the risks of progression to LC-MM and AL amyloidosis because these pathways differ biologically and clinically. No treatment is indicated unless disease progression occurs, and ongoing monitoring focuses on laboratory changes and early evidence of organ involvement.

Reference: 
S. Y. Kristinsson, T. E. Long, and S. Thorsteinsdóttir, “Light Chain Monoclonal Gammopathy of Undetermined Significance: Diagnosis, Biology, and Clinical Management,” European Journal of Haematology (2026): 1–9, https://doi.org/10.1111/ejh.70258. 

PET/CT Imaging for Therapy Assessment in Multiple Myeloma Including MRD — Cancers (July 2026) 

What is the purpose of the review? 
This narrative review examines published evidence on the role of [18F]FDG PET/CT in assessing treatment response in multiple myeloma (MM), with a particular focus on minimal residual disease (MRD) evaluation. It also reviews standardized response assessment criteria and emerging PET radiotracers that may have potential applications in specific clinical settings.

Summary  
The authors reviewed peer-reviewed literature published between 2014 and 2024 from PubMed, Scopus, Web of Science, and the Cochrane Library on PET imaging for treatment response assessment in multiple myeloma. The review found that [18F]FDG PET/CT enables whole-body evaluation of disease burden, detection of extramedullary disease, and assessment of early metabolic response, while standardized criteria such as Deauville, IMPeTUs, and IMWG improve the reproducibility of response assessment. The evidence reviewed indicates that PET negativity and complete metabolic response are associated with improved progression-free survival (PFS) and overall survival (OS), and that combining PET/CT with bone marrow-based MRD techniques, including next-generation flow cytometry (NGF) and next-generation sequencing (NGS), supports more comprehensive disease assessment and patient stratification.

Key points 
• Study design: Narrative review with a structured, non-systematic literature search of studies published between 2014 and 2024. 
• Population: Patients with multiple myeloma undergoing treatment response assessment. 
• Main findings: 
 - [18F]FDG PET/CT provides whole-body assessment of metabolically active disease, including skeletal and extramedullary involvement. 
 - PET/CT supports evaluation of early metabolic treatment response and MRD when baseline PET findings are positive. 
 - Standardized interpretation criteria (Deauville score, IMPeTUs, IMWG) improve consistency and reproducibility of PET response assessment. 
 - Quantitative PET parameters, including SUVmax and metabolic tumor volume (MTV), provide prognostic information. 
 - PET negativity and complete metabolic response are associated with longer PFS and OS in the reviewed evidence. 
 - Combining PET/CT with bone marrow MRD methods (NGF and NGS) provides complementary information for disease evaluation and risk stratification. 
 - Emerging radiotracers, including [11C]choline, [11C]methionine, [68Ga]pentixafor (CXCR4-targeted), and CD38-targeted immunoPET tracers, remain under investigation and have not been established as routine alternatives to [18F]FDG.

Strengths  
• Structured literature search across four major databases. 
• Focus on integrating evidence regarding therapy response, MRD assessment, standardized PET interpretation criteria, and emerging PET tracers.

Limitations  
• Narrative rather than systematic review; no registered protocol, PRISMA flow diagram, dual independent screening, published search strategy, or quantitative synthesis. 
• Study selection may be influenced by author judgment, and selection or citation bias cannot be excluded. 
• No formal quality or risk-of-bias assessment (e.g., QUADAS-2) of included studies. 
• Included studies were heterogeneous in design, sample size, treatment regimens, imaging timing, and PET positivity definitions. 
• Technical and interpretative variability in FDG PET/CT acquisition and interpretation may affect results despite standardized frameworks. 
• Evidence supporting non-FDG radiotracers is largely based on pilot, first-in-human, or preclinical studies. 
• Standardized interpretation frameworks, particularly IMPeTUs, require broader international validation. 
• Rapidly evolving treatment strategies may limit the applicability of findings from older studies to current clinical practice. 

Why this review matters 
This review indicates that [18F]FDG PET/CT is an important component of treatment response assessment in MM, providing whole-body evaluation of metabolically active disease and complementary information to bone marrow-based MRD testing. Standardized interpretation criteria have improved the reproducibility of PET assessment, while emerging radiotracers show investigational potential but require further validation before routine clinical use. The authors note that additional prospective studies are needed to standardize imaging timing, validate response criteria in contemporary treatment settings, and define the clinical role of newer PET tracers and response-guided strategies.

Reference: 
Daverio, A. L., Coccarelli, A., Henry, T., Danu, A., Agrigoroaie, L., Trabelsi, K., Kamoun, T., Rovera, G., Morbelli, S., & Deandreis, D. (2026). PET/CT Imaging for Therapy Assessment in Multiple Myeloma Including MRD. Cancers, 18(14), 2184. https://doi.org/10.3390/cancers18142184 
 

Research

Study of NSD2 using a dTAG system reveals its molecular mechanism and oncogenic implications in t(4;14) multiple myeloma — Blood (June 2026)

What is the purpose of the study? 
To investigate how the histone methyltransferase NSD2 regulates gene transcription and the chromatin mechanisms underlying its transcriptional effects. The researchers aim to identify NSD2 transcriptional targets and determine how NSD2 influences gene expression through chromatin regulation.

Summary 
Using a degradation tag (dTAG) system to acutely remove NSD2 and combining this approach with time-resolved SLAM-seq, the investigators identified 307 transcriptional targets of NSD2. Experiments using wild-type NSD2 and a catalytically inactive mutant showed that NSD2’s transcriptional effects depend largely on its SET domain methyltransferase activity and the deposition of H3K36me2.

Mechanistic analyses demonstrated that NSD2-mediated H3K36me2 opposes the repressive histone mark H3K27me3. Approximately half of the identified NSD2 target genes were regulated through an H3K27me3-dependent mechanism. Analysis showed that NSD2 depletion increased H3K27me3 primarily at intergenic genomic regions, suggesting regulation through distal regulatory elements, including enhancers, rather than directly at promoters.

NSD2 target genes were enriched for oncogenic pathways and included 24 transcription factors implicated in neurodevelopment and acute leukemia. Eight of these transcription factors are established oncogenic drivers in acute leukemia or multiple myeloma, supporting a molecular mechanism for NSD2's role in t(4;14) MM. 
 

Key points 
• NSD2 is a histone H3 lysine 36 dimethylation (H3K36me2) methyltransferase that is aberrantly expressed in approximately 10%–15% of patients with MM carrying the t(4;14) translocation. 
• Acute NSD2 degradation combined with SLAM-seq identified 307 transcriptional targets of NSD2. 
• NSD2-mediated transcriptional regulation was found to be almost entirely dependent on its SET domain catalytic activity. 
• NSD2-driven H3K36me2 deposition antagonized the repressive chromatin mark H3K27me3. 
• Treatment with two distinct Polycomb repressive complex 2 (PRC2) inhibitors indicated that approximately half of NSD2 target genes are regulated through an H3K27me3-dependent mechanism. 
• Increased H3K27me3 after NSD2 depletion occurred mainly at intergenic regions, suggesting regulation through distal regulatory elements, including enhancers. 
• NSD2 target genes were enriched for oncogenic pathways. 
• The identified targets included 24 transcription factors implicated in neurodevelopment and acute leukemia; 8 are known oncogenic drivers in acute leukemia or multiple myeloma.

Why this study matters 
This study identified 307 transcriptional targets of NSD2 and found that its transcriptional effects were largely dependent on SET domain methyltransferase activity and H3K36me2 deposition. The findings suggest that NSD2 antagonizes H3K27me3 accumulation at distal regulatory genomic regions, creating a chromatin environment favorable for target gene transcription. NSD2 target genes were enriched for oncogenic pathways and included multiple transcription factors implicated in neurodevelopment, acute leukemia, and MM.

Reference: 
Yubao Wang, Sanxiong Liu, Hussein Ghamlouch, Dylan C. Gagler, Patrick Blaney, Behnam Nabet, Faith E. Davies, Gareth J. Morgan; Study of NSD2 using a dTAG system reveals its molecular mechanism and oncogenic implications in t(4;14) multiple myeloma. Blood 2026; 147 (24): 2916–2929. doi: https://doi.org/10.1182/blood.2025031663 

Comparative Efficacy of Belantamab Mafodotin in Combination With Bortezomib and Dexamethasone Versus Standards of Care in Patients With Third-Line or Later Relapsed/Refractory Multiple Myeloma — American Journal of Hematology (June 2026) 
 

What is the purpose of the study? 
To conduct population-adjusted indirect treatment comparisons (ITCs) to evaluate the relative efficacy of belantamab mafodotin plus bortezomib and dexamethasone (BVd) versus four comparator regimens in patients with relapsed/refractory multiple myeloma (RRMM) who had received ≥2 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMD). The analysis assesses progression-free survival (PFS) and overall survival (OS) using data from DREAMM-7, KarMMa-3, ICARIA-MM, DREAMM-8, and ELOQUENT-3.

Key points

Study results  

BVd vs PVd 
• PFS: HR 0.517; 95% CI 0.275–0.972; p=0.041 (statistically significant) 
• OS: HR 0.604; 95% CI 0.331–1.103; p=0.101 (not statistically significant)

BVd vs Ide-cel (KarMMa-3 comparator) 
• PFS: HR 0.468; 95% CI 0.287–0.762; p=0.002 (statistically significant) 
• OS: HR 0.509; 95% CI 0.274–0.945; p=0.033 (statistically significant)

BVd vs IsaPd (ICARIA-MM comparator) 
• PFS: HR 0.538; 95% CI 0.346–0.836; p=0.006 (statistically significant) 
• OS: HR 0.348; 95% CI 0.195–0.623; p<0.001 (statistically significant)

BVd vs EPd (ELOQUENT-3 comparator) 
• PFS: HR 0.337; 95% CI 0.173–0.654; p=0.001 (statistically significant) 
• OS: HR 0.405; 95% CI 0.209–0.787; p=0.008 (statistically significant)

Methods  
• Population adjustment used: 
 - inverse probability of treatment weighting (PVd comparison; aligned with DREAMM-8 comparator context) 
 - unanchored matching-adjusted indirect comparison (other comparators)

• Weighted Cox proportional hazards models estimated PFS and OS. 
• PFS assessment source varied: 
 - independent review committee–assessed PFS: PVd and Ide-cel comparisons 
 - investigator-assessed PFS: IsaPd and EPd comparisons

Strengths  
• Feasibility assessment conducted across study design, eligibility criteria, baseline characteristics, and endpoint definitions before performing ITCs. 
• Use of available individual patient data for BVd-containing trials and structured adjustment methods for cross-trial comparisons. available individual patient data for BVd-containing trials and structured adjustment methods for cross-trial comparisons.

Limitations  
• Limited availability of individual patient data for comparator trials. 
• Potential residual confounding due to unanchored comparisons and incomplete covariate adjustment. 
• Small effective sample sizes after adjustment in some comparisons. 
• Heterogeneity across trials in design, follow-up duration, and endpoint definitions. 
• Potential bias from differences in post-protocol therapies, dose modifications, and subsequent lines of therapy affecting OS interpretation.

Why this study matters 
In this indirect comparison, BVd showed statistically significant improvements in PFS versus PVd, Ide-cel, IsaPd, and EPd, while OS was statistically significant versus Ide-cel, IsaPd, and EPd but not versus PVd. Results varied by comparator and endpoint, with some analyses limited by reduced effective sample sizes and differences across trial designs and assessment methods. The study notes that residual confounding and heterogeneity inherent to cross-trial comparisons limit definitive causal interpretation.

Reference: 
J. Richter, Y. Efebera, H. Yimer, et al., “Comparative Efficacy of Belantamab Mafodotin in Combination With Bortezomib and Dexamethasone Versus Standards of Care in Patients With Third-Line or Later Relapsed/Refractory Multiple Myeloma,” American Journal of Hematology (2026): 1–6, https://doi.org/10.1002/ajh.70408. 

Dosing patterns for talquetamab, including dose deescalation, in a real-world setting — Blood Immunology & Cellular Therapy (June 2026)

What is the purpose of the study? 
This retrospective study examines early real-world (RW) use of talquetamab in patients with relapsed/refractory multiple myeloma (RRMM) in the U.S. The objective is to describe patterns of step-up dosing (SUD), maintenance dosing schedules, and clinical use across two large national healthcare databases.

Summary 
Researchers analyzed data from two U.S. national databases that included patients treated with talquetamab between August 2023 and March 2025 (hospital database, n = 273) and through January 2025 (outpatient database, n = 257). The median number of prior lines of therapy was 5 (range, 4–7), 58.4% of patients had previously received BCMA-directed therapy, and SUD was performed primarily during inpatient hospitalization (79.5%). Cytokine release syndrome (CRS) occurred in 41.8% of patients and immune effector cell-associated neurotoxicity syndrome (ICANS) in 13.6%; talquetamab was mainly used as monotherapy, although combinations were reported in 9.7% of patients and planned bridging before BCMA CAR T-cell therapy in 14.4%.

Among patients with at least 6 months of follow-up (n = 95), the most common maintenance dosing schedule was every 2 weeks (55.8%), while 32.6% had transitioned to every 4 weeks or longer dosing intervals. The analysis also documented occasional dose re-escalation in a small number of patients, while noting that reasons for dosing changes and their effects on outcomes could not be determined from the available data. 

Key points 
• The study retrospectively analyzed two large US national healthcare databases to evaluate real-world talquetamab use in RRMM. 
• Hospital database: 273 patients (August 2023–March 2025); outpatient database: 257 patients (through January 2025). 
• Median prior lines of therapy: 5 (range, 4–7). 
• 58.4% of patients had previously received BCMA-directed therapies. 
• Step-up dosing (SUD) was primarily completed during a single inpatient hospitalization (79.5%). 
• CRS occurred in 41.8% of patients and ICANS in 13.6%. 
• Talquetamab was administered mainly as monotherapy; 9.7% received talquetamab-based combinations. 
• 14.4% of patients received talquetamab as planned bridging therapy before BCMA CAR T-cell therapy. 
• Among patients with ≥6 months of follow-up (n = 95): 
 - 55.8% were receiving dosing every 2 weeks. 
 - 32.6% transitioned to dosing every 4 weeks or longer. 
• A small number of patients underwent dose re-escalation during follow-up. 

Strengths  
• Combined two complementary nationwide US databases to provide information on both initial and subsequent dosing patterns. 
• Included patients treated in both academic and nonacademic settings, improving representation of real-world clinical practice.

Limitations  
• Retrospective, observational study design. 
• Possible missing or incomplete inpatient data due to generic billing codes. 
• Some variables that could influence dosing patterns (e.g., institution size, prior experience with talquetamab) were unavailable. 
• Overlap of individual patients between databases could not be confirmed because data was deidentified. 
• The extended follow-up database lacked information on talquetamab-related toxicities (e.g., dysgeusia) and the reasons or timing of dose de-escalation. 
• The study could not evaluate the impact of dose modifications on clinical or safety outcomes.

Why this study matters 
This retrospective analysis describes early real-world use of talquetamab for RRMM across two large US healthcare databases. Most patients underwent inpatient step-up dosing and subsequently received every-2-week maintenance dosing, while approximately one-third of patients with at least 6 months of follow-up transitioned to every-4-week or less frequent dosing. The authors note that additional studies are needed to determine how dose modifications affect treatment efficacy and safety.

Reference: 
Rahul Banerjee, Ruibin Wang, Hsien-Yen Chang, Jinghua He, Ibrahim Saber, Kathleen Gray, Xinke Zhang, Yi-Hsuan Liu; Dosing patterns for talquetamab, including dose deescalation, in a real-world setting. Blood Immunology & Cellular Therapy 2026; 2 (2): 100045. doi: https://doi.org/10.1016/j.bict.2026.100045 

 

Cardiovascular Toxicity of Monoclonal Antibodies Approved for Multiple Myeloma: Evidence Based on FAERS Database — Therapeutic Innovation & Regulatory Science (June 2026)

What is the purpose of the study? 
This pharmacovigilance study aims to evaluate cardiovascular toxicity signals associated with monoclonal antibodies approved for multiple myeloma using data from the FAERS database (January 1, 2016, to December 31, 2024). It assesses whether specific monoclonal antibodies were disproportionately associated with cardiovascular adverse events.

Summary 
The study analyzed FAERS reports accessed via OpenVigil 2.1 for monoclonal antibodies including daratumumab, isatuximab, elotuzumab, belantamab mafodotin, teclistamab, elranatamab, and talquetamab. A total of 1,160 cardiovascular toxicity events were identified, and events were categorized using MedDRA v24.0 standardized MedDRA queries. Disproportionality was evaluated using reporting odds ratio and information component methods. Heart failure was the most frequently reported toxicity for daratumumab, elotuzumab, and isatuximab, followed by embolic and thrombotic events. Daratumumab and isatuximab were associated with increased reports of hypertension, while only daratumumab was associated with increased arrhythmia. Most affected patients were male and aged ≥65 years. No increased risk signals were observed for cardiomyopathy, pulmonary hypertension, ischemic heart disease, or torsade de pointes/QT prolongation.

Key points 
• 1,160 cardiovascular toxicity events identified from FAERS reports involving monoclonal antibodies for multiple myeloma 
• Disproportionality analysis performed using reporting odds ratio and information component 
• Heart failure most commonly reported for daratumumab, elotuzumab, and isatuximab 
• Embolic and thrombotic events also frequently observed 
• Increased hypertension signals for daratumumab and isatuximab 
• Arrhythmia signal observed only with daratumumab 
• No increased risk signals for cardiomyopathy, pulmonary hypertension, ischemic heart disease, or torsade de pointes/QT prolongation 
• Affected patients were predominantly male and aged ≥65 years

Why this study matters 
The analysis identified cardiovascular toxicity signals associated with monoclonal antibodies used in multiple myeloma, particularly involving heart failure, embolic and thrombotic events, hypertension, and arrhythmia. No increased disproportionality signals were observed for cardiomyopathy, pulmonary hypertension, ischemic heart disease, or torsade de pointes/QT prolongation. These findings are based on pharmacovigilance data from FAERS over the study period.

Reference: 
Liang, T., Li, J. & Xu, C. Cardiovascular Toxicity of Monoclonal Antibodies Approved for Multiple Myeloma: Evidence Based on FAERS Database. Ther Innov Regul Sci (2026). https://doi.org/10.1007/s43441-026-00967-3 
 

Non-ICANS neurotoxicity after BCMA-directed CAR-T therapy: Clinical spectrum, outcomes, and a framework for neurology–oncology co-management — HemaSphere (June 2026)

What is the purpose of the study? 
To characterize the clinical presentation, management, and outcomes of severe non-ICANS immune-effector cell (IEC) neurotoxicity occurring after treatment with ciltacabtagene autoleucel (cilta-cel) in patients with relapsed or refractory multiple myeloma. It also seeks to propose a structured framework for triage, diagnostic evaluation, and hematology–neurology co-management.

Summary 
This retrospective single-center analysis included 117 consecutive patients with relapsed or refractory multiple myeloma who received in-label cilta-cel between May 2023 and December 2025. Severe non-ICANS IEC neurotoxicity was identified in 10 patients (8.5%), with a median onset of 45 days after CAR-T infusion (range, 11–160 days). Observed neurotoxicity syndromes included Guillain–Barré syndrome-like presentations (IEC-GBS; n=3), movement/neurocognitive treatment-emergent events with Parkinsonism-like features (IEC-PKS; n=3), cranial nerve palsies (IEC-NP; n=5), and encephalitis (n=2), with some patients experiencing overlapping syndromes.

Neurotoxicities were frequently severe (CTCAE Grades 4–5). Three patients with IEC-GBS died despite treatment escalation, and two additional patients died from infectious complications during immunosuppressive treatment. Following cilta-cel, all 10 patients achieved a complete response, and none had progressed at last follow-up; however, median survival was 8.1 months compared with not reached among patients without neurotoxicity (P<0.001). Patients with neurotoxicity demonstrated higher and later peak CAR-T expansion compared with those without neurotoxicity.

Key points 
• Study design: Retrospective single-center analysis of 117 patients treated with in-label cilta-cel. 
• Incidence: Severe non-ICANS IEC neurotoxicity occurred in 10 of 117 patients (8.5%). 
• Median onset: 45 days after CAR-T infusion (range, 11–160 days). 
• Neurotoxicity phenotypes observed: IEC-GBS (n=3);IEC-PKS (n=3); IEC-NP (n=5);IEC-encephalitis (n=2);Syndromes frequently overlapped or evolved sequentially. 
• Severity: Neurotoxicities were often CTCAE Grade 4 or 5. 
• Mortality: 
   - Non-relapse mortality among neurotoxicity patients: 50%. 
   - Deaths directly attributed to neurotoxicity: 3. 
   - Deaths attributed to infectious complications during immunosuppression: 2. 
   - Non-relapse mortality in patients without IEC-neurotoxicity: 8.4%.

• Treatment observations: 
   - High-dose corticosteroids, intravenous immunoglobulin (IVIG), intensified immunosuppression, extracorporeal antibody/cytokine depletion, intrathecal chemotherapy, and etoposide were used in selected cases. 
   - Dopaminergic therapy was commonly ineffective in IEC-PKS. 
   - In several cases, CAR-T copy numbers decreased after escalation therapy, while neurological outcomes remained poor or unchanged.

• Disease response: 
   - Following cilta-cel, all 10 patients achieved a complete response. 
   - None had progressed at last follow-up.

• Biomarker findings: 
 - 9 of 10 neurotoxicity patients had ALCpeak >3 × 10⁹/L. 
 - Neurotoxicity patients had significantly higher and later peak CAR-T expansion than patients without neurotoxicity.

Limitations 
• Retrospective single-center design. 
• Small subgroup size of patients with neurotoxicity. 
• Non-standardized management approaches confounded by disease severity, limiting causal inference. 
• Short follow-up and censoring limited survival comparisons.

Why this study matters 
Severe non-ICANS IEC neurotoxicity following in-label cilta-cel was clinically heterogeneous, frequently delayed, and occurred in a cohort with substantial non-relapse mortality and persistent neurological morbidity despite treatment. Neurological syndromes often overlapped or evolved over time, and reductions in CAR-T copy numbers after treatment escalation did not consistently correspond with neurological improvement. The authors state that prospective registries, standardized case definitions, biospecimen collection protocols, and predefined treatment algorithms are needed to better characterize and manage these toxicities.

Reference: 
Werner, J.-M., Gödel, P., Galldiks, N., Krone, C., Schroeter, M., Holtick, U., Flümann, R., Wunderlich, G., Hallek, M., Fink, G.R., Scheid, C., Onur, O.A. and Richardson, T. (2026), Non-ICANS neurotoxicity after BCMA-directed CAR-T therapy: Clinical spectrum, outcomes, and a framework for neurology–oncology co-management. HemaSphere, 10: e70404. https://doi.org/10.1002/hem3.70404 

Dexamethasone for Management of Cytokine Release Syndrome Associated With Talquetamab in Patients With Relapsed/Refractory Multiple Myeloma — American Journal of Hematology (June 2026)

What is the purpose of the study? 
This retrospective multicenter observational study evaluates outcomes associated with dexamethasone as the initial treatment for talquetamab-induced cytokine release syndrome (CRS) compared with tocilizumab as the initial intervention in patients with relapsed/refractory multiple myeloma (RRMM).

Summary 
The study included 211 patients with RRMM treated with talquetamab across seven US academic medical centers between August 2023 and June 2025. CRS occurred in 129 patients (61%), predominantly as Grade 1 (43%) or Grade 2 (16%) events. Among patients who developed CRS, dexamethasone was the first intervention in 46 patients, and tocilizumab was the first intervention in 42 patients. The proportion of patients whose CRS resolved after a single initial dose of treatment did not differ significantly between the dexamethasone-first and tocilizumab-first groups for Grade 1 CRS (50% vs. 77%; p=0.6381) or Grade 2 CRS (42% vs. 68%; p=0.2623). Interpretation of Grade 2 CRS outcomes is limited because only 12 patients received dexamethasone as the initial intervention for Grade 2 CRS.

Median CRS duration was 1 day in both groups, and there were no significant differences in step-up dose delays, hospitalization duration, intensive care unit admissions, immune effector cell-associated neurotoxicity syndrome (ICANS) incidence, or overall response rate. CRS recurrence after a subsequent step-up dose occurred more frequently in the dexamethasone-first group (50% vs. 14%; p<0.005); recurrent events were low grade and resolved following additional dexamethasone and/or tocilizumab treatment.

Key points 
• Study population: 211 patients with RRMM treated with talquetamab 
• CRS occurred in 129 patients (61%): 
  - Grade 1: 92 patients (43%) 
  - Grade 2: 34 patients (16%) 
  - Grade ≥3: 3 patients

• Initial CRS management: 
  - Dexamethasone first: 46 patients (36%) 
  - Tocilizumab first: 42 patients (33%) 
  - Supportive care only: 37 patients (29%)

• Median initial dexamethasone dose: 10 mg (range 4–20 mg). 
• The proportion of patients whose CRS resolved after a single initial treatment dose did not differ significantly between dexamethasone-first and tocilizumab-first groups for Grade 1 CRS (50% vs. 77%; p=0.6381) or Grade 2 CRS (42% vs. 68%; p=0.2623). 
• Median CRS duration was 1 day in both groups (p=0.96). 
• Step-up dose delays were similar between groups (35% vs. 48%; p=0.28). 
• CRS recurrence after subsequent step-up doses was more frequent with dexamethasone-first treatment (50% vs. 14%; p<0.005). 
• All recurrent CRS events were low grade and resolved following additional dexamethasone and/or tocilizumab treatment. 
• ICANS incidence was similar between groups (26% vs. 24%; p=0.99). 
• Overall response rates were similar: 
  - Dexamethasone-first: 86% 
  - Tocilizumab-first: 90% 
  - p=0.74

• Overall response rate for the entire cohort was 77%, with 50% of patients achieving a very good partial response (VGPR) or better.

Limitations 
• Retrospective study design
• Initial CRS management was determined by institutional protocols and clinician discretion rather than predefined criteria. 
• No propensity score matching or multivariable analysis was performed. 
• Differences existed in step-up dosing schedules and use of prophylactic medications across institutions. 
• Variability in dexamethasone dosing made it difficult to determine an optimal dose. 
• Interpretation of Grade 2 CRS outcomes was limited by the small number of patients who received dexamethasone first.

Why this study matters 
In this multicenter retrospective study of RRMM patients receiving talquetamab, the proportion of patients whose low-grade CRS resolved after a single initial treatment dose did not differ significantly between dexamethasone-first and tocilizumab-first approaches. No significant differences were observed in CRS duration, step-up dose delays, hospitalization duration, intensive care unit admissions, ICANS incidence, or overall response rates. CRS recurrence after subsequent step-up doses occurred more frequently in the dexamethasone-first group, although recurrent events were low grade and resolved following additional dexamethasone and/or tocilizumab treatment.

Reference: 
J. McElwee, G. Elsey, R. Gonzalez, et al., “Dexamethasone for Management of Cytokine Release Syndrome Associated With Talquetamab in Patients With Relapsed/Refractory Multiple Myeloma,” American Journal of Hematology (2026): 1–6, https://doi.org/10.1002/ajh.70414. 

Characteristics, treatment regimens, and outcomes of patients with true extramedullary multiple myeloma: a real-world monocentric analysis — Annals of Hematology (June 2026)

What is the purpose of the study? 
To evaluate the clinical characteristics, survival outcomes, and treatment patterns of patients with radiologically confirmed extramedullary disease (EMD) in multiple myeloma (MM). It also explores associations between anatomical sites of EMD, cytogenetic features, treatment approaches, and survival outcomes in a real-world cohort.

Summary 
This retrospective single-center study included 86 patients with radiologically confirmed true EMD (soft-tissue involvement without bone contiguity), comprising 19 patients with de novo EMD (22%) and 67 with secondary EMD at MM relapse (78%). Median overall survival (mOS) from MM diagnosis was 55 months; mOS from EMD diagnosis was 28 months for de novo EMD and 21 months for secondary EMD. High-risk cytogenetic abnormalities were present in 50% of patients with de novo EMD and 43% with secondary EMD.

More than 50 different treatment regimens were used, reflecting substantial treatment heterogeneity. Exploratory analyses suggested that central nervous system (CNS), pulmonary, and retroperitoneal involvement were associated with poorer survival, while lymph node involvement was associated with longer survival (p=0.011). Novel therapies, including CAR T-cell therapy and bispecific antibodies, were mainly used in later treatment lines, with responses in secondary EMD often being transient.

Key points 
• Study design: Retrospective, single-center analysis of 86 patients with radiologically confirmed true EMD in MM. 
• Population: 
 - De novo EMD: 19 patients (22%) 
 - Secondary EMD: 67 patients (78%)

• Survival outcomes: 
 - Median overall survival from MM diagnosis: 55 months 
 - Median overall survival from EMD diagnosis: De novo EMD (28 months); Secondary EMD (21 months)

• Cytogenetic findings: 
 - High-risk cytogenetic features present in 50% of patients with de novo EMD; 43% of patients with secondary EMD 
 - del(17p) was the most frequent cytogenetic abnormality

• Anatomical site findings (exploratory): 
 - CNS, pulmonary, and retroperitoneal involvement showed a trend toward shorter survival. 
 - Lymph node involvement was associated with longer survival (p=0.011). 
 - A proposed three-tier anatomical risk grouping showed a stepwise survival gradient but did not reach statistical significance (p=0.054).

• Treatment findings: 
 - More than 50 distinct treatment regimens were identified. 
 - CAR T-cell therapy and bispecific antibodies were primarily used in later treatment lines. 
 - Responses to these therapies in secondary EMD were frequently transient.

• Concurrent plasma cell leukemia (PCL): 
 - Present in 14% of patients 
 - CNS involvement was more common among patients with concurrent PCL than among those without PCL (42% vs. 12%; p=0.023)

Strengths 
• Well-characterized cohort of patients with radiologically confirmed true EMD. 
• Real-world assessment of treatment patterns and outcomes in a rare, high-risk MM subgroup.

Limitations 
• Retrospective, single-center design 
• Relatively small and heterogeneous patient cohort 
• No internal control group of MM patients without EMD 
• Potential selection bias from treatment at a tertiary referral center 
• Possible misclassification due to non-standardized imaging and incomplete availability of advanced imaging 
• Imaging-based response assessment was available for only 46% of treatment lines. 
• Treatment comparisons were limited by substantial selection bias and heterogeneous treatment histories 
• Anatomical site analyses and risk grouping were exploratory and required external validation 
• Multivariable analyses were limited by missing data and sample size

Why this study matters 
In this real-world cohort, EMD in multiple myeloma was associated with poor outcomes, with median overall survival from EMD diagnosis of 28 months for de novo EMD and 21 months for secondary EMD. Exploratory analyses suggested differences in survival according to anatomical site, with CNS, pulmonary, and retroperitoneal involvement associated with less favorable outcomes and lymph node involvement associated with longer survival. Treatment approaches were highly heterogeneous, and the study highlights the need for prospective registries, standardized definitions, and further research to better characterize and manage EMD.

Reference: 
Harzer, M., Gross-Fengels, N., Melzer, F. et al. Characteristics, treatment regimens, and outcomes of patients with true extramedullary multiple myeloma: a real-world monocentric analysis. Ann Hematol 105, 300 (2026). https://doi.org/10.1007/s00277-026-07118-6 

Prolonged Cytopenia After Idecabtagene Vicleucel for Multiple Myeloma is Associated with Poor Overall Survival — Transplantation and Cellular Therapy (June 2026)

What is the purpose of the study? 
To evaluate the incidence, duration, and outcomes of cytopenias occurring at Day 30 and Day 100 after treatment with idecabtagene vicleucel (ide-cel) in patients with relapsed or refractory multiple myeloma (RRMM). It also examines factors associated with these cytopenias, including the CAR-HEMATOTOX score.

Summary 
Using observational data from the Center for International Blood and Marrow Transplant Research, investigators identified 821 patients treated with ide-cel between 2021 and 2023. Cytopenias were defined as an absolute neutrophil count <500 cells/mm³ and/or a platelet count <20 × 10⁹/L at Day 30 or Day 100 after CAR-T infusion. The cumulative incidence of cytopenias was 25% at Day 30 and 2% at Day 100. Patients with Day 30 cytopenias had 12-month progression-free survival of 39% versus 45% (P=.01) and overall survival of 57% versus 76% (P<.01) compared with those without Day 30 cytopenias. Patients with Day 100 cytopenias had 12-month overall survival of 55% versus 82% (P<.01), while progression-free survival was 42% versus 53% (P=.12). A CAR-HEMATOTOX score ≥2 was associated with Day 30 cytopenias (hazard ratio 5.26, P<.001).

Key points 
• Population: 821 patients with relapsed or refractory multiple myeloma treated with ide-cel between 2021 and 2023. 
• Cytopenia definition: 
 - Absolute neutrophil count <500 cells/mm³ and/or 
 - Platelet count <20 × 10⁹/L.

• Cumulative incidence of cytopenias: 
 - Day 30: 25% 
 - Day 100: 2%

• Patients with Day 30 cytopenias had: 
 - 12-month progression-free survival of 39% versus 45% (P=.01) 
 - 12-month overall survival of 57% versus 76% (P<.01)

• Patients with Day 100 cytopenias had: 
 - 12-month progression-free survival of 42% versus 53% (P=.12) 
 - 12-month overall survival of 55% versus 82% (P<.01)

• A CAR-HEMATOTOX score ≥2 was associated with Day 30 cytopenias: 
 - Hazard ratio: 5.26 
 - P<.001

Why this study matters 
In this observational cohort of 821 patients treated with ide-cel, the cumulative incidence of cytopenias was 25% at Day 30 and 2% at Day 100. Patients with Day 30 cytopenias had 12-month progression-free survival of 39% versus 45% and overall survival of 57% versus 76%, while patients with Day 100 cytopenias had 12-month overall survival of 55% versus 82% but no significant difference in progression-free survival (42% versus 53%, P=.12). A CAR-HEMATOTOX score ≥2 was associated with Day 30 cytopenias (hazard ratio 5.26, P<.001).

Reference: 
Gurbakhash Kaur, Jennifer Logue, Ruta Brazauskas, Temitope Oloyede, Muhammad Bilal Abid, Sairah Ahmed, Mahmoud Aljurf, Rahul Banerjee, Asad Bashey, Amer M. Beitinjaneh, Natalie S. Callander, Paul Castillo, Bhagirathbhai Dholaria, Scott R. Goldsmith, Shahrukh Hashmi, Mohamed A. Kharfan-Dabaja, Hongtao Liu, Hira Mian, Taiga Nishihori, Kai Rejeski, Ayman Saad, Michael J. Slade, Cameron J. Turtle, Dan T. Vogl, Kirsten M. Williams, Baldeep Wirk, Marcelo C. Pasquini, Amy Moskop, Othman Salim Akhtar, Doris K. Hansen, Murali Janakiram, Prolonged Cytopenia After Idecabtagene Vicleucel for Multiple Myeloma is Associated with Poor Overall Survival, Transplantation and Cellular Therapy, 2026, ISSN 2666-6367, https://doi.org/10.1016/j.jtct.2026.06.021. 

Supportive care for talquetamab-related dysgeusia in multiple myeloma: mixed-methods evidence, nutrition-focused flowchart, and digital companion concept — Supportive Care in Cancer (June 2026)

What is the purpose of the study? 
To characterize patient experiences with talquetamab (TAL)-related dysgeusia in patients with multiple myeloma (MM), identify preferred dietary adaptations and coping strategies, and use these findings to develop a proposed supportive-care workflow and a digital companion concept for future validation.

Summary 
This prospective single-center study included 25 patients with multiple myeloma receiving talquetamab who reported new-onset taste changes. Using a structured questionnaire with free-text responses, investigators assessed patient-reported dysgeusia, xerostomia symptoms, dietary experiences, and coping strategies; objective psychophysical taste testing and salivary-flow assessment were not performed. Patients reported heterogeneous taste disturbances, including reduced or unpleasant perception of sweet flavors, aversions to bitter and sour flavors, spice-related mucosal sensitivity, reduced enjoyment of meals, and xerostomia-related intolerance to dry or fibrous foods. Based on these findings, the researchers developed an exploratory supportive-care workflow and a digital companion blueprint (GUSTABOR) intended for future evaluation rather than current clinical use.

Key points 
• Study design: Prospective, single-center exploratory mixed-methods study 
• Population: 25 patients with multiple myeloma treated with talquetamab (TAL) who reported new-onset taste changes 
• Assessments: Patient-reported dysgeusia, xerostomia symptoms, dietary experiences, and coping strategies collected through a structured questionnaire with free-text responses 
• Objective measures not performed: Psychophysical taste testing and salivary-flow assessment (sialometry) were not conducted

• Reported symptoms: 
 - Reduced or unpleasant perception of sweet flavors 
 - Aversions to bitter and sour flavors 
 - Spice-related mucosal sensitivity 
 - Reduced enjoyment of meals 
 - Xerostomia-associated intolerance to dry or fibrous foods and impaired swallowing comfort

• Frequently reported coping strategies: 
 - Mild herbs and aroma cues 
 - Umami-rich additions 
 - Sauce- or soup-based texture modification 
 - Temperature and plating adjustments 
 - Saliva-supportive measures 
 - Environmental and behavioral strategies

• Supportive-care outputs developed: 
 - An exploratory workflow incorporating cycle-based symptom screening, structured xerostomia and nutritional-risk assessment, phenotype-oriented dietary suggestions, safety escalation, and follow-up. 
 - A digital companion blueprint named GUSTABOR for future individualized dietary guidance.

• Authors' position:The workflow and GUSTABOR are exploratory concepts derived from patient-reported experiences and are not validated clinical tools.

Strengths 
• Focused investigation of an under-addressed supportive-care problem in talquetamab-treated patients 
• Integration of patient narratives with interprofessional clinical interpretation. 
• Generation of a practical framework that can be tested prospectively 
• Identification of multisensory adaptations involving flavor, aroma, texture, temperature, plating, salivary support, and dining environment

Limitations 
• Single-center design and modest sample size (n=25), limiting generalizability. 
• Potential confounding factors could not be adjusted for 
• Taste change and xerostomia were assessed by patient report using a self-designed questionnaire 
• Validated psychophysical taste testing, validated taste questionnaires, and objective salivary-flow assessment were not used in the cohort 
• Qualitative analysis was based on free-text responses and was not externally calibrated against a formal qualitative coding standard. 
• The proposed workflow and GUSTABOR blueprint are not validated clinical tools and cannot establish effectiveness 
• Cultural, socioeconomic, dental, olfactory, gastrointestinal, and nutritional determinants of taste preferences and eating behavior were not systematically assessed

Why this study matters 
Talquetamab-related dysgeusia was described as a clinically meaningful and heterogeneous symptom complex that was closely linked to oral dryness symptoms, food texture tolerance, eating enjoyment, and social participation in patients with multiple myeloma. Patient-reported experiences informed the development of an exploratory supportive-care workflow and the GUSTABOR digital companion blueprint. According to the authors, these concepts are not validated clinical tools and require prospective multicenter evaluation using validated taste measures, objective salivary-flow assessment, nutritional outcomes, patient-reported symptom instruments, and implementation endpoints before routine clinical adoption.

Reference: 
Fleischer, A., Roll, M., Panther, F. et al. Supportive care for talquetamab-related dysgeusia in multiple myeloma: mixed-methods evidence, nutrition-focused flowchart, and digital companion concept. Support Care Cancer 34, 668 (2026). https://doi.org/10.1007/s00520-026-10863-z 
 

CAR T-cell expansion after idecabtagene vicleucel is a predictor of outcomes in multiple myeloma — HemaSphere (June 2026)

What is the purpose of the study? 
To identify immune-related biomarkers associated with clinical response and progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (RRMM) treated with idecabtagene vicleucel (ide-cel), a BCMA-directed CAR T-cell therapy.

Summary 
This real-world, retrospective study included 90 patients with RRMM treated with commercial ide-cel between October 2021 and December 2024. Clinical response was assessed at 6 months after infusion, and immune parameters, CAR T-cell kinetics, and soluble BCMA (sBCMA) levels were analyzed in relation to ongoing response (OR) and treatment failure (TF), as well as progression-free survival (PFS). Median follow-up was 12 months, and median PFS was 13.1 months.

Patients with ongoing response (64%) showed significantly higher peak CAR T-cell expansion (Cmax) than those with treatment failure (398 vs 46 CAR T-cells/μL; P<0.001) and longer CAR T-cell persistence (28 vs 21 days; P=0.01). A Cmax threshold of ≥100 CAR T-cells/μL was associated with ongoing response at 6 months and longer PFS (18.9 vs 3.3 months; P<0.0001). This threshold remained independently associated with longer PFS in multivariable analysis (adjusted HR 0.18, 95% CI 0.08–0.38; P<0.001).

Baseline monocyte counts, T-cell counts, T-cell subset distributions, infused CAR T-cell dose, and baseline sBCMA levels did not differ significantly between OR and TF groups. A greater reduction in sBCMA during the first week after infusion and a higher effector-to-target ratio were associated with ongoing response. Higher CAR T-cell expansion was associated with a higher incidence of grade ≥2 cytokine release syndrome (P=0.02).

Key points 
• Population: 90 patients with relapsed/refractory multiple myeloma treated with ide-cel
• Median follow-up: 12 months
• Median PFS: 13.1 months
• Response at 6 months: 
 - Ongoing response (OR): 58 patients (64%). 
 - Treatment failure (TF): 32 patients (36%).

• Baseline findings: 
 - No significant differences in monocyte counts, T-cell counts, regulatory T cells, or naïve/memory/effector CD4 and CD8 T-cell subsets between OR and TF groups. 
 - No significant differences in infused CAR T-cell dose or CAR T-cell composition.

• CAR T-cell kinetics: 
 - Peak expansion occurred at a median of 9 days in both groups. 
 - Higher Cmax in OR vs TF: 398 vs 46 CAR T-cells/μL (P<0.001). 
 - Longer CAR T-cell persistence in OR vs TF: 28 vs 21 days (P=0.01).

• Threshold analysis: 
 - Cmax ≥100 CAR T-cells/μL was associated with ongoing response and longer PFS. 
 - Median PFS: 18.9 months vs 3.3 months for patients below the threshold (P<0.0001).

• sBCMA findings: 
 - Baseline sBCMA levels were similar between groups. 
 - Greater decline in sBCMA during the first week after infusion was associated with ongoing response. 
 - Cmax and Day 0:Day 7 sBCMA ratio were strongly correlated (r=0.73, P<0.001).

• Multivariable analysis: 
 - Cmax ≥100 CAR T-cells/μL was independently associated with longer PFS (adjusted HR 0.18; 95% CI 0.08–0.38; P<0.001). 
 - Intermediate/high-risk MyCARe score was independently associated with shorter PFS (adjusted HR 2.57; 95% CI 1.20–5.51; P=0.02).

• Safety: 
 - Higher CAR T-cell expansion was associated with grade ≥2 cytokine release syndrome. 
 - No significant association was observed with immune effector cell-associated neurotoxicity syndrome.

Why this study matters 
In this cohort of 90 patients with relapsed/refractory multiple myeloma treated with ide-cel, higher CAR T-cell expansion after infusion was associated with ongoing response at 6 months and longer progression-free survival. A peak CAR T-cell expansion threshold of ≥100 CAR T-cells/μL was independently associated with longer PFS, while higher MyCARe risk scores were independently associated with shorter PFS. Baseline immune cell characteristics and baseline sBCMA levels were not significantly associated with response, whereas early post-infusion CAR T-cell kinetics and changes in sBCMA levels were associated with ongoing response and PFS.

Reference: 
Ferment, B., Ouedrani, A., Talbot, A., Mouri, N., Zarnitzky, P., Stammler, R., Vaugeois, T., Diep, A., Harel, S., Royer, B., Theves, F., Forgeard, N., Allain, V., Caillat-Zucman, S. and Arnulf, B. (2026), CAR T-cell expansion after idecabtagene vicleucel is a predictor of outcomes in multiple myeloma. HemaSphere, 10: e70391. https://doi.org/10.1002/hem3.70391 

High-risk genomic features predict extramedullary progression in multiple myeloma with paraskeletal plasmacytomas — HemaSphere (June 2026)

What is the purpose of the study? 
To determine whether genomic features in newly diagnosed multiple myeloma (NDMM), particularly in patients with paraskeletal (PS) plasmacytomas, can identify those at increased risk of developing secondary extramedullary disease (EMD).

Summary 
This retrospective analysis included 888 NDMM patients (2015–2025) categorized as having no extraosseous disease (n=646), PS plasmacytomas (n=226), or primary EMD (n=16), with genomic profiling performed on bone marrow plasma cells and plasmacytoma tissue. Among patients without baseline EMD (n=872), secondary EMD developed more frequently in those with PS lesions compared with those without (8.0% [18/226] vs. 3.7% [24/646]; OR 2.24; P=0.017) and occurred earlier (median 22.3 vs. 38.0 months; P=0.017). Genomic analysis identified chromosome 1 abnormalities—particularly del(1p32), gain(1q21), and combined del(1p32)+gain(1q21)—as well as biallelic TP53 inactivation and biallelic MAPK pathway mutations as being associated with increased risk of subsequent EMD development, with additional spatial heterogeneity observed between bone marrow and plasmacytoma tissue.

Key points 
• Population: 888 NDMM patients; 872 without baseline EMD analyzed for progression risk. 
• Clinical finding: Secondary EMD incidence higher in PS group (8.0% vs. 3.7%; OR 2.24; P=0.017) and occurred earlier (22.3 vs. 38.0 months; P=0.017). 
• Genomic associations (BMPCs): 
 - del(1p32): OR 4.25 
 - Broad 1p deletions: OR 7.20 
 - del(1p32)+gain(1q21): OR 8.85 
 - TENT5C alterations: OR 3.39 
 - Biallelic MAPK activation: OR 13.45 
 - Biallelic TP53 inactivation: borderline association (OR 3.97)

• Tissue findings: PS and EMD lesions showed spatial genomic heterogeneity, with more complex and high-risk alterations in relapsed/refractory disease.

• Limitations: Retrospective design and relatively small number of tissue samples.

Why this study matters 
PS plasmacytomas were associated with an increased risk and earlier onset of secondary EMD compared with patients without PS involvement. Chromosome 1 abnormalities and selected biallelic genomic events were linked to higher risk of extramedullary progression across disease compartments. The study also identified spatial genomic heterogeneity between bone marrow and plasmacytoma tissue, suggesting variability in detectable high-risk alterations depending on sampling site.

Reference: 
Stork, M., Ondrouskova, E., Mayerova, J., Mareckova, A., Porc, J.P., Reigl, T., Mensikova, K., Sendlerova, N., Boichuk, I., Cieslar, J., Bilcikova, M., Adam, Z., Krejci, M., Sandecka, V., Knechtova, Z., Jelinkova, Z., Krticka, M., Nekuda, V., Rohan, T., Hrabcakova, V., Janska Vojtkova, L., Borsky, M., Radova, L., Jarosova, M., Pour, L. and Kotaskova, J. (2026), High-risk genomic features predict extramedullary progression in multiple myeloma with paraskeletal plasmacytomas. HemaSphere, 10: e70395. https://doi.org/10.1002/hem3.70395 

Minimally invasive characterization of peripheral blood measurable residual disease in multiple myeloma using high-sensitivity detection of ctDNA by next-generation sequencing — HemaSphere (June 2026)

What is the purpose of the study? 
To investigate a minimally invasive method for detecting peripheral residual disease (PRD) in patients with multiple myeloma (MM) using circulating tumor DNA (ctDNA) analysis from cell-free DNA (cfDNA) in blood. The aim is to investigate a sensitive blood-based method for detecting PRD in patients with MM and to evaluate its association with disease monitoring and relapse risk.

Summary 
The study included 84 patients with multiple myeloma enrolled in PETHEMA/GEM clinical trials, with 292 longitudinal samples analyzed. BM-MRD was assessed using EuroFlow-based next-generation flow cytometry (NGF), while PRD was evaluated in cfDNA using AltumTrackSeq®, an NGS method based on patient-specific somatic mutations identified at diagnosis.

Automated cfDNA isolation methods yielded cfDNA levels comparable to manual methods and enabled workflow standardization. Compared with BM-MRD assessed by NGF, the ctDNA-NGS approach showed a higher positive predictive value (88.9% vs. 34.5%) and specificity (98.4% vs. 70.3%) for predicting relapse during follow-up. Detectable ctDNA was associated with an increased risk of progression and/or death (hazard ratio [HR] 11.5; 95% confidence interval [CI] 2.66–49.4), and this association remained significant in multivariate analysis.

Key points 
• Population: 84 patients with multiple myeloma enrolled in PETHEMA/GEM clinical trials. 
• Samples analyzed: 292 longitudinal plasma samples. 
• Methods: 
 - BM-MRD assessed by EuroFlow-based next-generation flow cytometry (NGF). 
 - PRD assessed using AltumTrackSeq® ctDNA-NGS with patient-specific mutation panels.

• cfDNA findings: 
 - Median cfDNA concentration: 393.2 ng. 
 - Range: 17.3–6300 ng. 
 - Automated isolation methods yielded cfDNA levels comparable to manual methods and enabled standardization. 
 - Dual size-selection purification successfully removed genomic DNA contamination in 98% of samples with detectable contamination.

• Methodological features: 
 - Large plasma volumes and cfDNA inputs greater than 30 ng were used for ctDNA analysis. 
 - Patient-specific mutation panels and optimized tandem variant strategies were incorporated into the assay design. 
 - The assay achieved a theoretical sensitivity of 10-5 in a high proportion of samples, and approximately 20% of samples reached 10-6.

• Clinical performance: 
 - Positive predictive value for relapse prediction: ctDNA-NGS: 88.9%; BM-MRD by NGF: 34.5% 
 - Specificity for relapse prediction: ctDNA-NGS: 98.4%; BM-MRD by NGF: 70.3%

• Prognostic association: 
 - Detectable ctDNA was associated with increased risk of progression and/or death: HR 11.5 (95% CI 2.66–49.4). 
 - Positive PRD detected by NGS was associated with less favorable progression-free survival.

Limitations  
• According to the authors' analysis, the sensitivity for detecting plasma-positive cases was not superior to bone marrow assessment. 
• Retrospective study design
• Limited sample size
• Lack of direct comparison with NGS-based bone marrow MRD assessment using immunoglobulin genes
• Relatively short median follow-up of 43 months, which may have missed late events
• Limited number of BM-MRD-positive cases assessed by NGF in the cohort

Why this study matters 
In this study of 84 patients with multiple myeloma, ctDNA-NGS using AltumTrackSeq® showed higher positive predictive value (88.9% vs. 34.5%) and specificity (98.4% vs. 70.3%) for predicting relapse during follow-up than BM-MRD assessment by NGF. Detectable ctDNA was associated with an increased risk of progression and/or death (HR 11.5, 95% CI 2.66–49.4). The authors concluded that this assay provides a method for detecting imminent relapse risk in the peripheral blood of patients with multiple myeloma, while noting that further validation studies are needed.

Reference: 
Buenache, N., Lasa, M., Arroyo, A., González, C., Haertle, L., Ruiz-Heredia, Y., Ayala, R., Alonso, R., Martín-Muñoz, A., Rosa-Rosa, J.M., González, V., Calasanz, M.J., Rodríguez-Otero, P., Rosiñol, L., De Arriba, F., Ocio, E.M., Oriol, A., González, Y., Sureda, A., Lakhwani, S., Clavero, M.E., Ibáñez, A., Gómez, C., Orfao, A., Mateos, M.-V., Lahuerta, J.J., Cedena, M.T., Bladé, J., San Miguel, J., Puig, N., Paiva, B. and Martínez-López, J. (2026), Minimally invasive characterization of peripheral blood measurable residual disease in multiple myeloma using high-sensitivity detection of ctDNA by next-generation sequencing. HemaSphere, 10: e70405. https://doi.org/10.1002/hem3.70405 

Combined Immune Checkpoint Inhibitors and Radiation Therapy in Patients with Multiple Myeloma and Extramedullary Medullary Disease: A Real-World Retrospective Analysis — Cancers (June 2026)

What is the purpose of the study? 
This retrospective study evaluates the efficacy and safety of concurrent immune checkpoint inhibitors (nivolumab or pembrolizumab) with radiation therapy (RT) in patients with extramedullary disease (EMD) in multiple myeloma. The population consists of heavily pretreated, high-risk patients treated at Hackensack University Medical Center and John Theurer Cancer Center.

Summary  
A total of 21 patients with EMD and a median of 6 prior lines of therapy (range 2–13), including 47.6% triple-class refractory and 19.0% penta-refractory disease, received nivolumab or pembrolizumab concurrently with RT (commonly 3000 cGy). The overall response rate (ORR) was 47.6%, and the clinical benefit rate was 57.1%, with median progression-free survival (PFS) of 4 months and median overall survival (OS) of 12 months. Two patients achieved complete responses with nivolumab plus RT and remained disease-free at last follow-up, while most responses were not durable.

Key points 
• Study design: Retrospective analysis (2016–2025) 
• Population: 21 patients with extramedullary multiple myeloma (EMD), heavily pretreated 
• Therapy evaluated: Concurrent immune checkpoint inhibitors (nivolumab or pembrolizumab) + radiation therapy 
• Prior treatment burden: Median 6 prior lines; 47.6% triple-class refractory; 19.0% penta-refractory 
• Radiation regimen: Most commonly 3000 cGy (10–15 fractions) 
• Efficacy outcomes: 
 - ORR: 47.6% 
 - Clinical benefit rate: 57.1% 
 - Median PFS: 4 months 
 - Median OS: 12 months

• Deep responses: 2 complete responses with nivolumab + RT; both remained disease-free at last follow-up 
• Safety: Generally well tolerated; manageable immune-related adverse events; no treatment-related deaths

Strengths 
• Real-world cohort of rare, high-risk, heavily pretreated EMD patients 
• Evaluation of biologically plausible combination (ICI + RT)

Limitations 
• Retrospective design 
• Small sample size 
• No comparator arm 
• Heterogeneous concurrent therapies 
• Non-standardized response assessment and imaging 
• Lack of central radiographic review

Why this study matters 
Concurrent immune checkpoint inhibition with radiation therapy in heavily pretreated extramedullary multiple myeloma was associated with an ORR of 47.6% and a median PFS of 4 months, with generally manageable toxicity and no treatment-related deaths. Most responses were not durable, although two complete responses were observed and remained ongoing at last follow-up. These findings support further prospective evaluation of this combination to better define efficacy, durability, and patient selection in EMD.

Reference: 
Zhang, L., Bangolo, A., Amoozgar, B., Gill, S., Zhao, J., Bhullar, G. S., Singareddy, S., Singh, S., Ortiz, H., Muench, A., Peake, S., Azam, K., Noe, W., Ghanem, J., De Graaf, E., Sookoo, A., Reddy, M. N. R. K., Boban, S., Sakil, S., ... Biran, N. (2026). Combined Immune Checkpoint Inhibitors and Radiation Therapy in Patients with Multiple Myeloma and Extramedullary Medullary Disease: A Real-World Retrospective Analysis. Cancers, 18(12), 1996. https://doi.org/10.3390/cancers18121996 

Real-world evidence on infection risk in multiple myeloma treated with BiTEs and CAR-T cells: a meta-analysis — Experimental Hematology and Oncology (June 2026)

What is the purpose of the review? 
To evaluate the frequency of severe (grade 3–4) infections in adults with relapsed or refractory multiple myeloma (RRMM) receiving approved T-cell-redirecting therapies, including bispecific T-cell engagers (BiTEs) and chimeric antigen receptor T-cell (CAR-T) therapies, in real-world clinical practice.

Summary 
This systematic review and meta-analysis included 16 retrospective real-world studies involving 2,097 patients with RRMM, of whom 1,602 received BiTEs and 495 received CAR-T therapies. Overall, 24.2% of patients developed grade 3–4 infections, corresponding to a pooled event rate of 0.24 (95% CI, 0.21–0.28). The pooled severe infection rate was 0.26 (95% CI, 0.23–0.30) among patients treated with BiTEs and 0.19 (95% CI, 0.12–0.27) among patients receiving CAR-T therapies. Within the BiTE cohort, pooled severe infection rates were 0.27 (95% CI, 0.23–0.31) for BCMA-directed BiTEs and 0.25 (95% CI, 0.20–0.30) for GPRC5D-directed BiTEs.

Key points 
• Study design: Systematic review and meta-analysis of 16 retrospective real-world studies conducted according to PRISMA guidelines. 
• Population: 2,097 adults with RRMM 
 - 1,602 treated with BiTEs 
 - 495 treated with CAR-T therapies

• Patient characteristics: 
 - Mean age: 66.3 years 
 - 44.2% female 
 - Mean prior lines of therapy: 6.1 
 - Weighted median follow-up: 8.3 months

• Primary outcome: Severe (grade 3–4) infections. 
• Overall severe infection rate: 
 - 24.2% of patients 
 - Pooled event rate: 0.24 (95% CI, 0.21–0.28)

• Pooled severe infection rates by treatment type: 
 - BiTEs: 0.26 (95% CI, 0.23–0.30) 
 - CAR-T therapies: 0.19 (95% CI, 0.12–0.27)

• Pooled severe infection rates within the BiTE cohort: 
 - BCMA-directed BiTEs: 0.27 (95% CI, 0.23–0.31) 
 - GPRC5D-directed BiTEs: 0.25 (95% CI, 0.20–0.30)

• Heterogeneity analysis: 
 - Moderate-to-high heterogeneity was observed. 
 - Meta-regression in the BiTE cohort identified an inverse association between severe infection rates and prior BCMA-directed therapy exposure, which the authors noted may reflect selection bias.

• Interpretation of subgroup findings: The authors stated that observed differences in infection rates across treatment platforms and targets should be interpreted with caution because they were derived from indirect comparisons in non-randomized, heterogeneous cohorts. 

Limitations 
• Limitations inherent to retrospective real-world analyses. 
• Moderate heterogeneity across cohorts. 
• Potential patient overlap among multicenter consortium-based studies. 
• Indirect comparisons between therapeutic platforms. 
• Supportive care variables, including immunoglobulin replacement therapy (IgRT), antimicrobial prophylaxis, and vaccination strategies, were inconsistently reported and could not be formally evaluated.

Why this review matters 
In this meta-analysis of 16 retrospective real-world studies involving 2,097 patients with RRMM, severe (grade 3–4) infections occurred in 24.2% of patients receiving T-cell-redirecting therapies. The pooled severe infection rate was 0.26 (95% CI, 0.23–0.30) among BiTE-treated patients and 0.19 (95% CI, 0.12–0.27) among CAR-T-treated patients; within the BiTE cohort, pooled rates were 0.27 for BCMA-directed therapies and 0.25 for GPRC5D-directed therapies. The authors emphasized that differences across treatment platforms and targets should be interpreted with caution because these findings were based on indirect comparisons from heterogeneous, non-randomized retrospective cohorts.

Reference: 
Spataro, F., Desantis, V., Dicuonzo, G. et al. Real-world evidence on infection risk in multiple myeloma treated with BiTEs and CAR-T cells: a meta-analysis. Exp Hematol Oncol 15, 56 (2026). https://doi.org/10.1186/s40164-026-00798-w

A multicenter study of progression risk and outcomes in solitary bone plasmacytoma with and without marrow involvement — Blood Advances (June 2026)

What is the purpose of the study? 
To evaluate outcomes after definitive radiation therapy (RT) in patients with solitary bone plasmacytoma (SBP) and solitary bone plasmacytoma with minimal marrow involvement (SBPmm). The objective was to compare progression rates, patterns of progression, and factors associated with progression to multiple myeloma (MM) between these two groups.

Summary 
This multicenter study included 141 patients with SBP and 102 patients with SBPmm diagnosed between January 2010 and December 2024 who were treated with RT followed by observation. Approximately 92% of patients with SBPmm progressed to MM compared with 76% of patients with SBP (P = .01). Median time to progression (TTP) was 15 months (95% CI, 14–21) in SBPmm and 43 months (95% CI, 34–55) in SBP (P < .0001), and 67% of patients with SBPmm progressed within 2 years of diagnosis compared with 30% of patients with SBP.

Most progressions in both groups were to MM. Multifocal lytic bone lesions were the most common myeloma-defining event (MDE), occurring in 89% of patients with SBPmm and 81% of patients with SBP. High-risk cytogenetic abnormalities were associated with earlier progression in SBPmm: patients with del(17p) and 1q+ (gain or amplification) had 2-year progression rates of 100% and 82%, respectively. Among patients with SBP, 21% progressed with a second solitary bone lesion compared with 4% of patients with SBPmm (P < .01). In a small subgroup of patients with SBP who developed a second solitary plasmacytoma after a TTP greater than 36 months, 5 of 6 patients did not subsequently progress after RT to the second lesion.

Key points 
• Study population: 
 - 141 patients with SBP 
 - 102 patients with SBPmm

• All patients received definitive RT without upfront systemic therapy. 
• Progression to MM occurred in: 
 - Approximately 92% of patients with SBPmm 
 - 76% of patients with SBP 
 - P = .01

• Median TTP: 
 - SBPmm: 15 months (95% CI, 14–21) 
 - SBP: 43 months (95% CI, 34–55) 
 - P < .0001

• Progression within 2 years: 
 - 67% of patients with SBPmm 
 - 30% of patients with SBP

• Multifocal lytic bone lesions were the most common MDE: 
 - 89% of SBPmm progressions 
 - 81% of SBP progressions

• Progression with a second solitary bone lesion occurred in: 
 - 21% of patients with SBP 
 - 4% of patients with SBPmm 
 - P < .01

• In SBPmm: 
 - del(17p) was associated with a 100% 2-year progression rate. 
 - 1q+ was associated with an 82% 2-year progression rate.

•Anemia, renal failure, and hypercalcemia were uncommon causes of progression (≤10%).

Strengths  
• Largest multicenter study to date evaluating outcomes in SBP and SBPmm treated with RT alone 
• Included a uniformly treated cohort managed with RT alone in the era of novel agents 
• Diagnoses were confirmed using modern cross-sectional imaging techniques with characterization of minimal marrow involvement at baseline 
• The multicenter design enabled separate analysis of SBP and SBPmm as independent cohorts

Limitations  
• Retrospective study design 
• Missing data that may have reduced statistical power, particularly for risk-factor analyses 
• Differences in imaging modalities and methods used to determine clonal bone marrow involvement 
• Limited availability of cytogenetic data in some analyses 
• Although sensitivity analyses did not show significant TTP differences across imaging modalities, methodological variation remained a study limitation

Why this study matters 
This study found clear differences in progression rates, progression patterns, and risk factors between SBP and SBPmm after RT. Most patients with SBPmm progressed to MM within 2 years of diagnosis, and progression most commonly occurred through development of multifocal lytic bone disease rather than other SLiM-CRAB criteria. The findings suggest that SBPmm is a distinct high-risk clinical entity compared with SBP, with particularly high rates of early progression among patients with del(17p) or 1q+ abnormalities.

Reference: 
Kenneth J. C. Lim, Maximilian Steinhardt, Matthew J. Rees, Patricia Greipp, Katalin Kelemen, Angela Dispenzieri, Dragan Jevremovic, Linda Baughn, Francis K. Buadi, David Dingli, Suzanne R. Hayman, Prashant Kapoor, Eli Muchtar, Nelson Leung, Amie Fonder, Miriam Hobbs, Yi Lisa Hwa, Rahma Warsame, Taxiarchis V. Kourelis, Joselle Cook, Moritz Binder, Nadine Abdallah, Saurabh Zanwar, Yi Lin, Ronald S. Go, Mustaqeem A. Siddiqui, Ricardo D. Parrondo, Sikander Ailawadi, Vivek Roy, Rachel Cooke, Karen Dun, Adrian Zordan, Slavisa Ninkovic, Sharene H. Best, Gabriela A. Alatorre, J. E. Wiedmeier-Nutor, K. Martin Kortum, Hermann Einsele, Saurabh Chhabra, P. Leif Bergsagel, Robert A. Kyle, Morie A. Gertz, Shaji K. Kumar, S. Vincent Rajkumar, Rafael Fonseca, Wilson I. Gonsalves, Udit Yadav; A multicenter study of progression risk and outcomes in solitary bone plasmacytoma with and without marrow involvement. Blood Adv 2026; 10 (12): 4286–4295. doi: https://doi.org/10.1182/bloodadvances.2025019136 

Identification of Bone Marrow and Peripheral Blood Plasma Extracellular Vesicle Protein Biomarker Signatures for Multiple Myeloma Diagnosis and Staging — International Journal of Nanomedicine (June 2026)

What is the purpose of the study? 
To investigate whether the proteomic cargo of plasma-derived extracellular vesicles (EVs) from peripheral blood and bone marrow could serve as a minimally invasive liquid biopsy for the diagnosis and staging of multiple myeloma (MM). The study also evaluates machine learning-derived EV protein biomarker signatures for distinguishing monoclonal gammopathy of undetermined significance (MGUS), symptomatic MM, and relapsed disease.

Summary  
Plasma-derived EVs from peripheral blood and bone marrow were isolated from 33 patients with MM and 12 healthy donors, and their protein content was analyzed by mass spectrometry. Supervised machine learning identified a six-protein peripheral blood EV biomarker signature (APOC1, LGALS1, S100A7, CD226, ALAD, and KRT78) that generated four logistic regression diagnostic models with predictive accuracies greater than 85% and areas under the receiver operating characteristic curve (AUCs) greater than 0.91. The protein signature was characterized by increased APOC1 and LGALS1 abundance and decreased S100A7, CD226, ALAD, and KRT78 abundance, with proteins associated with immune modulation, immune surveillance, and proteostasis.

Key points 
• Study population: 33 patients with multiple myeloma and 12 healthy donors. 
• Samples analyzed: Extracellular vesicles (EVs) isolated from peripheral blood and bone marrow plasma. 
• Analytical methods: 
 - Mass spectrometry-based EV proteomic profiling 
 - Supervised machine learning for biomarker identification 
 - Logistic regression diagnostic models 
 - Performance assessed using AUC, accuracy, sensitivity, specificity, predictive values, and F1 score

• Main findings: 
 - A six-protein peripheral blood EV biomarker signature was identified: Increased: APOC1, LGALS1; Decreased: S100A7, CD226, ALAD, KRT78 
 - Four logistic regression models achieved: Predictive accuracy >85%; AUC >0.91 
 - Bone marrow-derived biomarkers showed reduced diagnostic performance when applied to peripheral blood samples (sensitivity <60%), indicating compartment-specific biomarker profiles. 
 - Peripheral blood EV models distinguished MGUS, newly diagnosed MM, and relapsed MM with: AUC ≥0.9;Sensitivity ≥0.81; Specificity ≥0.89; Positive predictive value ≥0.89; Negative predictive value ≥0.88

• Biological observations: 
 - The identified biomarkers were associated with immune modulation, impaired immune surveillance, proteostasis, homeostasis, and platelet activation pathways. 
 - Four of the six peripheral blood biomarkers (APOC1, S100A7, LGALS1, CD226) were linked to immune-related processes.

Strengths  
• EV isolation and characterization met MISEV2023 guidelines. 
• The study profiled EV proteomes across distinct MM disease stages. 
• Machine learning was used to identify reproducible combinations of biomarkers rather than relying solely on statistical significance. 
• Both peripheral blood and bone marrow EV proteomes were evaluated, allowing comparison between compartments.

Limitations  
• Incomplete age and sex matching between patient and control groups. 
• Modest cohort size relative to the dimensionality of the proteomic dataset. 
• The study was designed as a discovery-phase analysis, and the identified biomarker signatures require validation in larger, well-characterized cohorts.

Why this study matters 
This study identified a six-protein peripheral blood EV biomarker signature that demonstrated diagnostic performance with predictive accuracies greater than 85% and AUCs greater than 0.91 for distinguishing stages of multiple myeloma. The findings support the potential of EV proteomic profiling, combined with machine learning, as a minimally invasive approach for MM diagnosis and disease monitoring. The authors state that larger validation studies are needed to confirm the robustness and clinical applicability of these biomarker signatures.

Reference: 
Cheryl A, Sheridan R, Brennan K, Bazou D, Matallanas D, O’Gorman P, Iglesias-Martinez LF, Mc Gee MM. Identification of Bone Marrow and Peripheral Blood Plasma Extracellular Vesicle Protein Biomarker Signatures for Multiple Myeloma Diagnosis and Staging. Int J Nanomedicine. 2026 Jun 23;21:576858. doi: 10.2147/IJN.S576858. 

Clinical Course, Risk Factors, and Therapeutic Response in Multiple Myeloma with Central Nervous System Involvement — Blood Advances (June 2026)

What is the purpose of the study? 
This retrospective study evaluates the clinical characteristics, risk factors, treatments, and outcomes of patients with central nervous system multiple myeloma (CNS-MM) among individuals with pathology-confirmed extramedullary disease (EMD). It also assesses outcomes associated with different treatment approaches, including CAR-T cell therapy, bispecific antibodies, and intrathecal chemotherapy.

Summary 
Researchers retrospectively analyzed 304 patients with pathology-confirmed EMD treated between January 2000 and December 2023, of whom 20 (6.5%) had CNS-MM, defined by parenchymal or leptomeningeal involvement. CNS involvement occurred at a median of 19.2 months after multiple myeloma diagnosis, although 15% of patients had CNS involvement at diagnosis. CNS-MM was associated with high-risk cytogenetics (odds ratio [OR] 3.7) and additional visceral EMD (OR 4.6). Median overall survival after CNS-MM diagnosis was 4.2 months. Patients who received CAR-T cell therapy or bispecific antibodies had a median overall survival of 19.2 months compared with 1.2 months in patients who did not receive these immune effector therapies. Intrathecal chemotherapy demonstrated limited and transient benefit.

Key points 
• Retrospective analysis included 304 patients with pathology-confirmed extramedullary disease treated between January 2000 and December 2023. 
• 20 patients (6.5%) had central nervous system multiple myeloma (CNS-MM). 
• CNS involvement occurred at a median of 19.2 months after multiple myeloma diagnosis; 15% of patients had CNS involvement at diagnosis. 
• CNS-MM was associated with: 
 - High-risk cytogenetics (OR 3.7). 
 - Additional visceral extramedullary disease (OR 4.6).

• Median overall survival after CNS-MM diagnosis was 4.2 months. 
• Patients treated with CAR-T cell therapy or bispecific antibodies had a median overall survival of 19.2 months, compared with 1.2 months in patients who did not receive these immune effector therapies. 
• Intrathecal chemotherapy demonstrated limited and transient benefit.

Strengths  
• Included pathology-confirmed cases of extramedullary disease over a long study period (2000–2023)

Limitations  
• Retrospective study design 
• Prospective studies are needed to define optimal treatment strategies for CNS-MM

Why this study matters 
Central nervous system multiple myeloma was an uncommon but aggressive manifestation of extramedullary disease, associated with high-risk cytogenetics, additional visceral extramedullary disease, and a median overall survival of 4.2 months. In this retrospective cohort, patients who received CAR-T cell therapy or bispecific antibodies had longer median overall survival than those who did not receive these immune effector therapies, while intrathecal chemotherapy showed limited and transient benefit. Prospective studies are needed to determine optimal treatment approaches for CNS-MM.

Reference: 
Alexander Xiao, Saurabh S. Zanwar, Yi Lin, Prashant Kapoor, Nadine Abdallah, Francis Baudi, Moritz Binder, Angela Dispenzieri, David Dingli, Morie A Gertz, Wilson I Gonsalves, Suzanne R Hayman, Taxiarchis V. Kourelis, Nelson Leung, Eli Muchtar, Mustaqeem Siddiqui, Melinda SY Tan, Rahma Warsame, S Vincent Rajkumar, Shaji K Kumar; Clinical Course, Risk Factors, and Therapeutic Response in Multiple Myeloma with Central Nervous System Involvement. Blood Adv 2026; bloodadvances.2026020668. doi: https://doi.org/10.1182/bloodadvances.2026020668 
 

IRF2 is an essential transcription factor with pathogenic and prognostic impact in multiple myeloma — Blood (June 2026)

What is the purpose of the study? 
To identify essential transcription factors (TFs) that drive the development and progression of multiple myeloma (MM) and to investigate the biological and clinical role of interferon regulatory factor 2 (IRF2). Researchers evaluate whether IRF2 contributes to MM cell survival, disease progression, and patient outcomes.

Summary 
Using CRISPR-Cas9 library screening, the investigators identified 22 essential TFs in MM cells, including several interferon regulatory factor (IRF) family members. IRF2 was identified as a critical TF, and CUT&RUN analyses showed that it binds extensively to chromatin both independently and together with IRF1 and IRF4. Functional experiments demonstrated that IRF2 supports MM cell survival by suppressing necroptosis and promotes cell migration through regulation of genes involved in adhesion and GTPase signaling pathways.

The study also found evidence of IRF2-dependent transcriptional dysregulation in monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), suggesting involvement in early disease stages. Clinically, higher IRF2 expression was associated with shorter progression-free survival (PFS) and overall survival (OS) in both univariate and multivariate analyses, including after adjustment for established MM genetic risk factors.

Key points 
• MM remains an incurable hematologic malignancy, creating a need to identify new molecular targets. 
• CRISPR-Cas9 screening identified 22 essential transcription factors required for MM cell survival. 
• IRF2 emerged as a critical and previously underappreciated transcription factor in MM. 
• CUT&RUN experiments showed that IRF2 binds extensively across chromatin, both alone and in cooperation with IRF1 and IRF4. 
• IRF2 contributes to MM cell survival by suppressing necroptosis, a regulated form of cell death. 
• IRF2 knockdown increased ZBP1 expression and MLKL phosphorylation, findings associated with activation of the necroptotic pathway. 
• IRF2 regulates genes involved in GTPase signaling, adhesion, and migration, and its inhibition reduced MM cell migration. 
• Dysregulation of IRF2 target genes and associated pathways was observed in MGUS and SMM, indicating involvement before the development of active MM. 
• Higher IRF2 expression was associated with worse PFS and OS, independent of common MM genetic risk factors. 
• The authors identified IRF2 as a potential prognostic biomarker and therapeutic target in MM.

Strengths 
• Combined functional genomic screening (CRISPR-Cas9), chromatin-binding analyses (CUT&RUN), molecular studies, and clinical outcome analyses. 
• Investigated both biological mechanisms and clinical associations of IRF2 in MM.

Limitations 
• Additional in vivo studies are needed to fully define the clinical potential of IRF2. 
• Future studies are required to determine whether IRF2 expression can further improve patient stratification in MM.

Why this study matters 
This study identified IRF2 as an essential transcription factor in multiple myeloma and showed that it contributes to MM cell survival, migration, and regulation of necroptotic cell-death pathways. IRF2-related transcriptional alterations were detected in precursor conditions (MGUS and SMM), and higher IRF2 expression was associated with poorer progression-free and overall survival. The findings support further investigation of IRF2 as a prognostic biomarker and potential therapeutic target, although additional in vivo and clinical studies are needed.

Reference: 
Nahia Gómez-Echarte, Arantxa Carrasco-León, Alba Maiqués-Díaz, Naroa Barrena, Estibaliz Miranda, Leire Garate, Ane Amundarain, Patxi San Martín-Uriz, Stella Charalampopoulou, Luis Vitores Valcárcel, Beñat Ariceta, Paula Rodriguez-Marquez, Juan Roberto Rodriguez-Madoz, Kazuya Ishiguro, Francisco J. Planes, Paula Rodriguez-Otero, Constantine S. Mitsiades, José Ignacio Martín-Subero, Edurne San José-Enériz, Felipe Prosper, Xabier Agirre; IRF2 is an essential transcription factor with pathogenic and prognostic impact in multiple myeloma. Blood 2026; 147 (26): 3195–3208. doi: https://doi.org/10.1182/blood.2025029422 

Infections within 100 days of idecabtagene vicleucel and impact on survival for relapsed/refractory multiple myeloma: A CIBMTR Analysis — Transplantation and Cellular Therapy (June 2026) 
 

What is the purpose of the study? 
To characterize the burden, timing, patterns, risk factors, and clinical impact of infections in patients with relapsed/refractory multiple myeloma (RRMM) treated with idecabtagene vicleucel (ide-cel) using a large real-world registry. It also evaluates the association between infections and clinical outcomes, including overall survival.

Summary 
This real-world analysis included 807 patients with RRMM who received ide-cel after at least four prior lines of therapy between March 2021 and December 2023 using the Center for International Blood and Marrow Transplant Registry (CIBMTR) database. Within the first 100 days after ide-cel, the infection density was 0.49 for any infection, including 0.23 for bacterial infections, 0.22 for viral infections, and 0.012 for fungal infections. Bacterial infections predominated during the first 30 days after infusion, whereas viral infections were more common between days +30 and +100. After a median follow-up of 11.6 months among survivors, 364 patients relapsed and 222 died, resulting in a 1-year progression-free survival of 46.5% and an overall survival of 67.3%. Disease progression was the leading cause of death, followed by infections, and infection-related mortality was 1.1% by day +100. Independent predictors of infection were a history of infection before ide-cel, Karnofsky Performance Status (KPS) <80, grade ≥2 cytokine release syndrome, and grade ≥3 neurotoxicity. Recurrent infections (≥2 episodes) within 100 days and relapse within 100 days after ide-cel were associated with inferior overall survival.

Key points 
• Study population: 807 patients with RRMM treated with ide-cel after ≥4 prior lines of therapy. 
• Study period: March 2021 to December 2023 
• Data source: Center for International Blood and Marrow Transplant Registry (CIBMTR) 
• Infection density within 100 days post-ide-cel: 
 - Any infection: 0.49 
 - Bacterial infections: 0.23 
 - Viral infections: 0.22 
 - Fungal infections: 0.012

• Timing of infections: 
 - Bacterial infections predominated during the first 30 days after infusion 
 - Viral infections predominated between days +30 and +100

• Clinical outcomes: 
 - Median follow-up among survivors: 11.6 months 
 - 364 patients relapsed 
 - 222 patients died 
 - 1-year progression-free survival: 46.5% 
 - 1-year overall survival: 67.3% 
 - Disease progression was the leading cause of death, followed by infections 
 - Infection-related mortality by day +100: 1.1%

• Independent predictors of infection: 
 - History of infection before ide-cel 
 - Karnofsky Performance Status (KPS) <80 
 - Grade ≥2 cytokine release syndrome 
 - Grade ≥3 neurotoxicity

• Factors associated with inferior overall survival: 
 - Recurrent infections (≥2 episodes) within 100 days after ide-cel 
 - Relapse within 100 days after ide-cel

Why this study matters 
In this real-world cohort of patients with RRMM treated with ide-cel, infections were common during the first 100 days after treatment, with bacterial infections predominating during the first 30 days and viral infections predominating between days +30 and +100. Baseline infection history, poorer performance status, cytokine release syndrome, and neurotoxicity were independent predictors of infection, while recurrent infections and early relapse were associated with inferior overall survival. The findings underscore the importance of risk stratification, surveillance, and stringent infection prevention strategies to optimize outcomes after ide-cel, and further studies are needed to define optimal strategies for infection surveillance, prophylaxis, and management in high-risk patients.

Reference: 
Kitsada Wudhikarn, Lohith Gowda, Qiran Ye, Temitope Oloyede, Michael Martens, Rahul Banerjee, Srinivas S. Devarakonda, Hongtao Liu, Megan M. Herr, Jo-Anne H. Young, Tania Jain, Ajoy Dias, Taiga Nishihori, Abu-Sayeef Mirza, Siddhartha Ganguly, Amer M. Beitinjaneh, Mahmoud Aljurf, Baldeep Wirk, Nosha Farhadfar, Yvonne A. Efebera, Miguel-Angel Perales, Christen L. Ebens, Hemant S Murthy, Joshua A. Hill, Christopher E. Dandoy, Sanghee Hong, Zeinab El Boghdadly, Othman Salim Akhtar, Jeffery J. Auletta, Anna R. Huppler, Muhammad Bilal Abid, Infections within 100 days of idecabtagene vicleucel and impact on survival for relapsed/refractory multiple myeloma: A CIBMTR Analysis, Transplantation and Cellular Therapy, 2026, ISSN 2666-6367, https://doi.org/10.1016/j.jtct.2026.06.029.

Healthcare resource utilization and costs in patients with multiple myeloma administered ciltacabtagene autoleucel in outpatient versus inpatient settings after one to three prior lines of therapy — Journal of Comparative Effectiveness Research (June 2026)

What is the purpose of the study? 
To evaluate whether outpatient (OP) versus inpatient (IP) administration of ciltacabtagene autoleucel (cilta-cel) was associated with differences in healthcare resource utilization (HCRU) and imputed healthcare costs among patients with relapsed or refractory multiple myeloma (RRMM) who had received 1–3 prior lines of therapy. The analysis uses real-world electronic medical record data to compare outcomes during the first 30 and 90 days after infusion.

Summary  
This retrospective observational study analyzed electronic medical records from the Loopback Analytics database (2017–2025) and included 99 patients (37 OP; 62 IP) with RRMM treated with cilta-cel after 1–3 prior lines of therapy. During the first 30 days after infusion, 40.5% of patients treated in the OP setting did not require inpatient admission, and the OP group had significantly fewer inpatient days (adjusted incidence rate ratio: 0.31; p<0.001) and significantly lower inpatient-related imputed costs (adjusted mean difference: −$39,786; p<0.001) than the IP group. Similar findings were observed over 90 days, with estimated per-patient cost savings of approximately $40,000 at 30 days and $53,000 at 90 days for OP administration.

Key points 
• Study design: Retrospective observational study using the Loopback Analytics electronic medical records database (February 2017–June 2025) 
• Population: 99 patients with relapsed or refractory multiple myeloma treated with cilta-cel after 1–3 prior lines of therapy (37 OP; 62 IP) 
• Primary outcomes: All-cause and multiple myeloma-related healthcare resource utilization and per-patient-per-month imputed costs during the first 30 and 90 days after infusion 
• Main findings: 
 - 40.5% of patients receiving OP cilta-cel did not require inpatient admission within 30 days after infusion 
 - OP administration was associated with significantly fewer inpatient days than IP administration (adjusted incidence rate ratio: 0.31; p<0.001) 
 - OP administration was associated with significantly lower inpatient-related imputed costs (adjusted mean difference: −$39,786; p<0.001) 
 - Estimated cost savings associated with OP administration were approximately $40,000 per patient during the first 30 days and $53,000 per patient during the first 90 days 
 - Findings were consistent for both all-cause and multiple myeloma-related HCRU and costs

Strengths  
• Used electronic medical record data, providing a more comprehensive view of patient encounters within the EMR network than insurance claims alone 
• Included analyses of both all-cause and multiple myeloma-related healthcare utilization to reduce potential bias from miscoding 
• Findings were reported to be consistent with previous studies using multiple data sources

Limitations  
• Electronic medical records did not capture out-of-network care and may have had incomplete or variable data across sites. 
• Possible misclassification of prior lines of therapy and underestimation of multiple myeloma-related healthcare utilization due to incomplete coding. 
• The database did not distinguish planned from unplanned inpatient admissions. 
• Healthcare costs were imputed from published estimates rather than directly measured and may not reflect actual payer payments or variation in care intensity. 
• Follow-up was limited to the short term, preventing assessment of long-term HCRU and costs. 
• As a retrospective, non-randomized study, residual confounding from unmeasured patient, institutional, or practice-related factors may remain despite adjusted analyses. 
• Small sample size limited covariate adjustment and prevented use of more complex statistical approaches such as propensity score methods.

Why this study matters 
In this real-world observational study, outpatient administration of cilta-cel was associated with lower inpatient healthcare resource utilization and lower imputed healthcare costs than inpatient administration during the first 90 days after infusion in patients with relapsed or refractory multiple myeloma treated after 1–3 prior lines of therapy. Approximately 40.5% of patients treated in the outpatient setting did not require inpatient admission within 30 days of infusion. The authors noted that these findings should be interpreted in the context of the study's observational design, imputed cost estimates, and other stated limitations.

Reference: 
Janakiram M, Ghosh S, Alegria V, Perciavalle M, Emond B, Maitland J, Bixby T, Nagar SP, Qureshi ZP, Bakaloudi DR, Dima D. Healthcare resource utilization and costs in patients with multiple myeloma administered ciltacabtagene autoleucel in outpatient versus inpatient settings after one to three prior lines of therapy. J Comp Eff Res. 2026 Jun 29:e260052. doi: 10.57264/cer-2026-0052. 

Spatial transcriptomics identifies a suppressive, T-cell excluded tumor microenvironment in extramedullary myeloma — Blood Advances (June 2026) 

 
What is the purpose of the study? 
To characterize the tumor microenvironment (TME) and spatial tissue architecture of extramedullary disease (EMD) in multiple myeloma (MM) using spatial transcriptomics. It also examines cellular interactions between plasma cells (PCs) and the surrounding microenvironment to better understand mechanisms associated with disease progression and therapy resistance.

Summary 
Researchers performed spatial transcriptomics on tumor biopsies from patients with EMD in MM to examine the composition and organization of the TME. Although plasma cells showed substantial inter-patient heterogeneity, they retained a characteristic plasma cell transcriptome. The TME was predominantly composed of macrophages with a suppressive "M2" phenotype, while CD8+ T cells frequently expressed the exhaustion markers LAG3 and TIGIT. Three recurrent TME niches (immune excluded, immune suppressed, and immune permissive) were identified, with the immune excluded niche representing most tumours. Cell-cell interaction modelling predicted bidirectional signaling in which plasma cells influenced the TME through PGE2 and VEGFB, while receiving pro-survival signals through CD38, CXCR4, and BCMA. Fibroblasts and macrophages were predicted to contribute to a suppressive macrophage phenotype and fibrotic extracellular matrix that supports an immunosuppressive local environment.

Key points 
• The study used spatial transcriptomics to characterize the TME in EMD of MM. 
• Plasma cells demonstrated significant inter-patient heterogeneity while maintaining a characteristic plasma cell transcriptome. 
• The TME was dominated by macrophages with a suppressive "M2" phenotype. 
• CD8+ T cells frequently expressed the exhaustion markers LAG3 and TIGIT. 
• Three recurrent tumour microenvironment niches were identified: Immune excluded (the predominant niche in most tumors; Immune suppressed; Immune permissive 
• Abundant tumor-associated fibroblasts in the immune suppressed niche were associated with a suppressive extracellular matrix that may contribute to T-cell exclusion.

• Cell-cell interaction modelling predicted: 
 - Plasma cells modulate the TME through PGE2 and VEGFB. 
 - Plasma cells receive canonical pro-survival signals through CD38, CXCR4, and BCMA. 
 - Fibroblasts and macrophages collectively promote a suppressive macrophage phenotype and fibrotic extracellular matrix, supporting an immunosuppressive local environment.

• The findings indicate spatial organization of EMD characterized by niche substitution rather than niche independence and identify microenvironmental niches and signaling networks associated with this disease.

Strength 
Spatial transcriptomics enabled characterization of the spatial organization, immune composition, and predicted cell-cell interactions within EMD tumors.

Why this study matters 
This study found that the TME in EMD is predominantly immunosuppressive, with suppressive macrophages, exhausted CD8+ T cells, and distinct immune niches identified through spatial transcriptomics. Cell-cell interaction modelling predicted bidirectional signaling between plasma cells and the tumour microenvironment involving PGE2, VEGFB, CD38, CXCR4, and BCMA, with fibroblasts and macrophages contributing to a suppressive local environment. These findings describe the spatial organization and cellular signaling networks present in EMD without establishing causal relationships.

Reference: 
Nicholas Eardley Bingham, Julie R Boiko, Daniel C Jones, Daniel Wong, Tiffany Khong, Sridurga Mithraprabhu, Kathleen S. Ensbey, Anna E Elz, Evan W. Newell, Andrew Spencer, Geoffrey R Hill; Spatial transcriptomics identifies a suppressive, T-cell excluded tumor microenvironment in extramedullary myeloma. Blood Adv 2026; bloodadvances.2026020500. doi: https://doi.org/10.1182/bloodadvances.2026020500 

The ClinicalTrials.gov Landscape of Multiple Myeloma Clinical Trials: A 20-Year Analysis of Geographic Distribution and Growth Patterns: USMIRC Analysis — Current Oncology (June 2026)

What is the purpose of the study? 
To evaluate the global distribution, growth over time, and phase-specific patterns of interventional multiple myeloma (MM) clinical trials registered on ClinicalTrials.gov between 2006 and 2026. It also examines how trial activity, trial sites, and research infrastructure differed according to countries' economic classifications.

Summary  
This retrospective registry-based analysis included 845 interventional MM clinical trials registered on ClinicalTrials.gov from January 2006 to January 2026. Trial activity was concentrated in the U.S. (337 trials; 39.9%), followed by international trials (271; 32.1%), high-income OECD countries (129; 15.3%), and upper-middle-income countries (103; 12.2%); upper-middle-income countries had the highest compound annual growth rate (18.5%), while the U.S. had the highest population-adjusted trial density (0.99 trials per million population) and the largest number of trial sites and site-years. Phase 1 trials were primarily conducted in the U.S. and international collaborations, whereas Phase 3 trials were mostly multinational but continued to have most participating sites located in the U.S. and high-income OECD countries.

Key points 
• Study design: Retrospective registry-based analysis of 845 interventional multiple myeloma clinical trials registered on ClinicalTrials.gov (2006–2026). 
• Trial activity increased substantially over the 20-year study period across all economic regions. 
• The U.S. accounted for 337 trials (39.9%) and had the highest population-adjusted trial density (0.99 trials per million population), as well as the largest number of trial sites and site-years. 
• International trials represented 271 trials (32.1%), high-income OECD countries contributed 129 trials (15.3%), and upper-middle-income countries contributed 103 trials (12.2%). 
• Upper-middle-income countries showed the fastest growth in trial activity, with a compound annual growth rate of 18.5%.

• Phase-specific findings: 
 - Phase 1 trials were predominantly conducted in the U.S. and international collaborative trials. 
 - Phase 2 trials showed greater participation from high-income OECD countries. 
 - Phase 3 trials were mainly multinational, but most participating sites remained in the U.S. and high-income OECD countries.

• Most trial sites and research infrastructure remained concentrated in high-income regions despite increasing multinational trial designs. 
• Most trials and trial sites were supported by industry sponsors, with relatively few funded by public or cooperative research groups. 
• A temporary decline in trial initiation and site activity occurred around 2020, consistent with reported disruptions during the COVID-19 pandemic.

Strengths  
• The analysis covered a large registry of MM clinical trials over a 20-year period. 
• The study separately evaluated trial numbers, trial sites, site-years, and population-adjusted trial density, providing additional measures of research capacity. 
• Phase-specific analyses allowed comparison of geographic patterns across different stages of clinical development.

Limitations  
• The analysis relied on ClinicalTrials.gov, which may not include trials registered only in other registries. 
• Registry information on funding sources and trial sites may be incomplete. 
• Classification of trials as "international" does not indicate how participants were distributed across countries, and the presence of a trial site does not ensure equal patient enrollment. 
• ClinicalTrials.gov does not provide detailed country-level patient enrollment data. 
• Regional and temporal differences in trial registration practices may have influenced the observed geographic and temporal patterns.

Why this study matters 
Between 2006 and 2026, global multiple myeloma clinical trial activity increased substantially, but trial numbers, trial sites, and population-adjusted trial density remained concentrated in the U.S. and other high-income OECD countries. Although multinational trials and participation from upper-middle-income countries increased over time, research infrastructure remained unevenly distributed, with limited participation from lower-income regions.

Reference: 
Zayad, A., Younis, O., Awadallah, C., Kamboj, I., Mohammed, A., Shatnawi, A. E., Ali, A., Alzatary, H., Khan, A. M., Shaikh, H., Alkharabsheh, O., Shah, M. R., Mewawalla, P., McGuirk, J. P., Mahmoudjafari, Z., Mushtaq, M. U., Kort, J., Habib, A., Atrash, S., & Abdallah, A.-O. (2026). The ClinicalTrials.gov Landscape of Multiple Myeloma Clinical Trials: A 20-Year Analysis of Geographic Distribution and Growth Patterns: USMIRC Analysis. Current Oncology, 33(7), 396. https://doi.org/10.3390/curroncol33070396

Idecabtagene vicleucel and endogenous T-cell phenotypes linked to progression-free survival in relapsed multiple myeloma — HemaSphere (July 2026)

What is the purpose of the study? 
To evaluate whether bone marrow CAR-T-cell and endogenous T-cell phenotypes before and after treatment with idecabtagene vicleucel (ide-cel) were associated with progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (RRMM) enrolled in the KarMMa trial. The aim is to determine the prognostic value of dynamic immune profiling using multidimensional computational flow cytometry.

Summary  
The study analyzed 258 bone marrow aspirates from 107 patients with RRMM treated with ide-cel in the KarMMa trial. At screening, higher percentages of PD1+ cytotoxic T cells and ICOS−TIGIT+ regulatory T cells (Tregs) were associated with longer PFS. One month after infusion, the presence of >1% CAR-T cells, a CD4/CD8 CAR-T-cell ratio >0.09, and a greater abundance of non-activated, non-cytolytic CAR-T cells were associated with longer PFS, while at later assessments, lower percentages of ICOS+TIGIT− Tregs showed the strongest association with longer PFS.

Key points 
• Study population: 107 patients with RRMM from the KarMMa trial; 258 bone marrow aspirates were analyzed. 
• Treatment: Patients received idecabtagene vicleucel (ide-cel), an anti-BCMA CAR-T-cell therapy. 
• Immune profiling: Multidimensional computational flow cytometry identified 158 T-cell clusters (115 endogenous T-cell clusters and 43 CAR-T-cell subsets). 
• Baseline findings: Higher percentages of PD1+ cytotoxic T cells and ICOS−TIGIT+ Tregs at screening were associated with longer PFS.

• Month 1 findings: Longer PFS was associated with: 
 - >1% CAR-T cells in bone marrow 
 - CD4/CD8 CAR-T-cell ratio >0.09 
 - Greater abundance of non-activated, non-cytolytic CAR-T cells

•Later follow-up: Among endogenous T-cell subsets, lower percentages of ICOS+TIGIT− Tregs had the strongest association with longer PFS. 
• The study found that T-cell phenotypes before apheresis and both CAR-T-cell and endogenous T-cell phenotypes after infusion were associated with PFS.

Strengths  
• One of the largest studies of dynamic immune profiling in RRMM patients treated with anti-BCMA CAR-T cells. 
• Analysis was performed on bone marrow samples, allowing assessment of intratumoral CAR-T-cell persistence. 
• Comprehensive profiling identified both conventional and more complex immune cell subsets associated with PFS.

Limitations  
• External validation is required, particularly because some subgroup sample sizes were very small due to the methodology used to identify prognostic cutoffs. 
• The study could not distinguish the individual effects of lymphodepletion and CAR-T-cell infusion on immune changes. 
• Several findings require validation in future longitudinal studies before clinical application.

Why this study matters 
In patients with RRMM treated with idecabtagene vicleucel in the KarMMa trial, specific endogenous T-cell and CAR-T-cell phenotypes measured before and after treatment were associated with progression-free survival. The findings identify immune features that may have prognostic value, although the authors state that external validation and additional longitudinal studies are needed before these biomarkers can be applied in routine clinical practice.

Reference: 
Paiva, B., Manrique, I., Thompson, E., Campbell, T.B., Guerrero, C., Martin, N., Anderson, L.D., Jr., Berdeja, J.G., Lonial, S., Raje, N.S., Lin, Y., Moreau, P., San-Miguel, J.F., Munshi, N.C. and Kaiser, S. (2026), Idecabtagene vicleucel and endogenous T-cell phenotypes linked to progression-free survival in relapsed multiple myeloma. HemaSphere, 10: e70423. https://doi.org/10.1002/hem3.70423 

Redefining light-chain smoldering multiple myeloma: prevalence and progression risk — Leukemia (July 2026)

What is the purpose of the study? 
To define and characterize light-chain smoldering multiple myeloma (light-chain SMM) using serum free light chain (FLC) analysis and bone marrow plasma cell (BMPC) assessment within the iStopMM study. It also seeks to externally validate the proposed definition in the DALY-CARE population-based cohort and estimate the risk of disease progression.

Summary  
Researchers defined light-chain SMM as abnormal serum FLC values and FLC ratio, BMPC 10–59%, absence of detectable intact immunoglobulin on serum protein electrophoresis (SPEP) and immunofixation, and no myeloma-defining events. In the iStopMM study, 19% of individuals with abnormal FLC levels met the proposed definition, corresponding to a population prevalence of 0.08% among people older than 40 years. In the DALY-CARE cohort, light-chain SMM was associated with an annual progression risk of approximately 6%, increasing to approximately 9% among individuals with at least one high-risk feature according to the Mayo Clinic 2/20/20 risk model.

Key points 
• The study proposed revised diagnostic criteria for light-chain SMM based on: 
 - Abnormal serum FLC values and FLC ratio 
 - No detectable intact immunoglobulin by SPEP or immunofixation 
 - BMPC 10–59% 
 - Absence of myeloma-defining events

• The definition was developed using the nationwide iStopMM screening study and externally validated in the DALY-CARE population-based cohort. 
• In iStopMM, 19% of individuals with abnormal FLC levels had light-chain SMM, with an estimated prevalence of 0.08% among individuals older than 40 years. 
• Urine protein electrophoresis (UPEP) was negative in 28% of light-chain SMM cases in iStopMM and 37% in DALY-CARE where data were available. 
• In DALY-CARE, the annual progression risk was approximately 6%, increasing to approximately 9% among individuals with at least one Mayo Clinic 2/20/20 high-risk feature.

Strengths  
• Population-based screened design of the iStopMM study. 
• Systematic protocol-based bone marrow biopsies. 
• Complete serum FLC analysis for all screened participants. 
• Use of MALDI-TOF mass spectrometry (MALDI-TOF-MS) and next-generation flow (NGF). 
• External validation in a large population-based Danish cohort with assessment of progression risk.

Why this study matters 
The study proposes defining light-chain SMM by abnormal serum FLC analysis, absence of detectable immunoglobulin heavy chain on SPEP or immunofixation, and BMPC 10–59% without myeloma-defining events. Using this definition, the estimated annual progression risk was approximately 6%, with a higher risk of approximately 9% in individuals with at least one Mayo Clinic 2/20/20 high-risk feature. The proposed definition was developed in the iStopMM study and externally validated in the DALY-CARE cohort.

Reference: 
Maeng, C.V., Thorsteinsdóttir, S., Óskarsson, J.Þ. et al. Redefining light-chain smoldering multiple myeloma: prevalence and progression risk. Leukemia (2026). https://doi.org/10.1038/s41375-026-03028-8 

Signals in Peripheral Blood: Tracking Redox Status and DNA Damage Response During the Progression of Multiple Myeloma — International Journal of Molecular Sciences (July 2026)

What is the purpose of the study? 
To investigate whether changes in redox status and the DNA damage response (DDR) that occur during the progression from monoclonal gammopathy of undetermined significance (MGUS) to smoldering multiple myeloma (SMM) and multiple myeloma (MM) are reflected in peripheral blood mononuclear cells (PBMCs). The study evaluates whether PBMC-based measurements of oxidative stress, DNA damage, DNA repair capacity, chromatin structure, and apoptotic sensitivity differ across disease stages compared with healthy controls.

Summary  
The study included 76 participants: 17 with MGUS, 20 with SMM, 19 with MM, and 20 healthy controls. Compared with healthy controls, baseline DNA damage, nucleotide excision repair (NER) capacity, double-strand break repair (DSB/R) capacity, and chromatin relaxation increased progressively across the sequence healthy controls → MGUS → SMM → MM (all p < 0.001), while the glutathione redox ratio (GSH/GSSG) and apoptotic sensitivity progressively decreased (p < 0.001). The authors reported that these molecular alterations were detectable in PBMCs collected before treatment, suggesting that peripheral blood reflects systemic changes associated with MM progression.

Key points 
• Study population: 76 participants: 17 with MGUS; 20 with SMM; 19 with MM; 20 healthy controls 
 - Blood samples were collected at diagnosis before anti-myeloma or supportive treatment.

• Main findings 
 - Baseline DNA damage progressively increased from healthy controls to MGUS, SMM, and MM (p < 0.001). 
 - DNA repair capacity increased progressively across disease stages, including: Nucleotide excision repair (NER); Double-strand break repair (DSB/R) 
 - Chromatin relaxation progressively increased during disease progression. 
 - The GSH/GSSG ratio progressively decreased, indicating a shift toward a more pro-oxidant intracellular environment (p < 0.001). 
 - Apoptotic sensitivity progressively declined during disease progression (p < 0.001).

• Measurements performed in PBMCs 
 - Baseline DNA damage 
 - Abasic sites 
 - NER capacity 
 - DSB repair activity 
 - Chromatin condensation/relaxation 
 - GSH/GSSG ratio 
 - Apoptotic sensitivity

• Potential clinical relevance reported by the authors 
 - The observed molecular changes were detectable in peripheral blood, an easily accessible tissue. 
 - The authors state that these findings indicate potential utility for early detection, prognostic assessment, and future evaluation of treatment response, although these applications require further validation.

Why this study matters 
This study found progressive increases in DNA damage, DNA repair capacity, and chromatin relaxation, together with progressive decreases in the GSH/GSSG ratio and apoptotic sensitivity, in PBMCs across the MGUS–SMM–MM disease continuum. The authors conclude that these peripheral blood molecular alterations may have potential as minimally invasive biomarkers for early diagnosis and prognostic assessment of MM but emphasize that larger prospective studies are required to validate these findings before clinical application.

Reference: 
Malamos, P., Deligianni, E., Koutoulogenis, K., Courraud, J., Liacos, C.-I., Solia, E., Terpos, E., Dimopoulos, M. A., Kastritis, E., & Souliotis, V. L. (2026). Signals in Peripheral Blood: Tracking Redox Status and DNA Damage Response During the Progression of Multiple Myeloma. International Journal of Molecular Sciences, 27(14), 6103. https://doi.org/10.3390/ijms27146103 
 

Diagnosis and management of immune effector cell–associated enterocolitis after ciltacabtagene autoleucel — Blood Advances (July 2026)

What is the purpose of the study? 
To evaluate the clinical characteristics, risk factors, pathology findings, and treatment outcomes of immune effector cell–associated enterocolitis (IEC-EC) after ciltacabtagene autoleucel (cilta-cel) chimeric antigen receptor T-cell (CAR-T) therapy in patients with relapsed or refractory multiple myeloma. It also examined potential diagnostic and management approaches based on findings from a retrospective cohort.

Summary  
This retrospective study reviewed 229 consecutive patients who received cilta-cel at Mayo Clinic between February 2022 and November 2024 and identified 9 patients (3.9%) who developed IEC-EC, characterized by persistent, non-bloody grade 3 diarrhea with a median onset of 85 days (range, 35–166) after CAR-T infusion. Independent factors associated with IEC-EC were International Myeloma Society/International Myeloma Working Group (IMS/IMWG)-defined high-risk disease, prolonged cytokine release syndrome, and antecedent delayed neurotoxicity. Initial treatment with corticosteroids and supportive care did not produce durable responses, whereas biologic therapy resulted in durable responses in 3 of 5 treated patients (2/2 with vedolizumab and 1/3 with infliximab); none of these responders had gastrointestinal coinfection.

Key points 
• Study population 
 - Retrospective review of 229 consecutive patients with relapsed or refractory multiple myeloma treated with cilta-cel at Mayo Clinic (February 2022–November 2024). 
 - 9 patients (3.9%) developed IEC-EC.

• Clinical features 
 - IEC-EC presented with persistent, nonbloody grade 3 diarrhea, frequently requiring prolonged total parenteral nutrition. 
 - Median time from CAR-T infusion to symptom onset was 85 days (range, 35–166 days). 
 - Gastrointestinal coinfections were common. 
 - Duodenal biopsies most frequently showed mucosal injury resembling graft-versus-host disease; 2 cases demonstrated biopsy patterns resembling T-cell lymphoproliferative disorder (T-LPD).

• Risk factors: Independent factors associated with IEC-EC were: 
 - IMS/IMWG-defined high-risk disease 
 - Prolonged cytokine release syndrome 
 - Antecedent delayed neurotoxicity

• Treatment findings 
 - Initial treatment with intravenous or oral corticosteroids, bile acid sequestrants, intravenous immunoglobulin, and antimicrobial-directed therapy did not produce durable responses. 
 - Durable responses to biologic therapy occurred in 2 of 2 patients treated with vedolizumab; 1 of 3 patients treated with infliximab 
 - None of the patients with durable responses had gastrointestinal coinfection.

• Diagnosis 
The study emphasizes early gastroenterology evaluation with endoscopy including duodenal biopsy as an important component of diagnosis.

Strengths  
• Single-institution study enabled greater data granularity. 
• Centralized pathology and gastroenterology review. 
• Greater control over potential confounding factors.

Limitations  
• Retrospective study design
• Missing data
• Potential underreporting of cases and selection bias toward more severe cases
• Small number of IEC-EC cases limited generalizability
• Single-institution experience may not reflect treatment-access disparities

Why this study matters 
In this retrospective cohort, IEC-EC occurred in 3.9% of patients treated with cilta-cel and was associated with IMS/IMWG-defined high-risk disease, prolonged cytokine release syndrome, and antecedent delayed neurotoxicity. Initial corticosteroid-based treatment and supportive care did not produce durable responses, while biologic therapy was associated with durable responses in 3 of 5 treated patients. The study reports that early endoscopic evaluation with duodenal biopsy is important for diagnosis and states that early biologic therapy may be considered after failure of a short course of corticosteroids.

Reference: 
Kenneth J. C. Lim, Hee Eun Lee, Zongming Eric Chen, Adam Bledsoe, Ricardo Parrondo, Saurabh Chhabra, Katharine Dooley, Andre De Menezes Silva Corraes, Morie Gertz, Lisa Hwa, Haily Stephens, Prashant Kapoor, Melinda Tan, Taxiarchis Kourelis, Rahma Warsame, Joselle Cook, Moritz Binder, P. Leif Bergsagel, Udit Yadav, Erin Wiedmeier-Nutor, Susan Geyer, Sikander Ailawadhi, Rafael Fonseca, Shaji Kumar, Navreet Chowla, Yi Lin; Diagnosis and management of immune effector cell–associated enterocolitis after ciltacabtagene autoleucel. Blood Adv 2026; 10 (13): 4495–4507. doi: https://doi.org/10.1182/bloodadvances.2025018853 

Clinical Trials

A novel triple-knockout allogeneic BCMA CAR T cell therapy (CT0590) in multiple myeloma: preclinical and phase I study — Blood (June 2026)

What is the purpose of the study? 
This first-in-human phase I study evaluates the safety and preliminary antitumor activity of CT0590, a triple-knockout, BCMA-targeting allogeneic CAR T-cell therapy engineered with an NKG2A CAR to counter host natural killer (NK) cell-mediated rejection in patients with relapsed and refractory multiple myeloma (RRMM) and primary plasma cell leukemia (pPCL).

Summary 
CT0590 is a triple-knockout, HLA-I–deficient allogeneic CAR T-cell product targeting BCMA and expressing an NKG2A CAR. Preclinical in vitro and in vivo studies showed resistance to NK cell-mediated killing and antitumor activity. In the phase I study (NCT05066022), five patients (four with RRMM and one with pPCL) received CT0590. CT0590 was well tolerated, with no dose-limiting toxicities, no treatment-related deaths, and no graft-versus-host disease reported. Three patients achieved confirmed responses, including two stringent complete responses (sCRs). One patient with RRMM had an ongoing sCR lasting >23 months at data cutoff, and one patient with pPCL had an sCR lasting 20 months. Both patients with durable sCRs had robust expansion of universal CAR (uCAR) T cells (Cmax >280,000 copies/µg genomic DNA). Both patients with durable sCRs had higher baseline NKG2A expression on NK cells than nonresponders.

Key points 
• The product is HLA-I–deficient and designed to resist NK cell-mediated killing. 
• Preclinical studies demonstrated resistance to NK cell-mediated cytotoxicity and antitumor activity in vitro and in vivo models. 
• Phase I study (NCT05066022) enrolled five patients (RRMM n=4; pPCL n=1)
• CT0590 was well tolerated. 
• No dose-limiting toxicities were observed. 
• No treatment-related deaths were reported. 
• No graft-versus-host disease was observed. 
• Three of five patients achieved confirmed responses. 
• Two patients achieved stringent complete responses (sCRs). 
• One RRMM patient had an ongoing sCR >23 months at data cutoff. 
• One pPCL patient had an sCR lasting 20 months. 
• Both patients with durable sCRs showed robust uCAR T-cell expansion (Cmax >280,000 copies/µg gDNA). 
• Both patients with durable sCRs had higher baseline NKG2A expression on NK cells than nonresponders.

Why this study matters 
CT0590, a triple-knockout BCMA- and NKG2A-targeting allogeneic CAR T-cell therapy, was evaluated in a phase I study of five patients with RRMM or pPCL. No dose-limiting toxicities, treatment-related deaths, or graft-versus-host disease were observed, and three patients achieved confirmed responses, including two durable stringent complete responses. These findings provide early clinical evidence of safety and antitumor activity of CT0590 and support further clinical investigation.

Reference: 
Song Jin, Zhaohui Liao, Shuang Yan, Lingzhi Yan, Weiqin Yao, Jingjing Shang, Fang Tang, Ziling Zhu, Depei Wu, Nishanthan Rajakumaraswamy, Yi Luo, Daijing Yuan, Hua Jiang, Zonghai Li, Chengcheng Fu; A novel triple-knockout allogeneic BCMA CAR T cell therapy (CT0590) in multiple myeloma: preclinical and phase I study. Blood 2026; blood.2025032112. doi: https://doi.org/10.1182/blood.2025032112 

The prognostic factors and immune microenvironment of primary plasma cell leukemia: the KMMWP-2204 study — Haematologica (June 2026)

What is the purpose of the study? 
To identify prognostic factors and assess treatment outcomes in newly diagnosed primary plasma cell leukemia (pPCL) using the KMMWP-2204 cohort of 127 patients from 20 Korean centers, and to integrate these findings with exploratory single-cell RNA sequencing (scRNA-seq) data.

Summary 
The analysis included 127 patients with newly diagnosed pPCL from 20 Korean centers to identify prognostic factors and assess treatment outcomes, and integrated exploratory scRNA-seq data from bone marrow samples of 4 pPCL patients, 2 multiple myeloma patients, and 3 healthy donors. Patients with 5–19% and ≥20% circulating plasma cells (CPCs) had comparable survival. These findings support the revised 2021 International Myeloma Working Group 5% CPC diagnostic threshold. Poor performance status (OR 3.28; P=0.031), elevated lactate dehydrogenase (OR 3.45; P=0.019), and del(17p) (OR 3.58; P=0.025) independently predicted 6-month early mortality. Achievement of complete remission was associated with survival (HR for overall survival, 0.30; P=0.005), whereas autologous stem cell transplantation (ASCT) appeared to have a consolidative rather than independent effect in time-dependent analyses. Although use of intensive triplet or quadruplet induction regimens and ASCT increased in the post-2016 era, survival outcomes remained broadly similar across eras. Exploratory scRNA-seq analysis identified transcriptional features suggestive of altered immune differentiation and myeloid-associated immunoregulatory signaling in pPCL. 

Key points
• KMMWP-2204 cohort (n=127) from 20 Korean centers with exploratory scRNA-seq 
• 5–19% and ≥20% CPC groups had comparable survival 
• Findings support revised 2021 IMWG 5% CPC diagnostic threshold based on survival comparison 
• Independent predictors of 6-month early mortality: poor performance status, elevated LDH, del(17p) 
• Complete remission associated with survival (HR 0.30; P=0.005) 
• ASCT appeared to have a consolidative rather than independent effect in time-dependent analyses 
• Increased use of intensive regimens and ASCT post-2016, with similar survival outcomes across eras 
• scRNA-seq identified transcriptional features suggestive of altered immune differentiation and myeloid-associated immunoregulatory signaling

Why this study matters 
The study analyzed 127 patients with newly diagnosed pPCL from 20 Korean centers and identified factors associated with 6-month early mortality and survival, including performance status, lactate dehydrogenase, del(17p), and complete remission. Patients with 5–19% and ≥20% circulating plasma cells had comparable survival, and ASCT appeared to have a consolidative rather than independent effect in time-dependent analyses. Exploratory scRNA-seq analysis identified transcriptional features suggestive of altered immune differentiation and myeloid-associated immunoregulatory signaling in pPCL.

Reference: 
Kim M, Jang HC, Ahn J-S, Cho H, Lee J-J, Cho HJ, Kim DS, Jung J, Lee JH, Kim K, Byun JM, Yoon DH, Choi YS, Jo J-C, Yhim H-Y, Lee M-W, Lim S-N, Lee JH, Park S-S, Min C-K, Jung S-H. The prognostic factors and immune microenvironment of primary plasma cell leukemia: the KMMWP-2204 study. Haematologica; https://doi.org/10.3324/haematol.2026.300772 [Early view]. 

Longitudinal mechanisms of response, resistance and relapse to teclistamab in multiple myeloma: results from MajesTEC-1 — Haematologica (June 2026)

What is the purpose of the study? 
To evaluate associations between immune profiles and clinical response, resistance, and relapse to teclistamab in patients with triple-class–exposed relapsed/refractory multiple myeloma enrolled in MajesTEC-1 (NCT03145181/NCT04557098). It analyzes longitudinal changes in peripheral blood, bone marrow tumor microenvironment, and BCMA antigen expression.

Summary 
Bone marrow and peripheral blood samples were collected at baseline, during treatment, and at disease progression to assess immune and tumor plasma cell–related changes in patients treated with the BCMA-directed bispecific antibody teclistamab. Responders demonstrated greater T-cell margination, recovery, and increased T-cell activation in peripheral blood compared with nonresponders. Nonresponders showed sustained expression of T-cell checkpoint markers on CD4+ and CD8+ T cells, higher proportions of regulatory T cells over time, and findings described as suggestive of immune suppression and T-cell dysfunction, while relapse was associated with increased proportions of CD4+ and CD8+ T cells expressing CD39 and CD57 and reduced BCMA receptor density on bone marrow tumor plasma cells.

Key points 
• Teclistamab (BCMA-directed bispecific antibody) evaluated in MajesTEC-1 (NCT03145181/NCT04557098). 
• Responders exhibited greater T-cell margination, recovery, and activation in peripheral blood. 
• Nonresponders showed sustained checkpoint marker expression on CD4+ and CD8+ T cells. 
• Nonresponders had higher proportions of regulatory T cells over time. 
• Nonresponders exhibited findings described as suggestive of immune suppression and T-cell dysfunction. 
• Relapse was associated with increased proportions of CD4+ and CD8+ T cells expressing CD39 and CD57. 
• Reduced BCMA receptor density was observed on bone marrow tumor plasma cells at relapse.

Why this study matters 
The study describes longitudinal immune profiles and BCMA antigen expression changes associated with response, nonresponse, and relapse in patients treated with teclistamab. Differences were observed in T-cell activation-related features, regulatory T-cell proportions, checkpoint marker expression, and proportions of T cells expressing dysfunction-associated markers, along with reduced BCMA receptor density at relapse. These findings characterize immune and antigen-level correlates across treatment timepoints in MajesTEC-1.

Reference: 
Vishwamitra D, Skerget S, Cortes-Selva D, Perova T, Lau O, Davis C, Boominathan R, Patel J, Berge KV den, Guo Y, Miao X, Stephenson T, Hodin C, Uhlar C, Pei L, Trancucci D, Zuppa AF, Chastain K, Banerjee A, Kobos R, Bahlis NJ, van de Donk NW, Verona RI. Longitudinal mechanisms of response, resistance and relapse to teclistamab in multiple myeloma: results from MajesTEC-1. Haematologica; https://doi.org/10.3324/haematol.2026.300526 [Early view]. 

Mezigdomide, carfilzomib, and dexamethasone versus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma (SUCCESSOR-2): a phase 3, open-label, randomised controlled trial — The Lancet (June 2026)

What is the purpose of the study? 
To assess whether adding mezigdomide to carfilzomib and dexamethasone improves efficacy and safety compared with carfilzomib and dexamethasone alone in patients with relapsed multiple myeloma (RRMM) previously treated with anti-CD38 antibodies and lenalidomide.

Summary 
SUCCESSOR-2 was a phase 3, open-label, randomized controlled trial conducted at 160 hospital-based sites across 26 countries using a two-stage, inferentially seamless design. Adults with measurable RRMM were eligible if they had received at least one prior treatment regimen that included anti-CD38 antibodies and lenalidomide, had achieved at least a minimal response, and had evidence of disease progression during or after their most recent therapy. Participants were assigned to receive either oral mezigdomide (days 1–21 of each 28-day cycle) combined with intravenous carfilzomib and dexamethasone, or carfilzomib and dexamethasone alone.

A total of 479 patients were included in the efficacy analysis (288 in the mezigdomide–carfilzomib–dexamethasone group and 191 in the carfilzomib–dexamethasone group). The primary endpoint of progression-free survival was assessed in the population receiving the 1.0 mg mezigdomide dose across both study stages. At a median follow-up of 10.6 months, median progression-free survival was 18.0 months in the combination group versus 8.3 months in the control group (hazard ratio 0.48, 95% CI 0.36–0.63; p<0.0001).

Grade 3 or 4 adverse events were reported in 84% of patients receiving mezigdomide combination therapy and 56% receiving carfilzomib and dexamethasone alone. The most frequent severe events included neutropenia (61% vs 9%) and infections (34% vs 16%). Treatment-related grade 5 adverse events occurred in 3% versus 1% of patients. Deaths occurred in 22% versus 27%, most often due to disease progression.

Key points 
• Study design: Phase 3, open-label, randomized controlled trial with a two-stage, inferentially seamless design 
• Population: Adults with RRMM previously exposed to anti-CD38 antibodies and lenalidomide 
• Participants analyzed: 479 total 
 - Mezigdomide–carfilzomib–dexamethasone: 288 
 - Carfilzomib–dexamethasone: 191

• Baseline characteristics: 
 - 86% anti-CD38 antibody-refractory 
 - 76% lenalidomide-refractory 
 - Median of 2 prior lines of therapy (IQR 2–4)

• Primary endpoint: Progression-free survival (PFS) in patients receiving the 1.0 mg mezigdomide dose 
• Results: 
 - Median PFS: 18.0 vs 8.3 months 
 - Hazard ratio: 0.48 (95% CI 0.36–0.63) 
 - p<0.0001

• Safety: 
 - Grade 3 or 4 adverse events: 84% vs 56% 
 - Neutropenia: 61% vs 9% 
 - Infections: 34% vs 16% 
 - Treatment-related grade 5 adverse events: 3% vs 1% 
 - Deaths: 22% vs 27% (mostly due to disease progression)

Why this study matters 
In the phase 3 SUCCESSOR-2 trial, adding mezigdomide to carfilzomib and dexamethasone improved progression-free survival compared with carfilzomib and dexamethasone alone in patients with RRMM previously treated with anti-CD38 antibodies and lenalidomide (18.0 vs 8.3 months; hazard ratio 0.48; 95% CI 0.36–0.63; p<0.0001). The combination regimen was associated with higher rates of severe adverse events, including neutropenia and infections. The study used a randomized, open-label, two-stage, inferentially seamless phase 3 design.

Reference: 
Dimopoulos MA, Schjesvold F, Fu C, Hartley-Brown MA, Gomez C, Reece D, Mikala G, Alkharabsheh O, Parrish C, de Queiroz Crusoé E, Gálvez K, Idrobo H, White D, Gupta R, Lee C, Liu CJ, Quach H, Wang Y, Cerchione C, Forsyth C, Hungria V, Kalaskar P, Graklanov V, Ho PJ, Klaiber-Hakimi M, Kwong YL, Louzada M, Mazumder A, Miles O, Nagarajan C, Prasad SVSS, Raab MS, Varga G, von der Heyde E, Xia Z, Ochoa PA, Oriol A, Yuda J, Kuroda J, Gong J, Zhou Z, Maciag P, Yu B, Rocci A, Koo P, Katz J, Richardson PG; SUCCESSOR-2 Trial Investigators. Mezigdomide, carfilzomib, and dexamethasone versus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma (SUCCESSOR-2): a phase 3, open-label, randomised controlled trial. Lancet. 2026 Jun 14:S0140-6736(26)01088-3. doi: 10.1016/S0140-6736(26)01088-3. 

Talquetamab-Daratumumab in Relapsed or Refractory Myeloma — The New England Journal of Medicine (June 2026)

What is the purpose of the study? 
This phase 3 trial (MonumenTAL-3) evaluates whether talquetamab combined with daratumumab and pomalidomide (Tal-DP) or talquetamab combined with daratumumab (Tal-D) improved outcomes compared with daratumumab, pomalidomide, and dexamethasone (DPd) in patients with relapsed or refractory multiple myeloma (RRMM) who had received at least one previous line of therapy.

Summary 
A total of 864 patients with RRMM were randomly assigned to receive Tal-DP (287 patients), Tal-D (287 patients), or DPd (290 patients). At the interim analysis, with a median follow-up of 24.6 months, progression-free survival was longer with Tal-DP and Tal-D than with DPd, with 24-month progression-free survival estimates of 81.3%, 77.6%, and 51.2%, respectively (hazard ratio for disease progression or death: 0.28 [95% CI, 0.20–0.40] for Tal-DP vs. DPd and 0.33 [95% CI, 0.24–0.46] for Tal-D vs. DPd; P<0.001 for both comparisons).

Overall response rates were 88.2% with Tal-DP, 88.5% with Tal-D, and 77.6% with DPd. Complete response or better occurred in 71.1%, 69.0%, and 34.5% of patients, respectively, while measurable residual disease–negative complete response occurred in 52.3%, 46.3%, and 15.9% (P<0.001 for all comparisons). Overall survival at 24 months was 89.2% with Tal-DP, 87.9% with Tal-D, and 79.1% with DPd. Serious adverse events occurred in 63.0%, 52.6%, and 53.7% of patients, and fatal adverse events occurred in 1.8%, 4.0%, and 4.6%, respectively.

Key points 
• Study: Phase 3 MonumenTAL-3 trial (ClinicalTrials.gov: NCT05455320). 
• Population: Patients with RRMM who had received at least one prior line of therapy. 
• Treatment groups: 
 - Talquetamab + daratumumab + pomalidomide (Tal-DP; n=287) 
 - Talquetamab + daratumumab (Tal-D; n=287) 
 - Daratumumab + pomalidomide + dexamethasone (DPd; n=290)

• Primary endpoint: Progression-free survival assessed by an independent review committee. 
• Median follow-up: 24.6 months. 
• 24-month progression-free survival: 
 - Tal-DP: 81.3% 
 - Tal-D: 77.6% 
 - DPd: 51.2%

• Hazard ratio for disease progression or death: 
 - Tal-DP vs. DPd: 0.28 (95% CI, 0.20–0.40) 
 - Tal-D vs. DPd: 0.33 (95% CI, 0.24–0.46) 
 - P<0.001 for both comparisons.

• Overall response rate: 
 - Tal-DP: 88.2% 
 - Tal-D: 88.5% 
 - DPd: 77.6%

• Complete response or better: 
 - Tal-DP: 71.1% 
 - Tal-D: 69.0% 
 - DPd: 34.5%

• Measurable residual disease–negative complete response: 
 - Tal-DP: 52.3% 
 - Tal-D: 46.3% 
 - DPd: 15.9% 
 - P<0.001 for all comparisons

• 24-month overall survival: 
 - Tal-DP: 89.2% 
 - Tal-D: 87.9% 
 - DPd: 79.1%

• Hazard ratio for death: 
 - Tal-DP vs. DPd: 0.47 (95% CI, 0.30–0.73) 
 - Tal-D vs. DPd: 0.51 (95% CI, 0.33–0.78)

• Safety: 
 - Serious adverse events: 63.0% (Tal-DP), 52.6% (Tal-D), 53.7% (DPd) 
 - Fatal adverse events: 1.8% (Tal-DP), 4.0% (Tal-D), 4.6% (DPd)

Why this study matters 
Among patients with RRMM who had received at least one prior line of therapy, Tal-DP and Tal-D resulted in significantly longer progression-free survival than DPd. Higher overall response rates, complete response or better rates, measurable residual disease–negative complete response rates, and 24-month overall survival estimates were reported with Tal-DP and Tal-D than with DPd. Serious adverse events occurred in all treatment groups.

Reference: 
Mina R, Beksac M, Rodríguez-Otero P, Chen W, Mateos MV, Li J, Moreau P, Cohen YC, Min CK, Jelinek T, Ye JC, Magen H, Rubinstein SM, Fu W, Hungria V, Cengiz Seval G, Farias JS, Radocha J, Maral S, Turgut M, Koh Y, O'Leary D, Schmidt Filho J, Thertulien R, An G, Huang SY, Grosicki S, Tyczyńska A, Banerjee R, Pianko MJ, Martínez-López J, Steckiewicz P, Maruyama D, Fukushima K, Oriol A, Lopez Pardo J, Goldschmidt H, Pawlyn C, Perrot A, Zamagni E, Dimopoulos MA, Rasche L, Tolbert J, Terry W, Courtoux C, Liu X, Vasey SY, Connors K, Festa M, Heuck C, Langlois A, O'Rourke L, Zhou J, Qin X, Lu J, Gong J, Vieyra D, Voorhees PM; MonumenTAL-3 Investigators. Talquetamab-Daratumumab in Relapsed or Refractory Myeloma. N Engl J Med. 2026 Jun 13. doi: 10.1056/NEJMoa2604657. 

Patient-Centric First-in-Human Dose Selection: An Ex Vivo Minimal Anticipated Biological Effect Level Approach for T-Cell Engagers in Multiple Myeloma — Clinical Pharmacology and Therapeutics (June 2026) 

What is the purpose of the study? 
To evaluate the use of a novel ex vivo minimal anticipated biological effect level (MABEL) approach for calculating the first-in-human (FIH) starting dose of forimtamig, a GPRC5D×CD3 T-cell bispecific antibody, in a Phase 1 trial (NCT04557150) involving patients with relapsed/refractory multiple myeloma (RRMM). 

Summary 
Researchers compared conventional in vitro and novel ex vivo MABEL methods to calculate the FIH dose of forimtamig. In vitro assays used a multiple myeloma cell line and peripheral blood mononuclear cells from healthy donors and patients, whereas ex vivo assays used fresh bone marrow aspirates from patients with MM.  

Forimtamig increased tumor cell lysis, cytokine release, and T-cell activation in both assay systems. The investigators selected tumor cell lysis as the primary assay endpoint for FIH dose calculation.

The EC50 for tumor cell lysis was 0.6 pM in vitro and 9 pM in the most sensitive ex vivo patient sample, resulting in calculated FIH doses of 0.4 μg and 6 μg, respectively. The Phase 1 trial used a starting dose of 6 μg. Clinical activity was observed in the second dosing cohort (18 and 54 μg), and durable objective responses were observed in the third dosing cohort (54 and 162 μg). Cytokine release syndrome (CRS) was Grade 1 at the starting dose and was not observed in the second dosing cohort.

Key points 
• The study assessed a novel ex vivo MABEL strategy for determining the FIH dose of forimtamig in RRMM. 
• Ex vivo assays used fresh bone marrow samples from patients with multiple myeloma and autologous T cells. 
• Forimtamig increased: 
 - Tumor cell lysis 
 - Cytokine release 
 - T-cell activation

• The investigators selected tumor cell lysis as the primary assay endpoint for FIH dose calculation. 
• Calculated FIH doses: 
 - In vitro MABEL: 0.4 μg 
 - Ex vivo MABEL: 6 μg

• The selected FIH starting dose was 6 μg; the authors reported that this was approximately 15-fold higher than the dose calculated using the conventional in vitro approach. 
• Clinical activity was observed in the second dosing cohort (18 and 54 μg). 
• Durable objective responses were observed in the third dosing cohort (54 and 162 μg). 
• At the starting dose, CRS was Grade 1; CRS was absent in the second dosing cohort. 
• Regulatory authorities accepted the ex vivo MABEL approach without additional safety factors.

Strengths  
• The authors stated that the approach provides a more physiological reflection of the in vivo microenvironment. 
• The authors stated that the approach may allow more Phase 1 participants to receive doses that are clinically active and safe.

Limitations  
• Difficulty obtaining sufficient fresh patient bone marrow samples while maintaining immune-cell viability. 
• Requirement for specialized laboratories near treatment facilities. 
• Small sample size (9 fresh patient samples) due to limited sample availability. 
• Wide variability in results caused by inter-patient heterogeneity and limited sample numbers. 
• No direct comparison between fresh and cryopreserved samples from the same patient. 
• Limited availability of samples prevented additional analyses, including longitudinal IL-6 measurements and more detailed evaluation of immune-cell composition.

Why this study matters 
A novel ex vivo MABEL approach was used to calculate the first-in-human starting dose of forimtamig in a Phase 1 trial of patients with RRMM. The selected starting dose of 6 μg was tolerated, with Grade 1 cytokine release syndrome reported at the starting dose, and clinical activity was observed in the second dosing cohort, while durable objective responses were observed in the third cohort. The ex vivo MABEL approach produced a higher starting dose than the conventional in vitro MABEL calculation and was accepted by regulatory authorities.

Reference: 
Kraft, T.E., Marrer-Berger, E., Belli, S., Haegel, H., Schneider, A., Giusti, A.M., Bscheider, M., Jacob, W., Weisser, M., Blanco, L., Frances, N., Rossmann, E., Steiner, G., Azpiroz, A.Z., Paiva, B., Martinet, L. and Fauti, T. (2026), Patient-Centric First-in-Human Dose Selection: An Ex Vivo Minimal Anticipated Biological Effect Level Approach for T-Cell Engagers in Multiple Myeloma. Clin Pharmacol Ther. https://doi.org/10.1002/cpt.70366

BCMA/CD19 dual-targeting CAR T-cell therapy in older patients with newly diagnosed multiple myeloma: a phase 1 study — Blood Advances (June 2026)

What is the purpose of the study? 
This phase 1, single-arm, open-label study evaluates the safety and preliminary efficacy of AZD0120 (formerly GC012F), an autologous dual-targeting BCMA/CD19 CAR T-cell therapy manufactured using the FasTCAR platform, in transplant-ineligible patients aged ≥70 years with newly diagnosed multiple myeloma (NDMM) following VRD induction therapy.

Summary 
Eight patients received 2 cycles of VRd (bortezomib, lenalidomide, dexamethasone). Leukapheresis was performed after the first VRd cycle, followed by lymphodepletion with fludarabine and cyclophosphamide and infusion of AZD0120 at one of two dose levels. At a median follow-up of 9.8 months after infusion, 8/8 patients (100%) achieved stringent complete response (sCR).

Minimal residual disease (MRD) negativity at 10⁻⁶ sensitivity was reported in 8/8 patients (100%) at 1 month post-infusion. MRD assessments at later timepoints included 7 evaluable patients at 6 months (7/7 MRD-negative) and 2 evaluable patients at 12 months (2/2 MRD-negative), based on available assessments.

Cytokine release syndrome (CRS) occurred in 4/8 patients (50%), all grade 1. No cases of immune effector cell-associated neurotoxicity syndrome (ICANS) were reported. Grade ≥3 adverse events included neutropenia (75%), leukopenia (50%), and lymphopenia (25%). Infectious events were reported in a small number of patients and resolved with standard management.

Key points

Study design 
• Phase 1, single-arm, open-label, single-center trial (n = 8) 
• Population: NDMM, transplant-ineligible, age ≥70 years 
• Treatment sequence: 
 - VRD induction (2 cycles) 
 - Leukapheresis after cycle 1 VRD 
 - Lymphodepletion (fludarabine + cyclophosphamide) 
 - AZD0120 infusion

• No bridging therapy was administered 
• Dose escalation design with two dose levels evaluated 
• Frailty classification: 4 frail and 4 nonfrail patients

Efficacy outcomes 
• sCR: 8/8 patients (100%) at reported assessment 
• MRD negativity (10⁻⁶): 
 - 8/8 patients at 1 month 
 - 7/7 evaluable patients at 6 months 
 - 2/2 evaluable patients at 12 months

Safety outcomes 
• CRS: 4/8 patients (50%), all grade 1 
• ICANS: 0/8 patients. 
• Grade ≥3 adverse events: primarily hematologic cytopenias: 
• Neutropenia: 75% 
• Leukopenia: 50% 
• Lymphopenia: 25% 
• Infections occurred in a small number of patients and were resolved with treatment.

Limitations 
• Small sample size (n = 8). 
• Single-arm, non-comparative design. 
• Median follow-up 9.8 months. 
• Decreasing numbers of evaluable patients at later MRD timepoints (7 at 6 months; 2 at 12 months). 
• No comparator arm and no randomization.

Why this study matters 
AZD0120 was associated with 100% sCR and MRD negativity at 1 month in a small phase 1 cohort of older, transplant-ineligible patients with NDMM following VRD induction. CRS was limited to grade 1 events, and no ICANS was observed during the reported follow-up period. Interpretation is limited by the small sample size, single-arm design, and short follow-up, particularly for durability of response and safety in larger populations.

Reference: 
Jin Liu, Xiaoqiang Fan, Liying Peng, Jia Liu, Haiyan He, Wanting Qiang, Lina Jin, Lang Shi, Jing Lu, Pei Guo, Nina Shah, Qi Zhang, Lianjun Shen, Juan Du; BCMA/CD19 dual-targeting CAR T-cell therapy in older patients with newly diagnosed multiple myeloma: a phase 1 study. Blood Adv 2026; 10 (12): 4134–4143. doi: https://doi.org/10.1182/bloodadvances.2025019036 

Teclistamab-based induction treatment in transplant-eligible, newly diagnosed multiple myeloma: a phase 2 trial — Nature Medicine (June 2026)

What is the purpose of the study? 
The phase 2 GMMG-HD10/DSMM-XX (MajesTEC-5) study evaluates the safety, feasibility, and early efficacy of frontline teclistamab-based induction regimens in transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). Specifically, it assesses teclistamab combined with daratumumab and lenalidomide (Tec-DR), with or without bortezomib (Tec-DVR), through induction therapy, autologous stem cell transplantation (ASCT), and the premaintenance period.

Summary 
This prespecified pooled analysis included 49 transplant-eligible patients with NDMM who received Tec-DR (arms A and A1) or Tec-DVR (arm B). The primary endpoints were adverse events (AEs) and serious AEs, while secondary endpoints included overall response rate (ORR), minimal residual disease (MRD) negativity, and MRD-negative complete response (CR).

Grade 3 or 4 treatment-emergent adverse events occurred in 91.8% (45/49) of patients, most commonly lymphopenia (59.2%), neutropenia (59.2%), and leukopenia (18.4%). Serious adverse events occurred in 55.1% (27/49), and infections of any grade occurred in 81.6% (40/49), with grade 3 or 4 infections in 36.7% (18/49). Cytokine release syndrome (CRS) occurred in 67.3% (33/49), all grade 1–2, all resolved, and none resulted in treatment discontinuation. No treatment-related immune effector cell-associated neurotoxicity syndrome (ICANS) events or grade 5 treatment-emergent adverse events were reported.

By the premaintenance timepoint, the ORR was 100% (49/49), the MRD-negative CR rate was 91.8% (45/49), and MRD negativity was achieved in 100% of evaluable samples at postinduction cycle 3 (46/46 at 10⁻⁵ sensitivity), cycle 6 (46/46 at both 10⁻⁵ and 10⁻⁶ sensitivities), and premaintenance (40/40 at 10⁻⁵ sensitivity). The median stem cell yield was 8.1 × 10⁶/kg.

Key points

Study design 
• Ongoing, multicenter, open-label, nonrandomized phase 2 study (MajesTEC-5; NCT05695508) 
• Included 49 transplant-eligible patients with newly diagnosed multiple myeloma 
• Evaluated: 
 - Tec-DR: teclistamab + daratumumab + lenalidomide 
 - Tec-DVR: teclistamab + daratumumab + lenalidomide + bortezomib

• Analysis covered induction therapy, ASCT, and the premaintenance period.

Safety results 
• Grade 3–4 treatment-emergent adverse events: 91.8% (45/49) 
• Most common grade 3–4 hematologic events: 
 - Lymphopenia: 59.2% (29/49) 
 - Neutropenia: 59.2% (29/49) 
 - Leukopenia: 18.4% (9/49)

• Serious adverse events: 55.1% (27/49) 
• Most common serious adverse event: Pyrexia: 12.2% (6/49). 
• Infections: 
 - Any grade: 81.6% (40/49). 
 - Grade 3–4: 36.7% (18/49). 
 - Most common grade 3–4 infections: COVID-19: 6.1% (3/49); Pneumonia: 6.1% (3/49)

• CRS: 
 - Occurred in 67.3% (33/49) 
 - All events were grade 1–2 
 - All resolved

• No treatment discontinuation due to CRS 
• No treatment-related ICANS events 
• No grade 5 treatment-emergent adverse events

Efficacy results 
• Overall response rate (ORR): 100% (49/49) 
• MRD-negative complete response rate: 91.8% (45/49) 
• MRD negativity: 
 - Postinduction cycle 3: 100% (46/46) at 10⁻⁵ sensitivity 
 - Postinduction cycle 6: 100% (46/46) at 10⁻⁵ sensitivity; 100% (46/46) at 10⁻⁶ sensitivity. 
 - Premaintenance: 100% (40/40) at 10⁻⁵ sensitivity.

• Median stem cell yield: 8.1 × 10⁶/kg.

Strengths  
• The first study reported to evaluate the combination of teclistamab, daratumumab, and lenalidomide, with or without bortezomib, in transplant-eligible NDMM. 
• Included assessment of both safety and MRD responses through induction and ASCT

Limitations  
• Phase 2 study without a comparator arm, limiting direct comparison with non-teclistamab regimens 
• Relatively short follow-up period 
• Predominantly White study population, limiting racial generalizability 
• Enrolled patients were relatively fit 
• No patients had true extramedullary soft tissue plasmacytomas 
• Sustained MRD negativity and long-term outcomes could not yet be evaluated because of insufficient follow-up.

Why this study matters 
In this pooled premaintenance analysis of the phase 2 MajesTEC-5 study, Tec-DR and Tec-DVR induction regimens followed by ASCT produced an overall response rate of 100% and an MRD-negative complete response rate of 91.8% in transplant-eligible patients with NDMM. The safety profile was characterized primarily by hematologic adverse events, infections, and low-grade CRS, with no grade 5 treatment-emergent adverse events or treatment-related ICANS reported. The findings support the feasibility of these teclistamab-based regimens in this setting, although longer follow-up and comparative studies are needed to assess durability of response and longer-term outcomes.

Reference: 
Raab, M.S., Weinhold, N., Kortüm, K.M. et al. Teclistamab-based induction treatment in transplant-eligible, newly diagnosed multiple myeloma: a phase 2 trial. Nat Med (2026). https://doi.org/10.1038/s41591-026-04471-x

A Phase I Trial of Iopofosine I 131 and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma — Cancers (June 2026)

What is the purpose of the study? 
This phase 1 dose-escalation study evaluates the safety, tolerability, and dose schedules of iopofosine I 131 combined with low-dose dexamethasone (DEX) in patients with heavily pretreated relapsed/refractory multiple myeloma (RRMM). The study aims to identify maximum tolerated doses and determine a dose and schedule for future phase 2 evaluation.

Summary 
Patients with heavily pretreated RRMM received either single-dose or fractionated-dose iopofosine I 131 plus low-dose dexamethasone. The most common adverse events were hematologic toxicities, including thrombocytopenia (93.5%), lymphopenia (74.2%), anemia (71.0%), leukopenia (61.3%), and neutropenia (58.1%); all patients experiencing hematologic adverse events recovered, with a median recovery time of 21 days after nadir. Among 26 patients evaluable through 85 days after the first infusion, 22 (84.6%) achieved stable disease and 4 (15.4%) achieved a partial response. Exploratory analyses reported an overall response rate of 15.4% in the overall population, a 30% overall response rate in patients receiving ≥60 mCi total administered activity, and a clinical benefit rate of 100%. The maximum tolerated dose was 31.25 mCi/m² in the single-dose group and 20 mCi/m² × 2 doses in the fractionated-dose group.

Key points

Study population 
• Patients had heavily pretreated RRMM with limited treatment options. 
• Treatment consisted of iopofosine I 131 plus low-dose dexamethasone. 
• Both single-dose and fractionated-dose schedules were evaluated.

Safety and tolerability 
• Most common adverse events were hematologic: 
 - Thrombocytopenia: 93.5% 
 - Lymphopenia: 74.2% 
 - Anemia: 71.0% 
 - Leukopenia: 61.3% 
 - Neutropenia: 58.1%

• All patients with hematologic adverse events recovered, with a median recovery time of 21 days post-nadir. 
• Platelet, neutrophil, white blood cell, and lymphocyte count nadirs occurred between 15 and 43 days after infusion. 
• Nonhematologic adverse events were predominantly Grade 1–2. 
• Dose-limiting toxicities included: 
 - Four Grade 4 thrombocytopenia events lasting longer than 7 days 
 - One Grade 4 neutropenia event 
 - One Grade 3 insomnia event

• No infusion-site reactions were reported. 
• No infusions were discontinued because of adverse events. 
• No new safety signals were observed compared with previous studies of iopofosine. 
• No apparent effects on renal or liver function were reported. 
• The study reported no correlation between total administered dose (<60 mCi vs ≥60 mCi) and the severity or timing of cytopenias.

Dose findings 
• Maximum tolerated dose (single-dose schedule): 31.25 mCi/m² 
• Maximum tolerated dose (fractionated-dose schedule): 20 mCi/m² × 2 doses 
• Analysis of total administered activity suggested that clinical responses emerged at approximately 60 mCi total administered dose. 
• Based on safety, tolerability, and observed activity, the recommended phase 2 regimen was: 
 - 15 mCi/m² on Days 1 and 7 
 - Weekly oral dexamethasone 40 mg for up to 12 weeks

Clinical activity 
• Among 26 evaluable patients monitored through 85 days after the first infusion: 
 - 84.6% (22/26) achieved stable disease (SD) 
 - 15.4% (4/26) achieved a partial response (PR)

• Partial responses were observed in the highest single-dose cohort and in higher-dose fractionated cohorts. 
• In a post hoc exploratory analysis of total administered activity: 
 - The overall response rate (ORR) was 15.4% in the overall study population. 
 - The ORR was 30% in the ≥60 mCi cohort. 
 - The clinical benefit rate (CBR) was 100% in the overall study population.

• The contribution of low-dose dexamethasone to the observed clinical responses could not be determined from this study.

Strengths  
• Evaluation of both single-dose and fractionated-dose schedules. 
• Identification of maximum tolerated doses and a recommended phase 2 regimen. 
• Consistent biodistribution, target uptake, and retention characteristics were reported in available dosimetry analyses. 
• Safety, tolerability, and preliminary clinical activity were evaluated in a heavily pretreated RRMM population.

Limitations  
• The study was primarily designed to assess safety and tolerability, limiting conclusions regarding efficacy. 
• The contribution of low-dose dexamethasone to observed responses was unclear. 
• The study required prolonged enrollment because of protocol-mandated observation periods and limited participating sites. 
• Approval of new RRMM therapies during the enrollment period may have affected recruitment and treatment selection. 
• The prolonged enrollment period may have resulted in enrollment of patients with more advanced disease and heterogeneous prior treatment histories. 
• Additional studies are needed to determine the optimal dose, schedule, regimen, and potential combination approaches.

Why this study matters 
In this phase 1 study of heavily pretreated patients with RRMM, iopofosine I 131 plus low-dose dexamethasone demonstrated a safety profile characterized primarily by transient hematologic toxicities that recovered over time, with predominantly low-grade nonhematologic adverse events. The study established maximum tolerated doses for both single-dose and fractionated-dose schedules and observed stable disease in 84.6% of evaluable patients and partial responses in 15.4%, with exploratory analyses reporting a 30% overall response rate in patients receiving ≥60 mCi total administered activity. Because the trial was designed primarily to assess safety and tolerability, efficacy findings should be interpreted within the context of its phase 1 design and exploratory analyses.

Reference: 
Ailawadhi, S., Peterson, J. L., Oliver, K., Longcor, J., & Callander, N. (2026). A Phase I Trial of Iopofosine I 131 and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma. Cancers, 18(13), 2044. https://doi.org/10.3390/cancers18132044

Response profile and long-term outcomes in Cyclin D1-overexpressing multiple myeloma: insights from the CASSIOPEIA trial — Blood Cancer Journal (July 2026)

What is the purpose of the study? 
To analyze long-term data from the phase 3 CASSIOPEIA trial to evaluate the clinical significance of cyclin D1 (CCND1) overexpression, analyzed as an imperfect surrogate marker for the t(11;14) translocation, in patients with multiple myeloma (MM). It assesses the association of CCND1 overexpression with minimal residual disease (MRD) negativity rates and long-term outcomes, including progression-free survival (PFS) and overall survival (OS).

Summary  
RNA sequencing analysis of samples from 589 patients in the phase 3 CASSIOPEIA trial identified a CCND1 overexpression signature in 164 patients (27.8%), which was considered a surrogate marker for t(11;14) but is not a perfect representation of the translocation. Patients with the CCND1 signature had lower MRD negativity rates after induction (20.9% vs. 50.8%; p<0.0001) and after transplant and consolidation (59.1% vs. 78.2%; p<0.0001) compared with patients without the signature. Despite these differences, PFS and OS were similar between groups over a median follow-up of more than 7 years, and findings were consistent across treatment groups, including VTD or D-VTD induction followed by daratumumab maintenance or observation.

Key points 
• The analysis used data from the phase 3 CASSIOPEIA trial with a median follow-up of more than 7 years. 
• RNA sequencing identified a CCND1 overexpression signature in 164 of 589 patients (27.8%). 
• The CCND1 overexpression signature was analyzed as a surrogate marker for t(11;14), although the authors stated that it is not a perfect surrogate for the presence of the translocation. 
• MRD negativity after induction was: 
 - 20.9% in patients with the CCND1 signature 
 - 50.8% in patients without the CCND1 signature (p<0.0001) 
• MRD negativity after transplant and consolidation was: 
 - 59.1% in patients with the CCND1 signature 
 - 78.2% in patients without the CCND1 signature (p<0.0001)

• Progression-free survival (PFS) and overall survival (OS) were similar between patients with and without the CCND1 signature. 
• Results were consistent across randomized treatment groups: 
 - VTD or D-VTD induction in the first randomization 
 - Daratumumab maintenance or observation in the second randomization

Strengths  
• Analysis was based on data from the large phase 3 CASSIOPEIA trial. 
• Median follow-up exceeded 7 years, allowing assessment of long-term outcomes.

Limitations  
• The t(11;14) translocation was not systematically assessed in the CASSIOPEIA trial. 
• The CCND1 overexpression signature is not a perfect surrogate for the presence of t(11;14).

Why this analysis matters 
In this analysis of the CASSIOPEIA trial, patients with CCND1 overexpression, analyzed as a surrogate for t(11;14), had significantly lower MRD negativity rates after induction and after transplant/consolidation compared with patients without the signature. However, these differences were not associated with differences in long-term PFS or OS during more than 7 years of follow-up, with results consistent across treatment groups. The findings indicate that MRD assessment and genetic characterization provide complementary information in MM.

Reference: 
Perrot, A., Touzeau, C., Minvielle, S. et al. Response profile and long-term outcomes in Cyclin D1-overexpressing multiple myeloma: insights from the CASSIOPEIA trial. Blood Cancer J. 16, 110 (2026). https://doi.org/10.1038/s41408-026-01542-7 

Committee for Medicinal Products for Human Use — European Medicines Agency 

CHMP-EMA issues positive opinion on teclistamab for relapsed/refractory myeloma,with new indications and changes to marketing authorization

On Thursday, June 25, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) “adopted a positive opinion recommending a change to the terms of marketing authorization for the medicinal product, Tecvayli (teclistamab),” according to the EMA website.

New and full indications adopted by the CHMP for Tecvayli (teclistamab) include:  

1. Teclistamab “in combination with daratumumab for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least one prior therapy.”  
2. Teclistamab “as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody and have demonstrated disease progression on the last therapy.”

The CHMP’s recommendation is supported by “unprecedented Phase 3 data” from the MajesTEC-3 trial, “demonstrating that Tecvayli in combination with [subcutaneous] daratumumab achieved statistically significant improvements in progression-free and overall survival versus standard of care,” according to Johnson & Johnson.

The Phase 3 MajesTEC-3 trial, with nearly three years of follow-up, showed that teclistamab plus daratumumab SC reduced the risk of disease progression or death by 83.4% compared with standard of care (HR, 0.17; 95% CI, 0.12–0.23; p<0.0001) and improved overall survival (HR, 0.46; 95% CI, 0.32–0.65; p<0.0001), with benefits seen across all prespecified patient subgroups.  

At three years, overall survival was 83.3% with the combination versus 65.0% with standard of care, and more than 90% of patients who were progression-free at six months remained progression-free at three years, indicating durable disease control.

According to the CHMP, “detailed recommendations for the use of this product will be described in the updated summary of product characteristics (SmPC), which will be published on the EMA website in all official European Union languages after a decision on this change to the marketing authorization has been granted by the European Commission.”

References:

Tecvayli – opinion on variation to marketing authorization. European Medicines Agency. June 25, 2026.

CHMP recommendation advances Johnson & Johnson’s TECVAYLI®▼ (teclistamab) plus daratumumab as a potential standard of care for relapsed/refractory multiple myeloma. Johnson & Johnson press release. June 26, 2026. 

U.S. Food and Drug Administration

FDA approves subcutaneous isatuximab for myeloma treatment settings

On Thursday, July 9, the U.S. Food and Drug Administration (FDA) approved subcutaneous (SC) isatuximab-irfc for myeloma indications. It can be administered using the CirCLIQ on-body delivery system (OBDS/on-body injector) or by manual SC administration with a syringe and infusion set.  

SC isatuximab is the first anticancer treatment in the U.S. approved for administration through an on-body injector, and the first myeloma treatment available both through on-body injector and manual SC administration.

The FDA approved SC isatuximab-irfc for adult patients with MM in these treatment settings:

1. In combination with pomalidomide and dexamethasone (SC-Pd): for patients who have received at least one prior line of therapy, including lenalidomide and a proteasome inhibitor.  

2. In combination with carfilzomib and dexamethasone (SC-Kd): for patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy.  

3. In combination with bortezomib, lenalidomide and dexamethasone (SC-VRd): for patients with newly diagnosed multiple myeloma who are not eligible for an autologous stem cell transplant (ASCT).

The FDA approval was supported by clinical studies, showing high overall response rates (ORR) across the approved treatment combinations: the IRAKLIA study (ORR - 71.1% with SC isatuximab-irfc and 70.5% with IV isatuximab-irfc, demonstrating non-inferior efficacy); the IZALCO study (ORR – 79.7%); and the IsaSocut study (ORR – 97.3%).

The FDA-recommended dose for isatuximab is 1,400 mg, administered as SC injection using either the CirCLIQ on-body delivery system (OBDS) or manual administration with a syringe and infusion set, in combination with the approved treatment regimen.

The most common adverse reactions (≥20%) were upper respiratory tract infection, fatigue, pneumonia, musculoskeletal pain, and diarrhea.

The most common hematology laboratory abnormalities (≥40%) were decreased leukocytes, decreased neutrophils, decreased lymphocytes, decreased platelets, and decreased hemoglobin.

The FDA prescribing information also includes warnings and precautions for hypersensitivity reactions, other administration reactions, neutropenia, infections, secondary primary malignancies, laboratory test interference, and embryo-fetal toxicity.

References:

FDA approves isatuximab-irfc for subcutaneous injection for multiple myeloma indications. U.S. Food and Drug Administration news release. July 9, 2026.

Sanofi’s subcutaneous Sarclisa Escena approved in the US as first anticancer treatment administered via on-body injector. Sanofi press release. July 10, 2026.

FDA accepts new drug application for mezigdomide in combination with carfilzomib and dexamethasone (MeziKd) for patients with relapsed/refractory myeloma

On Monday, July 13, the U.S. Food and Drug Administration (FDA) accepted Bristol Myers Squibb's (BMS) New Drug Application (NDA) for mezigdomide in combination with carfilzomib and dexamethasone (MeziKd) to treat adults with relapsed or refractory multiple myeloma (RRMM).  

Mezigdomide is an investigational oral cereblon E3 ligase modulator (CELMoD) designed to promote degradation of the Ikaros and Aiolos proteins, increasing multiple myeloma cell death and stimulating immune activity.

The FDA has set May 13, 2027, as the Prescription Drug User Fee Act (PDUFA) target action date for the MeziKd NDA.

According to a press release from BMS, the application is supported by results from the Phase III SUCCESSOR-2 trial, which showed that MeziKd significantly improved progression-free survival (PFS) compared with carfilzomib and dexamethasone (Kd) alone. Median PFS was 18.0 months with MeziKd versus 8.3 months with Kd (hazard ratio 0.48; p<0.0001), corresponding to a 52% reduction in the risk of disease progression or death.

The benefit was observed in patients with RRMM, including those receiving treatment at first relapse after prior therapy with an anti-CD38 monoclonal antibody and lenalidomide. Investigators reported that the safety profile of the MeziKd regimen was consistent with previous studies of mezigdomide and with the known safety profiles of the individual drugs.

The SUCCESSOR-2 trial findings were presented as a late-breaking oral presentation at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting and were also published in The Lancet.

Mezigdomide is also being evaluated in the ongoing Phase 3 SUCCESSOR-1 trial in RRMM.

References:

U.S. Food and Drug Administration Accepts Bristol Myers Squibb's New Drug Application for Mezigdomide in Patients with Relapsed or Refractory Multiple Myeloma. BMS press release. July 13, 2026.

Dimopoulos MA, Schjesvold F, Fu C, et al. Mezigdomide, carfilzomib, and dexamethasone versus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma (SUCCESSOR-2): a phase 3, open-label, randomised controlled trial. Lancet. 2026 Jun 14:S0140-6736(26)01088-3. doi: 10.1016/S0140-6736(26)01088-3. 

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