At the end of every month, the International Myeloma Foundation Newsroom will feature a wrap-up of some of the most fascinating studies about multiple myeloma from medical journals. Here is the November 2024 edition.

The IMF team of medical editors has provided overviews of key studies. Yet, we encourage you to visit the actual articles in the journals for full details and to increase your understanding. Check the IMF Newsroom monthly for updates like this one.

In the Journals (Key Myeloma Research in November 2024) 

"Comparison of Time to Next Treatment or Death Between Front-Line Daratumumab, Lenalidomide, and Dexamethasone (DRd) Versus Bortezomib, Lenalidomide, and Dexamethasone (VRd) Among Transplant-Ineligible Patients With Multiple Myeloma"

Source

Hansen, D., Gautam, S., Lafeuille, M.-H., Rossi, C., Moore, B., Tardif-Samson, A., Thompson-Leduc, P., Fu, A., Cortoos, A., Kaila, S. and Fonseca, R. (2024), Comparison of Time to Next Treatment or Death Between Front-Line Daratumumab, Lenalidomide, and Dexamethasone (DRd) Versus Bortezomib, Lenalidomide, and Dexamethasone (VRd) Among Transplant-Ineligible Patients With Multiple Myeloma. Cancer Med, 13: e70308. https://doi.org/10.1002/cam4.70308  November 1, 2024. 

Overview

A study compared the effectiveness of two first-line treatments for transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM): daratumumab, lenalidomide, and dexamethasone (DRd) versus bortezomib, lenalidomide, and dexamethasone (VRd). Researchers analyzed real-world data from 2018 to 2023, focusing on time-to-next-treatment (TTNT) or death. After adjusting for patient differences, the median TTNT or death was 37.8 months for DRd and 18.7 months for VRd.  

The findings showed that DRd reduced the risk of needing a new treatment or death by 42% compared to VRd. This significant difference highlights DRd as a more effective first-line option for TIE NDMM patients, offering longer-lasting disease control.  

 

 

"Early minimal residual disease eradication in light chain amyloidosis generates deeper and faster cardiac response"

Source

Xu, T., Li, J., Yang, Y. et al. Early minimal residual disease eradication in light chain amyloidosis generates deeper and faster cardiac response. Clin Exp Med 24, 250 (2024). https://doi.org/10.1007/s10238-024-01511-z  November 1, 2024.

Overview

Minimal residual disease (MRD) is becoming an important marker in light chain (AL) amyloidosis, particularly in patients with heart involvement. A study of 63 patients treated with first-line proteasome inhibitors (mostly bortezomib) assessed MRD status within the first four treatment cycles using next-generation flow cytometry. Overall, 33.3% of patients achieved early MRD negativity. These patients were less likely to have the t(11;14) genetic abnormality and were more likely to achieve deeper hematologic and cardiac responses compared to MRD-positive patients.  

Patients with early MRD negativity were significantly more likely to experience substantial cardiac improvement, with higher rates of partial cardiac response (66.7% vs. 38.1%) and very good partial cardiac response (38.1% vs. 11.9%). They also had better progression-free survival, with a median that was not reached compared to 31.3 months in the MRD-positive group. These findings highlight that achieving MRD negativity early in treatment leads to faster and more robust cardiac recovery in patients with cardiac AL amyloidosis.  

 

 

"The FGF/FGFR/c-Myc axis as a promising therapeutic target in multiple myeloma"

Source

Giacomini, A., Taranto, S., Gazzaroli, G. et al. The FGF/FGFR/c-Myc axis as a promising therapeutic target in multiple myeloma. J Exp Clin Cancer Res 43, 294 (2024). https://doi.org/10.1186/s13046-024-03217-2 November 1, 2024. 

About 67% of multiple myeloma (MM) cases involve abnormal activity of the c-Myc protein, a key driver of cancer growth that has been difficult to target directly. Research has shown that fibroblast growth factor (FGF) signaling helps MM cells resist oxidative stress and stabilize c-Myc. Additionally, MM cells often secrete FGF ligands and activate FGF receptors (FGFRs), with FGFR3 alterations occurring in 15–20% of cases and linked to worse outcomes.  

Blocking the FGF/FGFR pathway may offer a way to indirectly target c-Myc in MM. This review highlights how the FGF/FGFR system influences c-Myc and supports the use of FGFR inhibitors, such as Pemigatinib, Futibatinib, and Erdafitinib, which are FDA-approved for other cancers. These drugs could be promising treatments for MM patients with abnormal FGF/FGFR activity, providing a new strategy against this challenging disease.  

 

 

 

"The challenge of oral therapies in patients over 75 years of age with multiple myeloma: a narrative literature review"

Source

Chloé Denis, Valérie Loizeau. The challenge of oral therapies in patients over 75 years of age with multiple myeloma: a narrative literature review. International Francophone Journal of Nursing Research. https://doi.org/10.1016/j.refiri.2024.100354. November 1, 2024. 

Multiple myeloma has seen increased use of oral anticancer therapies, which simplify treatment but also require long-term management. In France, advanced practice nurses (IPAs) are emerging as key players in supporting these patients. This narrative review of 20 studies explored factors that enhance the safe monitoring and management of patients on oral antineoplastic therapies, focusing on the challenges faced by elderly patients and the critical role of nursing care.  

The findings highlight that IPAs play an essential role in improving patient safety by addressing issues like medication adherence and side effect management. By coordinating care between hospitals and community settings, IPAs strengthen the overall care pathway for patients on oral cancer therapies. This collaborative approach ensures better outcomes for patients navigating the complexities of long-term treatment.  

 

 

 

"Representativeness of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) trial participants"

Source

Manmeet Kaur, Mary M Horowitz, Adam Mendizabal, Min Chen, Amy Foley, Jeffery J Auletta, Steven Devine, Anita D'Souza, Representativeness of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) trial participants, Transplantation and Cellular Therapy, 2024, ISSN 2666-6367, https://doi.org/10.1016/j.jtct.2024.10.014. November 1, 2024. 

Racial and ethnic minorities remain underrepresented in oncology clinical trials, including those involving hematopoietic cell transplantation (HCT). This study analyzed enrollment data from five Blood and Marrow Transplant Clinical Trials Network (BMT CTN) trials conducted from 2014 to 2020. The trials focused on conditions such as multiple myeloma, graft-versus-host disease (GVHD), and post-HCT maintenance therapy for FLT3+ acute myelogenous leukemia. Comparing trial participants to data from the SEER and CIBMTR databases revealed a significant drop in minority representation, especially between the general population and patients who received transplants. However, trials allowing alternate donor sources showed smaller declines, suggesting these options may improve trial access.  

The study found no disparities in trial enrollment by age or sex among HCT recipients, but the underrepresentation of minorities was linked to limited access to HCT itself. Expanding donor availability and improving outreach to underserved populations are critical steps to increase trial participation for minority groups. These changes are essential for ensuring equity in access to both HCT and clinical trials.  

 

 

 

"Bortezomib-based regimen affects cognitive functions in multiple myeloma patients through the VEGF pathway – Hypothesis that connects different knowledge streams"

Source

Marija Stanić Damić, Toni Valković, Duška Petranović, Andrej Belančić, Zinaida Perić, Bortezomib-based regimen affects cognitive functions in multiple myeloma patients through the VEGF pathway – Hypothesis that connects different knowledge streams, Medical Hypotheses, 2024,111510, ISSN 0306-9877, https://doi.org/10.1016/j.mehy.2024.111510. November 2, 2024. 

Multiple myeloma is associated with cancer-related cognitive impairment, which greatly impacts daily life. However, the causes of this impairment remain unclear. Bortezomib, a common treatment for multiple myeloma, cannot cross the blood–brain barrier but may still affect the central nervous system through unknown pathways. Researchers suggest that bortezomib could impair cognitive function by reducing levels of vascular endothelial growth factor (VEGF), a cytokine that protects brain health.  

Understanding how bortezomib affects cognition could lead to better care for multiple myeloma patients. VEGF may serve as a biomarker to identify cognitive dysfunction, and systematic cognitive assessments could help detect impairment early. This could guide treatment choices and enable preventive measures to protect cognitive function, ultimately improving patients’ quality of life. Future studies on this topic could advance both the understanding and management of cognitive challenges in multiple myeloma care.  

 

 

 

"Is obesity a cause of all cancer types?"

Source

Marc J. Gunter, Amy Berrington de Gonzalez, Is obesity a cause of all cancer types?, The Lancet Regional Health - Europe, Volume 46,2024, 101110, ISSN 2666-7762, https://doi.org/10.1016/j.lanepe.2024.101110. November 2024. 

Obesity, affecting over 1 billion people worldwide, is recognized as a major risk factor for several cancers. A new study by Sun et al., published in *The Lancet Regional Health Europe*, analyzed data from over 4 million people in Sweden to explore the link between body mass index (BMI) and cancer risk. The study confirmed obesity’s connection to 13 previously established cancers, such as breast, colorectal, and liver cancers, and identified 18 additional cancers potentially linked to obesity. These include head and neck cancers, B-cell lymphoma, small intestinal cancer, melanoma, and various genital and endocrine cancers. The findings highlight obesity’s far-reaching effects on cancer risk, showing consistent patterns between men and women for many of these cancers.  

While the study’s size and scope are unprecedented, it does have limitations, such as incomplete data on smoking and other confounding factors. Still, the results suggest that obesity might act as a "universal carcinogen," influencing cancer risk across many tissues through mechanisms like chronic inflammation and altered cell processes. The researchers emphasize the importance of public health strategies to combat obesity, which could reduce the incidence of multiple cancers. Future studies will aim to uncover the biological pathways linking obesity to cancer, paving the way for targeted prevention and treatments.  

 

 

"Molecular mechanisms promoting long-term cytopenia after BCMA CAR-T therapy in multiple myeloma"

Source

Alignani, Patxi San Martin-Uriz, Amaia Vilas-Zornoza, Saray Rodriguez-Diaz, Susana Inoges, Ascensión Lopez-Diaz de Cerio, Sofia Huerga, Esteban Tamariz, Jose Rifon, Ana Alfonso-Pierola, Juan Jose Lasarte, Bruno Paiva, Mikel Hernaez, Paula Rodriguez-Otero, Jesus San-Miguel, Teresa Ezponda, Juan Roberto Rodriguez-Madoz, Felipe Prosper; Molecular mechanisms promoting long-term cytopenia after BCMA CAR-T therapy in multiple myeloma. Blood Adv 2024; 8 (21): 5479–5492. doi: https://doi.org/10.1182/bloodadvances.2023012522  November 12, 2024.

Hematologic toxicity, or damage to blood cell production, is a common and severe side effect of CAR-T cell therapy in patients with relapsed or refractory multiple myeloma (MM). A study of 48 patients treated with BCMA-targeted CAR-T cells found that nearly all (95.7%) experienced cytopenia, a drop in blood cell counts. Severe cases of thrombocytopenia (low platelets) and neutropenia (low neutrophils) occurred in 57% and 53% of patients, respectively, one month after treatment. For a small subset, these conditions persisted for over a year. Baseline low blood counts and high inflammatory markers were strongly linked to prolonged cytopenia.  

To uncover the mechanisms behind these toxicities, researchers studied how CAR-T cells affect hematopoietic stem and progenitor cells (HSPCs), which generate blood cells. They found that substances released by activated CAR-T cells disrupted HSPC maturation, keeping the cells in an immature state. This effect was linked to specific inflammatory signals but could be reversed using inhibitors targeting molecules like IL-6, IL-17, and interferon γ. Further analysis using single-cell RNA sequencing revealed altered gene activity in pathways critical for blood cell development. These findings point to potential treatments to reduce blood cell toxicities and improve outcomes for CAR-T therapy patients.

 

 

"Management of complications of chimeric antigen receptor T-cell therapy: a report by the European Society of Blood and Marrow Transplantation"

Source

Penack O, Peczynski C, Boreland W, Wolff D, Moiseev I, Schoemans H, Koenecke C, Graham C, Peric Z. Management of complications of chimeric antigen receptor T-cell therapy: a report by the European Society of Blood and Marrow Transplantation. Haematologica 2024;109(11):3557-3565; https://doi.org/10.3324/haematol.2023.284810.  November 2024. 

CAR T-cell therapy is a standard treatment for relapsed or refractory blood cancers like non-Hodgkin lymphoma, multiple myeloma, and acute lymphoblastic leukemia. However, due to the rapid advancements in the field and the lack of standardized treatment guidelines, European centers vary widely in how they manage both short- and long-term complications of CAR T-cell therapy.  

A survey conducted by the European Society for Blood and Marrow Transplantation (EBMT) collected responses from 106 CAR T-cell centers (47% of those surveyed). Questions focused on product selection, logistics, and the management of complications such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), prolonged cytopenias, and post-treatment care.  

While some common approaches were identified, the survey revealed significant differences in key areas, such as treating severe or steroid-resistant CRS and ICANS, managing cytopenias, deciding on early discharge and outpatient care, and providing immunoglobulin substitution. These findings highlight the urgent need for standardized treatment guidelines and further clinical research to improve patient outcomes and harmonize care across centers.

 

 

"LILRB4 represents a promising target for immunotherapy by dual targeting tumor cells and myeloid-derived suppressive cells in multiple myeloma"

Source

Gong L, Sun H, Liu L, Sun X, Fang T, Yu Z, Sui W, Xu J, Wang T, Feng F, Lei L, Rui W, Liu Y, Zhao X, An G, Lin X, Qiu L, Hao M. LILRB4 represents a promising target for immunotherapy by dual targeting tumor cells and myeloid-derived suppressive cells in multiple myeloma. Haematologica 2024;109(11):3650-3669; https://doi.org/10.3324/haematol.2024.285099.  November 2024. 

CAR T-cell therapy is a standard treatment for relapsed or refractory blood cancers like non-Hodgkin lymphoma, multiple myeloma, and acute lymphoblastic leukemia. However, due to the rapid advancements in the field and the lack of standardized treatment guidelines, European centers vary widely in how they manage both short- and long-term complications of CAR T-cell therapy.  

A survey conducted by the European Society for Blood and Marrow Transplantation (EBMT) collected responses from 106 CAR T-cell centers (47% of those surveyed). Questions focused on product selection, logistics, and the management of complications such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), prolonged cytopenias, and post-treatment care.  

While some common approaches were identified, the survey revealed significant differences in key areas, such as treating severe or steroid-resistant CRS and ICANS, managing cytopenias, deciding on early discharge and outpatient care, and providing immunoglobulin substitution. These findings highlight the urgent need for standardized treatment guidelines and further clinical research to improve patient outcomes and harmonize care across centers.

 

 

"Soluble B-cell maturation antigen in lacrimal fluid as a potential biomarker and mediator of keratopathy in multiple myeloma"

Source

Munawar U, Theuersbacher J, Steinhardt MJ, Zhou X, Han S, Nerreter S, Vogt C, Kurian S, Keller T, Regensburger A-K, Teufel E, Mersi J, Bittrich M, Seifert F, Haider MS, Rasche L, Hillenkamp J, Einsele H, Kampik D, Kortüm KM, Waldschmidt JM. Soluble B-cell maturation antigen in lacrimal fluid as a potential biomarker and mediator of keratopathy in multiple myeloma. Haematologica 2024;109(11):3670-3680; https://doi.org/10.3324/haematol.2024.285205.  November 2024. 

Belantamab mafodotin (belantamab) is an innovative treatment for triple-class refractory multiple myeloma. It is an antibody-drug conjugate targeting B-cell maturation antigen (BCMA) and offers a valuable option for patients not eligible for CAR T-cell or bispecific antibody therapies. It is also used when patients progress on anti-CD38 treatments while reserving other advanced therapies.  

However, belantamab's use is limited by its unique ocular side effects, such as corneal microcysts and keratopathy. While lowering the dose helps reduce these side effects, their exact cause is not fully understood.  

This study reveals new insights into belantamab’s side effects. Researchers discovered soluble BCMA (sBCMA) in tear fluid, which correlates with tumor burden in patients. Although corneal cells do not express BCMA, sBCMA-bound belantamab may be absorbed by corneal cells through pinocytosis (a process where cells "drink" fluid from their surroundings). Blocking pinocytosis in lab experiments significantly reduced cell damage caused by belantamab.  

Patient profiles showed a delayed release of sBCMA into tear fluid after treatment, followed by keratopathy symptoms. Based on this mechanism, strategies to reduce sBCMA in tear fluid could prevent these side effects. Possible approaches include using other therapies to lower tumor burden before starting belantamab or combining belantamab with γ-secretase inhibitors, which are being tested in ongoing studies.  

These findings pave the way for improving the safety and effectiveness of belantamab for multiple myeloma patients.

 

 

"Superior outcomes and high-risk features with carfilzomib, lenalidomide, and dexamethasone combination therapy for patients with relapsed and refractory multiple myeloma: results of the multicenter KMMWP2201 study"

Source

Lee JH, Choi J, Min C-K, Park S-S, Jo J-C, Lee YJ, Kim JS, Eom H-S, Jung J, Moon JH, Cho HJ, Lee M- won, Yoon S-S, Byun JM, Lee JH, Lee J-J, Jung S-H, Shin H-J, Kim DY, Yi JH, Lee S-S, Do YR, Yoon DH, Cho H, Lee WS, Lee HS, Uhm J, Kim HJ, Jang HR, Kim S-H, Kim K. Superior outcomes and high-risk features with carfilzomib, lenalidomide, and dexamethasone combination therapy for patients with relapsed and refractory multiple myeloma: results of the multicenter KMMWP2201 study. Haematologica 2024;109(11):3681-3692; https://doi.org/10.3324/haematol.2024.285534.  November 2024. 

The combination of carfilzomib, lenalidomide, and dexamethasone (KRd) is a well-established treatment for relapsed and/or refractory multiple myeloma (RRMM), but evidence on its use in Asian populations has been limited. This retrospective study analyzed 364 RRMM patients treated with KRd across 21 centers between 2018 and 2020. The overall response rate was 90%, with 69% achieving a very good partial response or better. Median progression-free survival (PFS) was 23.4 months, and overall survival (OS) was 59.5 months, based on a median follow-up of 34.8 months.

High-risk cytogenetics, extramedullary disease, and rapid doubling of monoclonal protein before KRd were linked to worse PFS and OS. Patients who underwent delayed stem cell transplantation after KRd achieved longer survival. Grade 3 or higher side effects occurred in 56% of patients, with 9% discontinuing treatment due to adverse events. Cardiovascular toxicity was consistent with previous studies.

This study highlights the effectiveness of KRd in Asian patients with RRMM and provides valuable data to guide treatment strategies. The findings emphasize the importance of managing high-risk factors and considering stem cell transplantation to improve outcomes.

 

 

"Multiple myeloma in the young: insights on prognosis, clinical features and treatment outcome derived from nationwide German registry data and a nested multicenter sample"

Source

Kamili A, Ahmadi P, Leypoldt L, Marquard F, Schaefers C, Kosch R, Peters F, Kusche H, Zamrik T, Hanoun C, Seib M, Shumilov E, Leitner T, Khandanpour C, Bokemeyer C, Weisel K, Ghandili S. Multiple myeloma in the young: insights on prognosis, clinical features and treatment outcome derived from nationwide German registry data and a nested multicenter sample. Haematologica 2024;109(11):3795-3799; https://doi.org/10.3324/haematol.2024.285630. November 2024. 

Multiple myeloma (MM) is rare in patients under 40, accounting for less than 1% of cases. A study using data from Germany found that younger patients (≤40 years) had better survival outcomes than those aged 41–65. Five-year survival rates were 83% for younger patients compared to 64% for older ones, while 10-year survival was 69% versus 43%. Median survival for younger patients was 18.4 years, with females generally living longer than males.  

Clinically, young MM patients displayed unique features. They were more likely to have favorable ISS stage I at diagnosis (43%) but also experienced higher rates of extramedullary disease (38%) and extraosseous involvement. High-risk genetic markers, like **del(17p)** and **1q amplification**, were common, although their frequency differed from the general MM population.  

Most young patients received high-dose melphalan therapy with autologous stem cell transplantation (SCT), achieving a 90% response rate. About 30% also underwent allogeneic SCT, though this practice has declined with the advent of newer therapies like daratumumab and BCMA-directed treatments. These findings highlight the need for more research to better understand the unique biology of MM in younger patients and guide personalized treatment strategies.

 

 

"ZNF655 involved in the progression of multiple myeloma via the activation of AKT"

Source

Kou, H., Jiang, S., Wu, X., Jing, C., Xu, X., Wang, J., Zhang, C., Liu, W., Gao, Y., Men, Q., Lu, P., & Lv, Z. (2024). ZNF655 involved in the progression of multiple myeloma via the activation of AKT. Cell Biology International, 1-11. https://doi.org/10.1002/cbin.12256  November 3, 2024.   

Multiple myeloma (MM) is a blood cancer that remains incurable, with cases rising each year. Zinc finger protein 655 (ZNF655), known for its role in various biological processes, may influence MM progression, though its exact role has been unclear.  

This study investigated the effects of reducing ZNF655 in MM cells. Researchers found that knocking down ZNF655 significantly slowed cancer cell growth, stopped cell division, and triggered cell death. Further analysis revealed that ZNF655 affects MM progression by activating the AKT signaling pathway.  

These findings suggest that targeting ZNF655 could be a potential strategy for treating MM. Reducing ZNF655 levels may help control the disease and improve outcomes for patients.

 

 

"Focusing on exosomes to overcome the existing bottlenecks of CAR-T cell therapy"

Source

Zhang, SH., Peng, LL., Chen, YF. et al. Focusing on exosomes to overcome the existing bottlenecks of CAR-T cell therapy. Inflamm Regener 44, 45 (2024). https://doi.org/10.1186/s41232-024-00358-x  November 4, 2024.   

CAR-T cell therapy has revolutionized treatment for CD19+ cancers and multiple myeloma, delivering impressive results. However, several challenges limit its broader use, including complex production, safety concerns with viral vectors, limited success against solid tumors, severe side effects, and the gradual loss of CAR-T cell function over time.  

Exosomes, tiny vesicles released by cells, may offer solutions to these challenges. Tumor-derived exosomes can impair CAR-T cell effectiveness, but blocking their secretion might improve therapy outcomes. Exosomes could also simplify CAR-T cell manufacturing by providing a safer, non-viral production method.  

Emerging research explores using exosomes to activate and expand CAR-T cells in the lab and to enhance their performance in the body. Engineered exosomes may also serve as a direct tool to kill cancer cells or deliver targeted treatments, potentially expanding the reach and effectiveness of CAR-T therapies.

 

 

"Novel Drug Combinations and Donor Lymphocyte Infusions Allow Prolonged Disease Control in Multiple Myeloma Patients Relapsing After Allogeneic Transplant"

Source

Chiara Nozzoli, Martina Pucillo, Luisa Giaccone, Alessandro Rambaldi, Maria Teresa Lupo Stanghellini, Edoardo Benedetti, Domenico Russo, Nicola Mordini, Silvia Mangiacavalli, Paolo Bernasconi, Matteo Parma, Paola Carluccio, Piero Galieni, Paolo Rivela, Massimo Martino, Patrizia Chiusolo, Miriam Isola, Maria De Martino, Elena Oldani, Eliana Degrandi, Riccardo Boncompagni, Elisabetta Antonioli, Fabrizio Carnevale, Monica Tozzi, Carmine Selleri, Renato Fanin, Francesca Patriarca, NOVEL DRUG COMBINATIONS AND DONOR LYMPHOCYTE INFUSIONS ALLOW PROLONGED DISEASE CONTROL IN MULTIPLE MYELOMA PATIENTS RELAPSING AFTER ALLOGENEIC TRANSPLANT: New treatments for Multiple Myeloma patients relapsing after Allo transplant, Transplantation and Cellular Therapy, 2024, ISSN 2666-6367, https://doi.org/10.1016/j.jtct.2024.10.015. November 4, 2024. 

Allogeneic stem cell transplantation (allo-SCT) can provide long-term survival for some multiple myeloma (MM) patients, even after relapse. This study analyzed 242 MM patients who underwent allo-SCT between 2009 and 2018 to identify factors predicting long-term outcomes and survival after relapse.  

The median overall survival (OS) for all patients was 39.4 months, with progression-free survival (PFS) at 19.0 months. Relapse occurred in 59% of patients at a median of 14.3 months after transplantation. Factors like older age, extensive prior treatments, and unrelated or haploidentical donors were linked to poorer outcomes.  

Among relapsed patients, those who relapsed later (after 6 months) and received at least three lines of salvage treatment, including donor lymphocyte infusions (DLI), showed better survival, with a median OS of 20.2 months from relapse. Patients transplanted earlier in their disease and with HLA-matched sibling donors had the best chance of long-term survival.  

This study highlights the importance of timing, donor matching, and aggressive salvage treatments in improving outcomes for MM patients post-allo-SCT.

 

 

"Fluctuation of physical function during chimeric antigen receptor T-cell therapy during rehabilitation intervention: Real-world data and risk factor analyses"

Source

Hamada R, Arai Y, Kitawaki T, Nakamura N, Murao M, Matsushita M, et al. Fluctuation of physical function during chimeric antigen receptor T-cell therapy during rehabilitation intervention: Real-world data and risk factor analyses. eJHaem. 2024; 1–8. https://doi.org/10.1002/jha2.1043  November 4, 2024. 

This study examined exercise tolerance in 77 patients undergoing CAR T-cell therapy who participated in rehabilitation programs. Using the 6-minute walking distance (6MWD) test to measure physical function, researchers found no significant changes in exercise capacity before and 30 days after therapy. The median 6MWD remained stable at around 450 meters.  

However, moderate to severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were linked to reduced exercise tolerance. Other factors, such as age, had little impact.  

The findings suggest that with proper rehabilitation, CAR T-cell therapy patients, including older adults, can maintain physical function. Addressing CRS and ICANS may further improve outcomes for these patients.

 

 

"Evaluation of the Prognostic Value of the Mayo Additive Staging System and Minimal Residual Disease in Newly Diagnosed Multiple Myeloma Patients"

Source

Song, Y., Zhao, R., Fu, W., Zhao, J., Wang, Q. and Zhang, R. (2024), Evaluation of the Prognostic Value of the Mayo Additive Staging System and Minimal Residual Disease in Newly Diagnosed Multiple Myeloma Patients. Cancer Med, 13: e70382. https://doi.org/10.1002/cam4.70382  November 4, 2024. 

This study evaluated the Mayo additive staging system (MASS) and minimal residual disease (MRD) as tools to predict outcomes in 238 newly diagnosed multiple myeloma (NDMM) patients. Researchers used fluorescence in-situ hybridization to assess cytogenetic abnormalities and next-generation flow cytometry to measure MRD.  

Patients were grouped by MASS stages (I, II, III) and MRD status: sustained MRD-negative (Group 1), non-sustained MRD-negative (Group 2), sustained MRD-positive (Group 3), and non-sustained MRD-positive (Group 4). Group 1 patients had the best progression-free survival (PFS), regardless of their MASS stage. High-risk patients (MASS III) with sustained MRD-negative status showed better outcomes than those with MRD-positive status.  

The study concludes that sustained MRD negativity significantly improves outcomes, even for high-risk patients, while the combination of high-risk factors and MRD positivity predicts poor survival. Treatment response was identified as a key independent factor influencing prognosis.  

 

 

"CAR T Cells and T-Cell Therapies for Cancer: A Translational Science Review"

Source

Brudno JN, Maus MV, Hinrichs CS. CAR T Cells and T-Cell Therapies for Cancer: A Translational Science Review. JAMA. Published online November 04, 2024. doi:10.1001/jama.2024.19462 November 4, 2024. 

CAR T-cell therapy is a breakthrough treatment where T cells are genetically modified to target and kill cancer cells. This approach has improved survival outcomes for patients with several blood cancers, including large B-cell lymphoma and multiple myeloma.  

Currently, six CAR T-cell therapies are FDA-approved for blood cancers such as acute lymphoblastic leukemia, large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, and multiple myeloma. For large B-cell lymphoma, CAR T-cell therapy increased 4-year overall survival rates to 54.6% compared to 46.0% with standard treatments. In multiple myeloma, it prolonged progression-free survival to 13.3 months compared to 4.4 months with conventional therapies. Pediatric acute lymphoblastic leukemia patients also achieved long-lasting remission after CAR T-cell therapy.  

While CAR T-cell therapy shows promise, it comes with risks such as cytokine release syndrome (40% to 95% of patients) and neurological side effects (15% to 65%). Research is ongoing to create new CAR T-cell therapies that are more effective, safer, and applicable to solid tumors. Although no CAR T-cell therapies are FDA-approved for solid cancers yet, other T-cell-based therapies are making progress in treating conditions like melanoma and sarcoma, despite challenges like capillary leak syndrome.  

Overall, CAR T-cell therapy represents a significant advance in cancer treatment, particularly for blood cancers, and offers hope for improved outcomes in solid tumors with continued innovation.

 

 

"Busulfan and cyclophosphamide for autologous stem cell transplantation in patients with multiple myeloma after proteasome inhibitor and/or immunomodulatory drug treatment"

Source

Jeon, M.J., Yu, E.S., Kim, D.S. et al. Busulfan and cyclophosphamide for autologous stem cell transplantation in patients with multiple myeloma after proteasome inhibitor and/or immunomodulatory drug treatment. Sci Rep 14, 26847 (2024). https://doi.org/10.1038/s41598-024-78350-1 November 5, 2024. 

High-dose melphalan (MEL-200) is the standard pre-transplant treatment for multiple myeloma (MM) patients undergoing autologous stem cell transplantation (ASCT). However, busulfan (BU) and cyclophosphamide (CY) are alternatives when melphalan isn’t available. This study compared the outcomes of MEL-200 and BU/CY in MM patients treated with proteasome inhibitors (PIs) and/or immunomodulatory drugs (IMIDs).  

A total of 137 patients were analyzed: 113 received MEL-200, and 24 received BU/CY. The BU/CY group had a higher percentage of patients achieving very good partial response (VGPR) or complete remission (CR) before and after ASCT, as well as more post-ASCT maintenance therapy. Median progression-free survival (PFS) was 29.7 months for MEL-200 and 46.8 months for BU/CY. Multivariate analysis showed better PFS with BU/CY. Factors like early-stage disease (Stage I) and achieving VGPR or CR before ASCT were linked to longer PFS.  

No deaths related to treatment occurred within 100 days post-transplant in either group. The results suggest BU/CY is a safe and effective alternative to MEL-200 for MM patients undergoing ASCT after PI and/or IMID therapy.  

 

 

"Disease Characteristics and Outcomes of 493 Young Myeloma Patients Treated With Modern Therapies: A Canadian Myeloma Research Group Database Study"

Source

Tanguay, M., Roy, J., Su, J., Gul, E., Reece, D., Venner, C., White, D., Chu, M., Jimenez-Zepada, V., Song, K., Mccurdy, A., Mian, H., Sebag, M., Bergstrom, D., Stakiw, J., Reiman, A., Kotb, R., Aslam, M., Kaedbey, R., Louzada, M. and LeBlanc, R. (2024), Disease Characteristics and Outcomes of 493 Young Myeloma Patients Treated With Modern Therapies: A Canadian Myeloma Research Group Database Study. Cancer Med, 13: e70332. https://doi.org/10.1002/cam4.70332 November 5, 2024. 

Young patients aged 50 or younger account for about 10% of multiple myeloma (MM) cases, but they are underrepresented in research. This study analyzed data from 493 such patients in the Canadian Myeloma Research Group database, excluding those with concurrent conditions like amyloidosis or POEMS syndrome. The median age was 46, and most patients (72.7%) had intermediate-risk disease (R-ISS II), with 24.1% showing high-risk cytogenetics. First-line treatments included proteasome inhibitors (89.9%), autologous stem cell transplants (ASCT) (92.1%), and maintenance therapy post-ASCT (65.6%).  

The median progression-free survival (PFS) was 45 months. Notably, patients who received maintenance therapy after ASCT had a significantly longer PFS (52.3 months) compared to those who did not (23.6 months). These findings highlight the importance of post-transplant maintenance therapy in extending remission. However, despite modern treatments, the study emphasizes the need for innovative therapies to achieve more durable responses, as the overall survival in this population has yet to be determined.  

This research underscores the unique challenges of treating young MM patients. While current therapies improve outcomes, the relatively short PFS signals an urgent need for treatments that provide deeper and longer-lasting disease control for this subset of patients.

 

 

"30-Minute infusion of isatuximab in patients with newly diagnosed multiple myeloma: Results of a Phase 1b study analysis"

Source

Ocio, E.M., Perrot, A., Moreau, P., Mateos, M.-V., Bringhen, S., Martínez-López, J., Karlin, L., Wang, S.-Y., Oprea, C., Li, Y., Kodas, E. and San-Miguel, J. (2024), 30-Minute infusion of isatuximab in patients with newly diagnosed multiple myeloma: Results of a Phase 1b study analysis. HemaSphere, 8: e70041. https://doi.org/10.1002/hem3.70041 November 5, 2024

This study explored the use of a faster infusion method for isatuximab (Isa), an anti-CD38 antibody used to treat multiple myeloma (MM). Traditionally infused over 75 minutes, Isa was administered in just 30 minutes to patients receiving maintenance therapy after long-term treatment. The faster method involved a 250 mL infusion bag delivered at increased flow rates. A total of 45 patients across different treatment groups participated, receiving 210 fast infusions. Results showed the 30-minute infusion was well-tolerated, with no increase in infusion reactions (IRs) or other safety concerns, and a median infusion time of 30 minutes was achieved after the first dose adjustment.  

The new infusion method proved safe and effective across cohorts, with common side effects like upper respiratory infections and diarrhea consistent with prior studies. Importantly, the shorter infusion reduced clinical visit times, offering patients greater convenience and improving hospital care efficiency. While the study focused on maintenance therapy, the 30-minute infusion is now being evaluated in earlier treatment phases and for other delivery methods, including subcutaneous administration. These findings suggest that faster infusions can enhance the patient experience without compromising safety or efficacy, benefiting both newly diagnosed and relapsed/refractory MM patients.

 

 

"LncRNA MALAT1 silencing represses CXCL12-induced proliferation, invasion, and homing behavior in multiple myeloma by inhibiting CXCR4"

Source

Ning, J., Yang, R., Wang, H., Ma, H., & Cui, L. (2024). LncRNA MALAT1 silencing represses CXCL12-induced proliferation, invasion, and homing behavior in multiple myeloma by inhibiting CXCR4. Hematology, 29(1). https://doi.org/10.1080/16078454.2024.2422154  November 6, 2024. 

This study investigated how the long non-coding RNA MALAT1 affects the ability of multiple myeloma (MM) cells to "home" or migrate to the bone marrow, a key factor in disease progression. Researchers analyzed bone marrow samples from MM patients and found that both MALAT1 and CXCR4, a receptor involved in cell migration, were overexpressed in plasma cells. These proteins were linked to increased bone damage. Lab experiments showed that MALAT1 boosted CXCR4 levels, leading to higher MM cell growth, survival, and invasion. When CXCR4 was silenced, these effects were reversed, including reductions in proteins like ICAM-1 and VLA-4 that help MM cells stick and migrate.

The study also demonstrated that CXCL12, a signaling molecule in the bone marrow, enhanced MM cell proliferation, invasion, and expression of homing-related proteins. However, silencing MALAT1 blocked these effects, indicating its role in supporting MM cell migration and bone marrow infiltration through CXCR4. The findings suggest that targeting MALAT1 could be a promising approach to limit MM progression by disrupting its ability to promote cell migration and invasion.

 

 

"Multi-omics reveal immune microenvironment alterations in multiple myeloma and its precursor stages"

Source

Cheng, Y., Sun, F., Alapat, D.V. et al. Multi-omics reveal immune microenvironment alterations in multiple myeloma and its precursor stages. Blood Cancer J. 14, 194 (2024). https://doi.org/10.1038/s41408-024-01172-x  November 6, 2024

This study explored how the immune environment in the bone marrow changes as multiple myeloma (MM) progresses, starting from the early stages of monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM) to newly diagnosed MM. Researchers used advanced techniques like single-cell RNA sequencing (scRNA-Seq) and mass cytometry (CyTOF) to analyze immune cells at different stages of the disease. They found that the number of granulocytes (a type of white blood cell) in the bone marrow decreases as MM progresses, and this decline was linked to worse survival outcomes. Granulocytes were also less effective in fighting infections, a common problem in MM patients. Enhancing granulocyte function might be a potential strategy to slow the progression of MM.

The study also showed that immune cells such as natural killer (NK) cells and CD8+ T cells became less effective in fighting the cancer as the disease advanced. These cells shifted to a less active state, with increased levels of inhibitory markers like TIM3, TIGIT, and PD1, which prevent them from attacking tumor cells. The researchers suggested that targeting these markers could restore the immune system’s ability to combat MM. Additionally, changes in the types of plasma cells in the bone marrow were observed, with certain subtypes of plasma cells being linked to faster disease progression. Specifically, the loss of a protein marker called CD56 was associated with more aggressive forms of MM, such as plasma cell leukemia.

The findings also included insights into gene expression patterns that could help predict when MM will progress. For example, a decrease in specific gene signatures in plasma cells was associated with disease progression. This could help doctors identify which patients are at risk of developing more severe forms of MM, allowing for earlier interventions. 

The study suggests that boosting immune cell activity, especially granulocytes, NK cells, and CD8+ T cells, could help prevent MM from advancing. The study also highlights the potential for using immune checkpoint inhibitors to improve immune function and for monitoring specific plasma cell markers to predict disease progression. These insights could guide the development of new treatments to delay or prevent MM progression.

 

 

"Recent advances in and applications of ex vivo drug sensitivity analysis for blood cancers"

Source

Lee, H., Ko, N., Namgoong, S. et al. Recent advances in and applications of ex vivo drug sensitivity analysis for blood cancers. Blood Res. 59, 37 (2024). https://doi.org/10.1007/s44313-024-00032-8  November 6, 2024. 

Blood cancers like leukemia, multiple myeloma (MM), and lymphoma are challenging to treat because they vary so much between patients. Traditional treatments have limitations, but precision medicine offers a promising approach by customizing treatment based on a patient's individual characteristics. One key tool in precision medicine is ex vivo drug sensitivity analysis. This method tests cancer cells from patients against different drugs to predict which treatments will be most effective. 

The study reviews recent advancements in ex vivo drug sensitivity analysis, including new ways to measure how drugs affect cancer cells and how combinations of drugs might work better together. Researchers are also using this technique to evaluate advanced treatments like antibody-drug conjugates (ADCs), which combine antibodies with drugs to target cancer cells more precisely. These improvements in testing and treatment strategies are helping doctors better understand which therapies will work for each patient, leading to more effective treatments.

The review concludes that ex vivo drug sensitivity analysis is a major step forward for precision medicine in blood cancers. It has helped refine drug response predictions, allowing for more accurate treatment choices. It has also opened new possibilities for combining drugs to overcome resistance and improve patient outcomes. As technology continues to improve, these methods will likely lead to even more personalized treatments, offering hope for better management of blood cancers and other diseases.

 

 

"Characteristics and treatment patterns of long-surviving patients with multiple myeloma: over 13 years of follow-up in the Connect® MM Registry"

Source

Howard R. Terebelo, James Omel, Lynne I. Wagner, James W. Hardin, Robert M. Rifkin, Sikander Ailawadhi, Brian G.M. Durie, Mohit Narang, Kathleen Toomey, Cristina J. Gasparetto, Prashant Joshi, Edward Yu, E. Dawn Flick, Ying-Ming Jou, Hans C. Lee, Rafat Abonour, Sundar Jagannath, Characteristics and treatment patterns of long-surviving patients with multiple myeloma: over 13 years of follow-up in the Connect® MM Registry, Clinical Lymphoma Myeloma and Leukemia, 2024, ISSN 2152-2650, https://doi.org/10.1016/j.clml.2024.11.001. November 6, 2024. 

Over the past 15 years, treatments for multiple myeloma (MM) have improved, leading to longer survival for many patients. The Connect MM Registry, a large study in the U.S., tracked patients with newly diagnosed MM to understand more about long-term survivors (LTS). This study looked at factors like patient age, treatment, quality of life (QoL), and overall survival (OS) for those who survived 8 years or more after their diagnosis.

The study included 3,011 adults diagnosed with MM from 2009 to 2016. Of these, 518 were long-term survivors, and 2,493 were not. LTS patients tended to be younger and healthier at the time of diagnosis compared to those who didn’t survive as long. Many LTS patients received stem cell transplants, and only a small percentage (2%) had disease progression within 6 months of starting their first treatment. At the time of the study, 63% of LTS patients were still receiving treatment, and their QoL scores were consistently higher than those of non-LTS patients.

The results of this study, which showed that the 8-year survival rate for patients was about 40%, are similar to data from other sources, like the SEER database. This study highlights the value of real-world data from registries, showing how long-term follow-up of patients outside of clinical trials can provide important insights into the survival and treatment of MM.

 

 

"Mutations of ARID1B, PIK3C2B, KMT2B, and FAT1 genes influence clinical outcome in newly diagnosed myeloma"

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Marta Morawska, Michał Kiełbus, Magdalena Paziewska, Monika Szelest, Agnieszka Karczmarczyk, Joanna Zaleska, Paulina Własiuk, Krzysztof Giannopoulos, Norbert Grząśko, Mutations of ARID1B, PIK3C2B, KMT2B, and FAT1 genes influence clinical outcome in newly diagnosed myeloma, Cancer Genetics, 2024, ISSN 2210-7762, https://doi.org/10.1016/j.cancergen.2024.11.001. November 6, 2024. 

This study aimed to better understand the genetic changes in patients with newly diagnosed multiple myeloma and how these changes might affect their outcomes. The researchers analyzed the DNA of 20 patients using a specific testing kit and found 724 genetic mutations. All patients had mutations in the RTK-RAS pathway, and more than half also had changes in the PI3K, NOTCH, and WNT pathways. Certain gene mutations were linked to specific clinical features, such as myeloma type, prognosis, and kidney function.

The study found that mutations in genes like PIK3C2B, ARID1B, and others were related to how long patients stayed in remission (progression-free survival). These results suggest that understanding these genetic changes could help doctors predict how patients will do and make better treatment decisions. The researchers believe that further investigation of these genetic markers could lead to more targeted treatments and better ways to classify multiple myeloma patients based on their genetic profiles.

 

 

"Advanced molecular diagnostics: Driving precision in hematological malignancies"

Source

Li Bao, Xuechun Lu, Yaozhu Pan, Advanced molecular diagnostics: Driving precision in hematological malignancies, Cancer Pathogenesis and Therapy, 2024, ISSN 2949-7132, https://doi.org/10.1016/j.cpt.2024.09.001. November 6, 2024. 

Advances in molecular biology and genomics are transforming the diagnosis and treatment of blood cancers, building on the established MICM (morphology, immunology, cytogenetics, and molecular biology) diagnostic framework. A special issue titled *“Precision Medicine in Hematological Cancers”* focuses on addressing challenges like drug resistance, side effects, and disease recurrence. It highlights how integrating advanced molecular tools can improve diagnostic accuracy and enable safer, more effective treatments tailored to individual patients.  

One study by Hou et al. examined how immune aging and inflammation affect the efficacy of immune checkpoint inhibitors (ICIs) in older patients. Their findings suggest that age-related immune changes can reduce ICI effectiveness, emphasizing the need for personalized strategies that account for age and immune status. Another study by Huang et al. analyzed genetic mutations in acute myeloid leukemia (AML) patients treated with the DCAG regimen. Patients with PTPN11 mutations had particularly poor outcomes, pointing to the importance of developing targeted therapies for this high-risk group and offering new guidelines for stratified treatment.  

In multiple myeloma, Wang et al. explored the link between genetic mutations and clinical features using second-generation sequencing. They found mutations in RNA pathways were more common in younger male patients, while advanced disease stages were associated with mutations in NF-κB and DNA damage repair pathways. These findings improve understanding of multiple myeloma’s genetic basis and could help refine staging and treatment approaches.  

While molecular diagnostics have enhanced precision in managing hematological cancers, rare and complex cases remain a challenge. The special issue underscores the importance of ongoing clinical research to address these difficulties. By advancing molecular insights and exploring personalized treatments, it aims to improve outcomes for patients and support the broader adoption of precision medicine.  

 

 

"Proteasome inhibitors related thrombotic microangiopathy: a systematic and comprehensive review"

Source

Chen, C., Li, Y., Shi, P. et al. Proteasome inhibitors related thrombotic microangiopathy: a systematic and comprehensive review. Blood Cancer J. 14, 196 (2024). https://doi.org/10.1038/s41408-024-01182-9  November 7, 2024.  

Proteasome inhibitors (PIs), key treatments for multiple myeloma, can sometimes cause thrombotic microangiopathy (TMA), with carfilzomib being the most commonly implicated. A systematic review of 44 studies involving 115 cases of PI-induced TMA revealed that carfilzomib accounted for 101 cases. Treatment strategies varied: supportive care alone was used in 28 cases, therapeutic plasma exchange (TPE) in 43, eculizumab (ECU) in 9, and a combination of TPE and ECU in 13.  

Eculizumab proved particularly effective for patients who didn’t respond to initial TPE, achieving complete remission in seven cases. However, the need for dialysis emerged as a strong indicator of poor prognosis. For patients with suspected PI-TMA, stopping the causative drug immediately is recommended, even if lab results are not yet conclusive.  

When diagnosis is difficult, a kidney biopsy may help if feasible. A thorough evaluation of the complement system, including genetic testing and analysis of complement function and antibodies, is essential. Early use of eculizumab may benefit patients with complement abnormalities or those who fail to respond to standard treatments, offering hope for better outcomes in these challenging cases.  

 

 

"A single-cell transcriptomic map of the murine and human multiple myeloma immune microenvironment across disease stages"

Source

Verheye, E., Kancheva, D., Satilmis, H. et al. A single-cell transcriptomic map of the murine and human multiple myeloma immune microenvironment across disease stages. J Hematol Oncol 17, 107 (2024). https://doi.org/10.1186/s13045-024-01629-3  November 7, 2024. 

Relapse is common in multiple myeloma (MM), highlighting the need to understand the tumor-immune microenvironment (TME) and uncover resistance mechanisms that limit long-term success of immunotherapies. Using an immunocompetent mouse model (5T33MM) and single-cell RNA sequencing, researchers mapped the dynamic changes in the MM-TME in bone marrow and spleen at different disease stages. These findings were compared with human MM data, offering insights into shared disease processes.  

The study revealed that T cells in the TME increase during MM progression but exhibit signs of exhaustion. Neutrophils, initially harmless, develop pro-tumorigenic properties as the disease advances. Conventional dendritic cells (cDCs) were less active in MM, suggesting potential for immune-boosting therapies. Testing the anti-CD40 agonist (αCD40) therapy showed promise by activating cDCs and T cells, leading to a significant short-term anti-tumor response in pre-clinical evaluations.  

This comprehensive immune atlas provides valuable insights into how MM progresses and how immune cells evolve within the TME. These findings could support immune-based patient stratification and guide the development of more effective, long-lasting immunotherapies for MM.

 

 

"Long-Term Safety and Efficacy of the Fully Human CAR-T Therapy CT103A in Relapsed/Refractory Multiple Myeloma"

Source

Qiuxia Yu, Di Wang, Zhe Li, Ning An, Chunhui Li, Yuhan Bao, Xinyu Wen, Xiaolu Long, Jue Wang, Lijun Jiang, Wei Mu, Peiling Zhang, Chang Shu, Huan Ye, Hongyu Gui, Songbai Cai, Guang Hu, Wen Wang, Aihua Du, Chunrui Li, Long-Term Safety and Efficacy of the Fully Human CAR-T Therapy CT103A in Relapsed/Refractory Multiple Myeloma, Molecular Therapy, 2024, ISSN 1525-0016, https://doi.org/10.1016/j.ymthe.2024.11.013. November 8, 2024. 

CT103A, a fully human CAR-T therapy targeting BCMA, continues to demonstrate promising results for patients with relapsed/refractory multiple myeloma (RRMM) after extended follow-up. With a median follow-up time of 45 months, all 18 patients treated with CT103A achieved at least partial remission, and 77.8% achieved complete or stringent complete remission (CR/sCR). Notably, one patient maintained a response for nearly five years, and seven patients remained MRD-negative with ongoing sCR.  

The treatment's safety profile improved over time, with fewer adverse events during the follow-up period. Patients experienced a median progression-free survival of 22.6 months and a median overall survival of 50.2 months. The CAR-T cells showed persistence in the body for a median of 14 months. These findings highlight the durable clinical benefits of CT103A, offering hope for more effective long-term treatment in RRMM.

 

 

"Immune safety challenges facing the preclinical assessment and clinical progression of cell therapies"

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Stephanie M. Bates, Kelly V. Evans, Louise Delsing, Ryan Wong, Georgina Cornish, Mahnoush Bahjat, Immune safety challenges facing the preclinical assessment and clinical progression of cell therapies, Drug Discovery Today, 2024, 104239, ISSN 1359-6446, https://doi.org/10.1016/j.drudis.2024.104239. November 8, 2024. 

Cell therapies are transforming treatments for severe diseases, including end-stage cancer, neurodegenerative disorders, and cardiac conditions, and even extending to regenerative fields like dentistry and ocular health. While these therapies hold incredible promise, they also come with significant immune safety challenges.  

Key factors influencing immune responses include the source of the cells (autologous from the patient versus donor-derived allogeneic), the type of cells used, and the methods of genetic engineering and manufacturing. These factors can increase the risk of unwanted immune reactions. This review outlines the potential immune risks associated with cell therapies and discusses strategies to minimize these risks, ensuring safer and more effective treatments for patients.

 

 

"New insights into CAR T-cell hematological toxicities: manifestations, mechanisms, and effective management strategies"

Source

Yang, Y., Peng, H., Wang, J. et al. New insights into CAR T-cell hematological toxicities: manifestations, mechanisms, and effective management strategies. Exp Hematol Oncol 13, 110 (2024). https://doi.org/10.1186/s40164-024-00573-9  November 9, 2024. 

CAR T-cell therapy is a powerful treatment for relapsed or refractory blood cancers, but it comes with serious risks, including cytokine release syndrome (CRS), neurotoxicity (ICANS), infections, and hematological toxicities (HTs). HTs can involve cytopenias, hemophagocytic lymphohistiocytosis (HLH), coagulopathies, and B-cell aplasia, significantly affecting patient outcomes and quality of life.  

While progress has been made in understanding CRS and ICANS, the mechanisms behind HTs remain unclear. This knowledge gap complicates treatment decisions and can lead to unnecessary medical interventions. A recent review examines the causes and symptoms of HTs in CAR T-cell therapy and offers strategies to manage these toxicities, aiming to improve patient care and therapy outcomes.

 

 

"Clinical and immunological characteristics of high-risk double-hit multiple myeloma"

Source

Shang, Y., Chen, G., Liu, L. et al. Clinical and immunological characteristics of high-risk double-hit multiple myeloma. BMC Cancer 24, 1373 (2024). https://doi.org/10.1186/s12885-024-13124-6  November 10, 2024. 

Double-hit multiple myeloma (DHMM) is a subtype of multiple myeloma characterized by aggressive disease features, including higher β2-MG levels and an increased percentage of bone marrow plasma cells. Patients with DHMM also show a higher proportion of poorly differentiated plasma cells, highlighting abnormal bone marrow proliferation.  

Analysis of lymphocyte subpopulations revealed that DHMM has elevated levels of regulatory T cells (Tregs), especially inducible Tregs (iTregs), along with higher levels of TGF-β1 and IL-10, which were positively linked to iTregs. Additionally, DHMM shows increased expression of PD-1 on CD8+ T cells and a higher proportion of CD38high Tregs. Laboratory studies demonstrated that targeting TGF-β1 or CD38 with specific antibodies can effectively reduce CD38high Tregs.  

These findings provide new insights into the biological and immunological characteristics of DHMM, offering a foundation for developing more targeted therapies for this challenging myeloma subtype.

 

 

"Impact of lenalidomide-bortezomib-dexamethasone induction on patients with newly diagnosed multiple myeloma and renal impairment: Results from the Connect® MM Registry"

Source

Ailawadhi, S., Lee, H.C., Omel, J. et al. Impact of lenalidomide-bortezomib-dexamethasone induction on patients with newly diagnosed multiple myeloma and renal impairment: Results from the Connect® MM Registry. Blood Cancer J. 14, 198 (2024). https://doi.org/10.1038/s41408-024-01177-6  November 11, 2024. 

This analysis from the Connect® MM Registry examined how lenalidomide-bortezomib-dexamethasone (RVd) induction therapy affects kidney function in patients with newly diagnosed multiple myeloma (NDMM) and renal impairment (RI). The study included 344 transplant-eligible and 289 non-transplant-eligible patients who received RVd for at least three cycles.  

Improved kidney function was observed at 3, 6, and 12 months across all levels of baseline renal impairment. Progression-free survival (PFS) was longer in transplanted patients compared to non-transplanted ones, regardless of initial kidney function. For those with creatinine clearance >60 mL/min, median PFS was 49.4 months (transplanted) and 35.7 months (non-transplanted). In patients with clearance ≤60 mL/min, PFS was 47.6 months (transplanted) and 29.1 months (non-transplanted).  

These findings suggest that RVd induction therapy can improve kidney function and long-term outcomes in NDMM patients with renal impairment, regardless of their eligibility for transplant.

 

 

"Phase 1 study of isatuximab monotherapy in Chinese patients with relapsed/refractory multiple myeloma"

Source

Sun, M., Jing, H., Qu, X. et al. Phase 1 study of isatuximab monotherapy in Chinese patients with relapsed/refractory multiple myeloma. Sci Rep 14, 27550 (2024). https://doi.org/10.1038/s41598-024-59186-1   November 11, 2024. 

This Phase 1 trial (NCT03733717) evaluated the pharmacokinetics (PK), safety, and effectiveness of isatuximab (Isa), an anti-CD38 antibody, in Chinese patients with relapsed/refractory multiple myeloma (RRMM). Twenty-one patients, heavily pretreated with a median of four prior therapies, received Isa at 20 mg/kg intravenously weekly during the first cycle, then every two weeks.  

The PK profile showed increased drug exposure with repeated doses, consistent with results from other populations. Nearly half of the patients (47.6%) experienced grade 3 or higher treatment-related adverse events (TEAEs), but serious events were rare, and only one patient stopped treatment due to side effects.  

Preliminary results showed an overall response rate of 19.0% and a clinical benefit rate of 33.3%. These findings confirm that Isa is safe, tolerable, and effective for treating Chinese RRMM patients, aligning with data from Western and East-Asian studies.

 

 

"Genetically determined telomere length in monoclonal gammopathy of undetermined significance, multiple myeloma risk and outcome"

Source

Giaccherini, M., Clay-Gilmour, A.I., Liotti, R. et al. Genetically determined telomere length in monoclonal gammopathy of undetermined significance, multiple myeloma risk and outcome. Blood Cancer J. 14, 200 (2024). https://doi.org/10.1038/s41408-024-01181-w  November 11, 2024. 

This study explored the relationship between genetically determined telomere length (gdLTL) and the risk of developing multiple myeloma (MM) and its precursor condition, monoclonal gammopathy of undetermined significance (MGUS). Using genetic data from 746 MGUS cases, 879 controls, 2066 MM cases, and 2050 controls, the researchers created two telomere length scores (teloscores) based on specific genetic markers.  

The study found that individuals with longer gdLTL had a higher risk of developing MGUS, especially those with the longest telomeres. However, the results did not show a clear link between telomere length and the progression of MGUS to MM. Additionally, no strong association was found between gdLTL and MM survival rates.  

These findings suggest that longer telomeres may increase the risk of MGUS but do not seem to affect the progression to MM or overall survival in MM patients. Further research is needed to confirm these results.

 

 

"Targeting CLK2 and serine/arginine-rich splicing factors inhibits multiple myeloma through downregulating RAE1 by nonsense-mediated mRNA decay mechanism"

Source

Liu Y, Liao Y, Lai S, et al. Targeting CLK2 and serine/arginine-rich splicing factors inhibits multiple myeloma through downregulating RAE1 by nonsense-mediated mRNA decay mechanism. Cancer Sci. 2024; 00: 1-14. doi:10.1111/cas.16387  November 11, 2024. 

This study looks at the role of CLK2, a protein that affects RNA splicing, in multiple myeloma (MM), a type of cancer. Researchers found that higher levels of CLK2 were linked to a worse prognosis in MM patients. When they increased CLK2 in MM cells, it made the cells grow faster and progress through the cell cycle more quickly. On the other hand, reducing or blocking CLK2 slowed down cell growth, caused the cells to die, and stopped them from progressing through the cell cycle.

In experiments with mice, overexpressing CLK2 led to faster tumor growth, while inhibiting CLK2 slowed it down. The study also discovered that CLK2 works by affecting a protein called SRSF, which influences the splicing of RNA. In particular, CLK2 inhibition led to a decrease in the protein RAE1, which is linked to cancer cell growth. Reducing RAE1 also slowed down cell growth, while increasing RAE1 sped it up and reduced the effect of blocking CLK2.

The study suggests that targeting the CLK2/SRSFs/RAE1 pathway could be a potential new treatment approach for multiple myeloma.

 

 

"What to Do When Denosumab Is Stopped?"

Source

Watts NB. What to Do When Denosumab Is Stopped? JAMA Netw Open. 2024;7(11):e2443879. doi:10.1001/jamanetworkopen.2024.43879 November 11, 2024. 

This study explores the effects of transitioning patients from denosumab, a medication for osteoporosis, to other treatments, focusing on maintaining bone mineral density (BMD) and reducing fracture risk. Researchers followed a small group of patients in the first year of a trial: 25 continued using denosumab, while 76 switched to zoledronate, a bisphosphonate given intravenously. The study revealed differences in BMD outcomes depending on how long patients had been on denosumab.

Denosumab is a drug that blocks RANKL, a protein involved in bone breakdown. It reduces bone loss and strengthens bones, significantly lowering the risk of fractures. However, once stopped, bone resorption markers rebound quickly, and BMD gains can be lost within 1-2 years, potentially increasing the risk of fractures. This rapid rebound poses challenges for patients who discontinue denosumab.

The study highlights potential strategies for managing this issue. Switching to zoledronate may help maintain BMD in some patients, but timing and dosing appear crucial, as bone turnover suppressed by denosumab affects how well zoledronate works. Other options, like osteoanabolic agents such as teriparatide, have shown mixed results, with some initial BMD loss after transitioning from denosumab.

The findings emphasize that long-term use of denosumab may be the best approach for fracture prevention. For those who must stop, more research is needed to identify the safest and most effective strategies to minimize BMD loss and maintain fracture protection.

 

 

"CD34+ and CD34− MM cells show different immune-checkpoint molecule expression profiles: high expression of CD112 and CD137 ligand on CD34+ MM cells"

Source

Fukui-Morimoto, A., Serizawa, K., Fujimoto, K. et al. CD34+ and CD34− MM cells show different immune-checkpoint molecule expression profiles: high expression of CD112 and CD137 ligand on CD34+ MM cells. Int J Hematol (2024). https://doi.org/10.1007/s12185-024-03867-0  November 12, 2024. 

Multiple myeloma (MM) is still incurable, even with new treatments. A specific group of MM cells, called CD34+ cells, can self-renew and resist therapy. These cells often remain in minimal residual disease and grow during relapse, making them a key challenge in MM treatment.

Researchers studied how immunotherapies like immune checkpoint inhibitors, CAR-T therapy, and bispecific antibodies affect CD34+ MM cells. Using advanced techniques, they found that CD34+ cells have more active pathways related to inflammation and immune responses compared to other MM cells. These cells also show high activity in PD-1 signaling, which is linked to immune suppression.

CD34+ MM cells frequently express immune checkpoint molecules such as CD112, CD137L, and GAL9. Meanwhile, T cells in MM patients often express TIGIT and CD137, suggesting that interactions between these molecules may weaken T cells' ability to attack CD34+ MM cells. Researchers also discovered that CD34+ cells have high levels of FcRH5, a target for certain therapies. This finding supports further exploration of FcRH5-targeted treatments for MM. 

These results highlight the importance of targeting CD34+ MM cells to improve immunotherapy outcomes for MM patients.

 

 

"Discovery of SZJK-0421: A Novel Potent, Low Toxicity, Selective Second Generation of CRM1 Inhibitor for the Treatment of Both Hematological and Solid Tumors"

Source

Hang Miao, Yanru Qin, DingLu Shao, Qinghua Chen, Yupeng Pan, Meng Lei, Ruokun Wu, Xinran Ye, Xueyuan Wang, Yongqiang Zhu, Discovery of SZJK-0421: A Novel Potent, Low Toxicity, Selective Second Generation of CRM1 Inhibitor for the Treatment of Both Hematological and Solid Tumors, Journal of Medicinal Chemistry, 2024,ISSN 1520-4804, https://doi.org/10.1021/acs.jmedchem.4c02169. November 12, 2024. 

The protein CRM1 helps transport important growth-regulating proteins in cells and is often overproduced in many cancers, including blood and solid tumors. Selinexor (KPT-330) is an approved drug that blocks CRM1, but its use is limited due to severe side effects, like nausea and damage to the digestive system.

Researchers developed new CRM1 inhibitors, focusing on SZJK-0421, which is more reversible than Selinexor. SZJK-0421 effectively blocks CRM1 activity in cancer cells, works well in the body, and causes fewer side effects. Tests in rats showed that SZJK-0421 has minimal impact on the brain and reduces damage to the digestive system, avoiding issues like nausea and vomiting. 

SZJK-0421 also showed strong anti-cancer effects in animal models of both solid and blood cancers, making it a promising alternative to current CRM1 inhibitors.

 

 

"Induction Chemotherapy-Related Covert Cardiac Remodeling in Pre-Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma: A Retrospective Observational Study"

Source

Dai, C., Lin, W., Liu, F., Chen, X., Chen, Y., Jiang, Y., Bai, J., Lv, Y., Zheng, J., Deng, H., Du, X., Wu, S. and Xue, Y. (2024), Induction Chemotherapy-Related Covert Cardiac Remodeling in Pre-Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma: A Retrospective Observational Study. Cancer Med, 13: e70329. https://doi.org/10.1002/cam4.70329  November 12, 2024.  

Autologous stem cell transplantation (ASCT) is a critical treatment for multiple myeloma, offering extended disease control for many patients. However, the chemotherapy used before ASCT can negatively impact heart health. A recent study conducted at Guangdong Provincial People's Hospital analyzed 47 patients who underwent induction chemotherapy before ASCT. Researchers found that over half of the patients (51%) developed or experienced worsening diastolic dysfunction, where the heart struggles to relax and fill properly. Additionally, nearly 20% experienced arrhythmias (irregular heartbeats), along with other changes in heart function and structure.  

These findings highlight the need to carefully balance the benefits of chemotherapy with its potential cardiovascular risks. While chemotherapy is essential to prepare patients for ASCT, close monitoring and proactive management of heart health are crucial. Tailoring treatment to minimize heart damage could help ensure patients receive the full benefits of this life-extending therapy without unnecessary complications.

 

 

"Prognostic risk and survival of asymptomatic IgM monoclonal gammopathy: Results from a Spanish Multicenter Registry"

Source

Moreno, D.F., Jiménez, C., Escalante, F., Askari, E., Castellanos-Alonso, M., Arnao, M., Heredia, Á., Canales, M.Á., Alcalá, M., Bermúdez, A., Saus Carreres, A., Casanova, M., Palomera, L., Motlló, C., García-Sánchez, R., Ríos Rull, P., García-Sanz, R. and Fernández de Larrea, C. (2024), Prognostic risk and survival of asymptomatic IgM monoclonal gammopathy: Results from a Spanish Multicenter Registry. HemaSphere, 8: e70029. https://doi.org/10.1002/hem3.70029  November 12, 2024. 

Asymptomatic IgM gammopathy, including IgM monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic Waldenström macroglobulinemia (AWM), can progress to symptomatic Waldenström macroglobulinemia (SWM). A study of 956 patients across 25 Spanish centers followed participants for a median of 5.7 years. During this time, 156 patients progressed to symptomatic disease. The risk of progression was 13% at 5 years and 20% at 10 years. Researchers identified key risk factors for progression, including high serum IgM (≥10 g/L), significant bone marrow infiltration (≥20%), elevated β2-microglobulin (≥3 mg/L), and low albumin (<4 g/dL).  

Using these factors, the study created a risk model dividing patients into low-, intermediate-, and high-risk groups, with 5-year progression risks of 4.5%, 15.7%, and 42.8%, respectively. For patients without bone marrow evaluations, having 2 or 3 risk factors was associated with a 27% progression risk at 5 years. Importantly, the presence of the MYD88 L265P mutation negatively impacted AWM patients but did not affect the overall model. While asymptomatic patients had survival rates similar to the general population at 5 years, symptomatic patients faced significantly worse outcomes. This model helps predict disease progression and emphasizes the need for personalized monitoring and care for asymptomatic patients.

 

 

"Dimethyl Fumarate Augments Anticancer Activity of Ångstrom Silver Particles in Myeloma Cells through NRF2 Activation"

Source

B. Wu, Z.-X. Wang, H. Xie, P.-L. Xie, Dimethyl Fumarate Augments Anticancer Activity of Ångstrom Silver Particles in Myeloma Cells through NRF2 Activation. Adv. Therap. 2024, 2400363. https://doi.org/10.1002/adtp.202400363  November 13, 2024

Multiple myeloma (MM) is a blood cancer that remains incurable due to relapse and resistance to treatments. Researchers studied the use of angstrom-scale silver particles (F-AgÅPs) as a potential therapy for MM. These tiny silver particles are created using a specialized method and coated with fructose. Lab tests showed that F-AgÅPs are highly toxic to MM cells at low doses, primarily by increasing reactive oxygen species (ROS) levels. This oxidative stress damages the cancer cells and triggers the buildup of NRF2, a protein that helps regulate the cell’s response to stress.  

Further experiments demonstrated that using an ROS blocker reduced the cytotoxic effects of F-AgÅPs, while activating NRF2 with the drug dimethyl fumarate (DMF) made the silver particles even more effective. In a mouse model of MM, combining F-AgÅPs with DMF successfully slowed tumor growth. This study suggests that targeting oxidative damage with F-AgÅPs and NRF2 activation could be a promising new treatment strategy for MM.

 

 

"Cytopenias in BCMA CAR T: unraveling inflammatory mechanisms"

Source

Adam S. Sperling; Cytopenias in BCMA CAR T: unraveling inflammatory mechanisms. Blood Adv 2024; 8 (21): 5527–5528. doi: https://doi.org/10.1182/bloodadvances.2024014308  November 12, 2024. 

Chimeric antigen receptor (CAR) T-cell therapy targeting BCMA has shown remarkable success in treating relapsed and refractory multiple myeloma (RRMM), offering high remission rates. However, a common complication is prolonged cytopenias—low blood cell counts lasting beyond 30 days after treatment. These cytopenias increase the risk of serious infections and bleeding, often requiring ongoing use of growth factors. This study by Palacios-Berraquero et al sheds light on the risk factors and mechanisms behind these long-term complications.  

Analyzing data from 48 RRMM patients treated with BCMA-targeting CAR T cells, the researchers found that baseline low blood counts and high inflammatory markers, such as ferritin, were linked to prolonged cytopenias. Persistent inflammation, likely triggered by CAR T-cell activity, appeared to suppress normal blood cell production. In lab experiments, stem and progenitor blood cells exposed to inflammatory cytokines produced during CAR T-cell activity showed impaired development, which could be reversed with specific inhibitors. These findings suggest that inflammation and cytokine activity play a critical role in long-term cytopenias.  

The study highlights the need for a deeper understanding of how CAR T-cell therapy impacts blood cell production. It also emphasizes the importance of developing strategies to mitigate these effects while preserving the therapy’s effectiveness. Future research focusing on targeted interventions could help improve the safety of this promising treatment for patients with multiple myeloma.

 

 

"Comparison of patients with myeloma receiving zoledronic acid vs denosumab: a nationwide retrospective cohort study"

Source

Ghulam Rehman Mohyuddin, Jenny S. Guadamuz, Mustafa S. Ascha, Brian C.-H. Chiu, Pritesh R. Patel, Karen Sweiss, Rebecca Rohrer, Douglas Sborov, Gregory S. Calip; Comparison of patients with myeloma receiving zoledronic acid vs denosumab: a nationwide retrospective cohort study. Blood Adv 2024; 8 (21): 5539–5541. doi: https://doi.org/10.1182/bloodadvances.2024013600  November 12, 2024.  

Chimeric antigen receptor (CAR) T-cell therapy targeting BCMA has shown remarkable success in treating relapsed and refractory multiple myeloma (RRMM), offering high remission rates. However, a common complication is prolonged cytopenias—low blood cell counts lasting beyond 30 days after treatment. These cytopenias increase the risk of serious infections and bleeding, often requiring ongoing use of growth factors. This study by Palacios-Berraquero et al sheds light on the risk factors and mechanisms behind these long-term complications.  

Analyzing data from 48 RRMM patients treated with BCMA-targeting CAR T cells, the researchers found that baseline low blood counts and high inflammatory markers, such as ferritin, were linked to prolonged cytopenias. Persistent inflammation, likely triggered by CAR T-cell activity, appeared to suppress normal blood cell production. In lab experiments, stem and progenitor blood cells exposed to inflammatory cytokines produced during CAR T-cell activity showed impaired development, which could be reversed with specific inhibitors. These findings suggest that inflammation and cytokine activity play a critical role in long-term cytopenias.  

The study highlights the need for a deeper understanding of how CAR T-cell therapy impacts blood cell production. It also emphasizes the importance of developing strategies to mitigate these effects while preserving the therapy’s effectiveness. Future research focusing on targeted interventions could help improve the safety of this promising treatment for patients with multiple myeloma.

 

 

"Allogeneic Hematopoietic Stem Cell Transplantation in Refractory Multiple Myeloma—A Retrospective Multicenter Analysis"

 

Source

Richardson, T., Kobbe, G., Fenk, R., Schroeder, T., Crysandt, M., Neuerburg, C., Holderried, T.A.W., Schütte, D., Gödel, P., Hallek, M., Scheid, C. and Holtick, U. (2024), Allogeneic Hematopoietic Stem Cell Transplantation in Refractory Multiple Myeloma—A Retrospective Multicenter Analysis. Eur J Haematol. https://doi.org/10.1111/ejh.14346  November 13, 2024. 

Patients with multiple myeloma (MM) often relapse despite advances in treatment. Allogeneic hematopoietic cell transplantation (allo-SCT) is a potential option for refractory MM, but it has limited durability and significant side effects. This study examined outcomes for 128 patients who underwent allo-SCT at five German centers between 2010 and 2021. Patients had a median of six prior therapies. After a median follow-up of 6.4 years, the median progression-free survival (PFS) was 7 months, and overall survival (OS) was 19 months. Non-relapse mortality (NRM) was 28% at six years.

Survival rates at one, two, and six years were 61%, 49%, and 38% for OS, and 45%, 34%, and 25% for PFS. Achieving a complete response (CR) before transplant was the most important predictor of better outcomes. While allo-SCT may be curative for a small group of patients, identifying those likely to benefit is crucial to avoid unnecessary toxicity in others.

 

"Natural killer cell biology and therapy in multiple myeloma: challenges and opportunities"

 

Source

Bisht, K., Merino, A., Igarashi, R. et al. Natural killer cell biology and therapy in multiple myeloma: challenges and opportunities. Exp Hematol Oncol 13, 114 (2024). https://doi.org/10.1186/s40164-024-00578-4  November 13, 2024. 

Despite improvements in treatment, multiple myeloma (MM) is still not curable. Natural killer (NK) cells are a promising treatment option for MM. These cells are classified by surface markers, such as CD56 and CD16a, and can trigger an immune response against tumors. NK cells are more effective when there are fewer mutations in the MM cells and when they can detect signs of tumor transformation. Higher NK cell activity is linked to better survival and prognosis in MM, while lower activity is seen in advanced stages of the disease.

The role of NK cells in fighting MM varies depending on disease stage, and their function is influenced by factors like the bone marrow environment and the presence of certain receptors on the NK cells. Treatments like stem cell transplants, immunomodulation, and other therapies can also affect NK cells. This review discusses how NK cells change in different stages of MM and suggests ways to enhance their effectiveness in treatment.

 

 

"Exploring the Relationship Between Daratumumab Treatment and Stem Cell Collection in Newly Diagnosed Multiple Myeloma (NDMM) Patients Undergoing Transplantation: Insights From a Single-Center Investigation"

Source

Chougule, D., Aggarwal, G., Sood, N. et al. Exploring the Relationship Between Daratumumab Treatment and Stem Cell Collection in Newly Diagnosed Multiple Myeloma (NDMM) Patients Undergoing Transplantation: Insights From a Single-Center Investigation. Indian J Hematol Blood Transfus (2024). https://doi.org/10.1007/s12288-024-01914-8  November 14, 2024. 

The purpose of this study was to understand how daratumumab-based induction therapy affects stem cell collection in multiple myeloma patients. Daratumumab is known to provide long-lasting responses in these patients, but it may also reduce the yield of CD34+ stem cells and increase the need for plerixafor, a drug used to help with stem cell collection for a transplant.

In this study, 91 patients with multiple myeloma were examined. Out of these, 8 received daratumumab as part of their treatment. The results showed that there was no significant difference in stem cell yield between patients who received daratumumab and those who did not. However, patients on daratumumab therapy needed more plerixafor during the stem cell collection process.

In conclusion, adding daratumumab to induction therapy did not affect the amount of stem cells collected but did increase the need for plerixafor to assist with stem cell mobilization.

 

 

"From regulation to deregulation of p53 in hematologic malignancies: implications for diagnosis, prognosis and therapy"

Source

Ahmadi, S.E., Rahimian, E., Rahimi, S. et al. From regulation to deregulation of p53 in hematologic malignancies: implications for diagnosis, prognosis and therapy. Biomark Res 12, 137 (2024). https://doi.org/10.1186/s40364-024-00676-9 November 14, 2024. . 

The p53 protein, which is produced by the TP53 gene, plays an important role in protecting cells from becoming cancerous by maintaining genetic stability and responding to stress. When p53 is not working properly, it can contribute to the development of blood cancers and affect how well patients respond to treatment. This review looks at how p53 is regulated, how mutations in the TP53 gene impact blood cancers, and new treatment strategies aimed at targeting p53. Mutations in TP53 can make blood cancers harder to treat and lead to worse outcomes for patients. However, treatments that reactivate p53 or use gene therapy show promise in improving survival rates. Understanding how p53 works and the effects of its mutations is key to developing better ways to diagnose and treat blood cancers.

 

 

"Spatial transcriptomics reveals profound subclonal heterogeneity and T-cell dysfunction in extramedullary myeloma"

Source

Mara John, Moutaz Helal, Johannes Duell, Greta Mattavelli, Emilia Stanojkovska, Nazia Afrin, Alexander M. Leipold, Maximilian J. Steinhardt, Xiang Zhou, David Žihala, Anjana Anilkumar Sithara, Julia Mersi, Johannes M. Waldschmidt, Christine Riedhammer, Sofie-Katrin Kadel, Marietta Truger, Rudolf A. Werner, Claudia Haferlach, Hermann Einsele, Kai Kretzschmar, Tomáš Jelínek, Andreas Rosenwald, K. Martin Kortüm, Angela Riedel, Leo Rasche; Spatial transcriptomics reveals profound subclonal heterogeneity and T-cell dysfunction in extramedullary myeloma. Blood 2024; 144 (20): 2121–2135. doi: https://doi.org/10.1182/blood.2024024590  November 14, 2024. 

Extramedullary disease (EMD) is a serious complication of multiple myeloma (MM) that worsens the prognosis for patients, even with new immunotherapies. In this study, researchers used advanced techniques like spatial transcriptomics and single-cell RNA sequencing to study EMD biopsies and understand the 3D structure of the tumor and its surrounding environment. They found that immune and stromal cells in the tumors were very different between patients, and the tumor cells themselves showed genetic instability. They also found that certain antigens important for bispecific antibody therapy, like GPRC5D and TNFRSF17, were expressed differently in the tumor. The immune response in the tumors was complex, with both exhausted T cells and activated CD8+ T cells showing different patterns of infiltration. This information suggests that targeting these immune cells could be a promising treatment strategy. Overall, the study highlights how spatial transcriptomics can provide new insights into the tumor environment and suggests that therapies targeting the immune system could improve outcomes for patients with EMD.

 

 

"Location, location, location: EMD in MM"

Source

Madhav V. Dhodapkar; Location, location, location: EMD in MM. Blood 2024; 144 (20): 2070–2071. doi: https://doi.org/10.1182/blood.2024026430   November 14, 2024. 

In this commentary, the authors discuss how the location and immune environment of extramedullary disease (EMD) in multiple myeloma (MM) can affect treatment outcomes. EMD refers to tumor cells growing outside the bone marrow, and patients with EMD often have worse outcomes, even with new immune therapies. The authors highlight a study using spatial transcriptomics, which revealed that EMD lesions have complex variations in both tumor and immune cells. These variations, including the presence of different types of T cells, suggest that while EMD lesions are not immune-excluded, they may be immune-suppressed. This means that targeting the immune suppression in EMD could improve treatment results. The authors also suggest that understanding the specific features of EMD lesions, such as antigen differences, could help tailor therapies, including combining T-cell redirection with other treatments. They conclude that focusing on the location and immune environment of EMD lesions could be key to improving patient outcomes and potentially finding a cure for MM.

 

 

"Clinical features, pathophysiology, and management of acute myelopathy following CAR T-cell therapy"

Source

Xavier Deschênes-Simard, Bianca D. Santomasso, Parastoo B. Dahi; Clinical features, pathophysiology, and management of acute myelopathy following CAR T-cell therapy. Blood 2024; 144 (20): 2083–2094. doi: https://doi.org/10.1182/blood.2024025679  November 14, 2024. 

Chimeric antigen receptor (CAR) T-cell therapy has become a groundbreaking treatment for patients with certain blood cancers, especially those whose cancer doesn't respond to other treatments. However, this therapy can cause side effects, including cytokine release syndrome and neurotoxicity, known as ICANS. Recently, cases of a rare condition called acute myelitis (inflammation of the spinal cord) after CAR T-cell therapy have been reported. While there are guidelines for managing ICANS, there is less information about how to investigate and treat acute myelitis. This study looks into the symptoms, causes, and best ways to manage this rare complication based on reported cases.

 

 

"Symptoms of Hematologic Tumors Patients after CAR-T Therapy: a Systematic Review and Meta-Analysis"

Source

Wan Sun, Shuo Wang, Jiachen Han, Lang Zhuo, Jiang Cao, Fang Zhou, Symptoms of Hematologic Tumors Patients after CAR-T Therapy: a Systematic Review and Meta-Analysis, Journal of Pain and Symptom Management, 2024, ISSN 0885-3924, https://doi.org/10.1016/j.jpainsymman.2024.11.002. November 14, 2024. 

This study looked at the symptoms experienced by patients with blood cancers after receiving Chimeric Antigen Receptor T-cell (CAR-T) therapy. The goal was to understand the severity and frequency of these symptoms, and how they differ across various factors like geographic location, type of cancer, and time after treatment. Researchers reviewed eight studies that reported symptom scores and incidents up until November 2023. They found that sleep problems, fatigue, and depression were among the most severe symptoms, while sadness, memory issues, cough, and nausea were the most common. Patients reported higher symptom severity and frequency in the first 90 days after receiving CAR-T therapy. The study concluded that CAR-T patients often experience multiple symptoms, and the tools and timing used to measure them can impact the results.

 

 

"Preclinical evaluation of the CD38-targeting engineered toxin body MT-0169 against multiple myeloma"

Source

Bruins, W.S.C., Rentenaar, R., Newcomb, J., Zheng, W., Ruiter, R.W.J., Baardemans, T., Poma, E., Moore, C., Robinson, G.L., Lublinsky, A., Zhang, Y., Syed, S., Milhollen, M., Dash, A.B., van de Donk, N.W.C.J., Groen, R.W.J., Zweegman, S. and Mutis, T. (2024), Preclinical evaluation of the CD38-targeting engineered toxin body MT-0169 against multiple myeloma. HemaSphere, 8: e70039. https://doi.org/10.1002/hem3.70039 November 14, 2024. 

This study introduces MT-0169, a new treatment for multiple myeloma (MM), a type of blood cancer that often becomes resistant to existing therapies. MT-0169 is an engineered immunotoxin that combines an antibody targeting CD38 (a protein on MM cells) with a toxin that stops cells from making proteins, ultimately causing cell death. In lab tests, MT-0169 successfully killed MM cells from both newly diagnosed and heavily treated patients, even those resistant to a drug called daratumumab. Importantly, it showed minimal harm to healthy blood cells. The treatment worked well in mice, including in models with human-like bone marrow. These results suggest that MT-0169 could be a promising therapy for patients with relapsed or refractory MM, especially those who don't respond to current CD38-targeting treatments.

 

 

"Immediate improvement in patient care: Auditing adherence to the British Society for Haematology guidelines on screening and management of the long-term consequences of multiple myeloma and treatment"

Source

Sweeney K, Niblock A, Greenfield D, Snowden J. Immediate improvement in patient care: Auditing adherence to the British Society for Haematology guidelines on screening and management of the long-term consequences of multiple myeloma and treatment. eJHaem. 2024; 1–4. https://doi.org/10.1002/jha2.999  November 15, 2024. 

This study aimed to improve the care of multiple myeloma patients by addressing the long-term health issues that can arise from both the disease and its treatment. Researchers adapted an audit tool to measure how well healthcare providers followed guidelines for managing these long-term effects. A checklist was created to help implement these guidelines. The baseline audit showed that some areas, like vaccinations, dental check-ups, and bone health management, were being well managed. However, there were gaps in monitoring things like cholesterol, blood sugar, kidney function, and geriatric assessments for older patients. 

A follow-up audit after three months showed that most areas improved, with high compliance in areas like monitoring bone health and supplementation. However, geriatric assessments, which are important for older patients, were still not being done. The results showed that using a checklist can help ensure that healthcare providers follow the guidelines more consistently and that educating patients about self-management is key. The next steps include using this checklist for all patients annually and finding ways to improve geriatric assessments in care.

 

 

"Comparing stem cell mobilization with chemotherapy and cytokine (G-CSF) versus cytokine alone in myeloma patients (MOCCCA): a randomized phase II, open-label, non-inferiority trial"

Source

Jeker, B., Thalmann, L., Bacher, U. et al. Comparing stem cell mobilization with chemotherapy and cytokine (G-CSF) versus cytokine alone in myeloma patients (MOCCCA): a randomized phase II, open-label, non-inferiority trial. Bone Marrow Transplant (2024). https://doi.org/10.1038/s41409-024-02468-z November 15, 2024. 

This study compared two methods for mobilizing stem cells in newly diagnosed myeloma patients preparing for autologous stem cell transplantation (ASCT). One method used only G-CSF (a growth factor to help produce stem cells), while the other used a combination of chemotherapy and G-CSF. The goal was to see if using only G-CSF could be as effective as the standard method for collecting enough stem cells.

The results showed that the combination of chemotherapy and G-CSF worked better, yielding more CD34+ stem cells than G-CSF alone. Specifically, patients who received the combined treatment had a higher median stem cell yield (9.99 million cells/kg) compared to those who received G-CSF alone (7.42 million cells/kg). The study found no significant differences in side effects or recovery between the two groups, but the use of G-CSF alone was less effective for stem cell collection.

Overall, the study concluded that using chemotherapy with G-CSF is more effective than using G-CSF alone for mobilizing stem cells in these patients.

 

 

"CT-defined muscle density as a prognostic factor in multiple myeloma undergoing autologous stem cell therapy: a retrospective single center study."

Source

Surov, A., Pönisch, W., Borggrefe, J. et al. CT-defined muscle density as a prognostic factor in multiple myeloma undergoing autologous stem cell therapy: a retrospective single center study. J Cancer Res Clin Oncol 150, 499 (2024). https://doi.org/10.1007/s00432-024-06009-5  November 15, 2024. 

This study aimed to understand how skeletal muscle quality, measured by muscle density (SMD), affects survival in patients with multiple myeloma (MM). The researchers looked at data from 127 MM patients who had whole-body CT scans between 2009 and 2019. They measured skeletal muscle index (SMI), muscle density, and other factors like albumin levels and fat in the muscles.

The study found that patients who survived had lower muscle density compared to those who did not survive, and those who did not survive also had lower fat content in their muscles. However, when the data was analyzed further, muscle density and other muscle-related factors were not found to be important predictors of overall survival (OS) or progression-free survival (PFS) in these patients.

In conclusion, the study found that muscle density measurements did not have a significant impact on survival in multiple myeloma patients undergoing stem cell therapy, supporting earlier studies that suggested body composition may not be as important in this type of cancer.

 

 

"A systematic literature review on clonal evolution events preceding relapse in multiple myeloma"

Source

Maja Zimmer Jakobsen, Rasmus Froberg Brøndum, Henrik Gregersen, Hanne Due, Karen Dybkær, A systematic literature review on clonal evolution events preceding relapse in multiple myeloma, Critical Reviews in Oncology/Hematology, 2024,104560,ISSN 1040-8428, https://doi.org/10.1016/j.critrevonc.2024.104560. November 15, 2024. 

This study aimed to understand why multiple myeloma (MM) keeps returning and becoming resistant to treatment. The researchers reviewed 28 articles from 631 publications to find factors that drive relapse and drug resistance in MM. They found that genetic changes, mutational patterns, and non-genetic factors play a major role in how the cancer evolves. Specific genetic mutations, like those in the MAPK-Ras pathway and changes in chromosomes 1 and 17, were linked to the development of resistant cancer cells. The review also highlighted that treatments like melphalan and APOBEC activity affect the mutation patterns in MM. To better understand how MM evolves, the researchers suggest using advanced methods to study the tumor's genetic diversity more closely.

 

 

"Increased CSN5 expression enhances the sensitivity to lenalidomide in multiple myeloma cells"

Source

Takumi Yamamoto, Arisu Furukawa, Yue Zhou, Nobuaki Kono, Shojiro Kitajima, Hiroto Ohguchi, Yawara Kawano, Shingo Ito, Norie Araki, Sumio Ohtsuki, Takeshi Masuda, Increased CSN5 expression enhances the sensitivity to lenalidomide in multiple myeloma cells, iScience, 2024, 111399, ISSN 2589-0042, https://doi.org/10.1016/j.isci.2024.111399. November 15, 2024. 

Lenalidomide (LEN) is a commonly used treatment for multiple myeloma (MM), but some patients do not respond to it, a situation known as primary resistance. In this study, researchers investigated why certain MM cells resist LEN treatment. They found that LEN-resistant cells had lower levels of a protein called CSN5 compared to cells that responded to the drug. The researchers discovered that CSN5 is broken down by a process called the ubiquitin-proteasome pathway, which is controlled by the cullin-RING ubiquitin ligase (CRL). This breakdown of CSN5 interferes with the process that helps LEN destroy certain proteins (IKZF1 and IKZF3), which is essential for its effectiveness. These findings suggest that the lack of CSN5 contributes to LEN resistance, providing insight that could lead to new treatments to overcome this challenge.

 

 

"Clinical significance of complete remission and measurable residual disease in relapsed/refractory multiple myeloma patients treated with T-cell redirecting immunotherapy"

Source

Zabaleta A, Puig N, Cedena M-T, et al. Clinical significance of complete remission and measurable residual disease in relapsed/refractory multiple myeloma patients treated with T-cell redirecting immunotherapy. Am J Hematol. 2024; 1-10. doi:10.1002/ajh.27526  November 16, 2024. 

In this study, researchers looked at how measurable residual disease (MRD) affects patients with relapsed or refractory multiple myeloma (RRMM) who were treated with T-cell redirecting immunotherapy, such as CAR T cells and T-cell engagers (TCE). They found that achieving MRD negativity (no detectable cancer at a very low level) was linked to a significant reduction in the risk of disease progression or death. Patients who stayed MRD negative for a longer time had better survival outcomes, while those who remained MRD positive had poor outcomes. CAR T cell therapy showed higher rates of MRD negativity compared to TCE. However, once MRD negativity was achieved, survival outcomes were similar between the two treatments. The study concluded that achieving and maintaining MRD negativity is the most important factor for predicting survival, and should be a key goal in treating RRMM patients with these therapies.

 

 

"Improved safety of chimeric antigen receptor T cells indirectly targeting antigens via switchable adapters"

Source

Park, H.B., Kim, K.H., Kim, J.H. et al. Improved safety of chimeric antigen receptor T cells indirectly targeting antigens via switchable adapters. Nat Commun 15, 9917 (2024). https://doi.org/10.1038/s41467-024-53996-7 November 18, 2024.  

In this study, researchers explored a new approach to make CAR T-cell therapy safer and more effective for treating cancers. One of the challenges with CAR T-cells is that they sometimes attack normal cells, causing harmful side effects. To solve this, the researchers developed a "switchable" CAR-T system. This system uses an adaptor that targets cancer cells without harming normal cells, even if the tumor antigen is not highly selective, like CD40. They tested this in a mouse model of lymphoma and found that the switchable CAR-T cells could kill the cancer cells while sparing normal cells, such as macrophages. Additionally, by adding a special tag, they could even turn off the CAR-T cells if needed, improving safety. This new system could help make CAR T-cell therapy safer while still being effective against tumors.

 

 

"Elotuzumab-mediated ADCC with Th1-like Vγ9Vδ2 T cells to disrupt myeloma–osteoclast interaction"

Source

Inoue Y, Tenshin H, Teramachi J, et al. Elotuzumab-mediated ADCC with Th1-like Vγ9Vδ2 T cells to disrupt myeloma–osteoclast interaction. Cancer Sci. 2024; 00: 1-5. doi:10.1111/cas.16401  November 18, 2024.   

In this study, researchers explored how expanding a specific type of immune cell, Th1-like γδ T cells, can help target both multiple myeloma (MM) cells and osteoclasts (OCs), which play a role in drug resistance. These T cells were activated using zoledronic acid (ZA) and IL-2, and their effectiveness was tested with the monoclonal antibody elotuzumab (ELO), which targets SLAMF7 on the surface of MM cells and OCs.

The results showed that when combined with ELO, these expanded γδ T cells could more effectively kill MM cells and OCs, especially those expressing SLAMF7. The addition of ELO enhanced the T cells' ability to kill both MM cells and OCs in a lab setting. Importantly, SLAMF7 expression was found to be high on OCs, especially when they developed from monocytes, and this was further increased by RANKL treatment, a key factor in osteoclast formation.

This combination of γδ T cells and ELO offers a promising approach to overcoming the challenges posed by MM and OC interactions, suggesting that it could help disrupt the harmful cycle between these two cell types in multiple myeloma. Further studies could lead to innovative immunotherapies using this method.

 

 

"Symptom experience of patients undergoing treatment for multiple myeloma: a longitudinal real-world electronic patient-reported outcomes study"

Source

Patel, M.N., Nina, A., Branchaud, B. et al. Symptom experience of patients undergoing treatment for multiple myeloma: a longitudinal real-world electronic patient-reported outcomes study. Support Care Cancer 32, 802 (2024). https://doi.org/10.1007/s00520-024-08985-3  November 18, 2024.   

This study looked at how multiple myeloma (MM) patients experience symptoms throughout their treatment and how these symptoms affect their quality of life. Patients were asked to complete weekly symptom surveys using a symptom monitoring app. The study focused on comparing patients who were on their 4th line of therapy (LOT) or more (heavily pretreated) with those on earlier lines of therapy.

The results showed that common and severe symptoms included fatigue, muscle pain, general pain, numbness/tingling, and insomnia. Patients on later lines of therapy (LOT ≥4) reported more numbness/tingling and fatigue compared to those on earlier treatments. While some symptoms like fatigue and muscle pain lasted for months in heavily pretreated patients, those on earlier treatments also had ongoing symptoms like numbness and shortness of breath.

Heavily pretreated patients had more weeks with multiple severe symptoms and more frequent high levels of symptom bother. However, quality of life scores were similar for both groups. The study concluded that patients with MM, regardless of their treatment stage, have significant symptom management needs, but heavily pretreated patients face the greatest challenges. This suggests that better symptom management strategies are needed for all patients, especially those on later lines of therapy.

 

 

"Selinexor combined with bortezomib, lenalidomide, and dexamethasone for the treatment of newly diagnosed multiple myeloma with extramedullary disease"

Source

Yin, J., Zhou, X., Li, X. et al. Selinexor combined with bortezomib, lenalidomide, and dexamethasone for the treatment of newly diagnosed multiple myeloma with extramedullary disease. Sci Rep 14, 28557 (2024). https://doi.org/10.1038/s41598-024-79537-2  November 19, 2024. 

This study looked at the effectiveness and safety of a treatment called XVRd (Selinexor combined with bortezomib, lenalidomide, and dexamethasone) for newly diagnosed multiple myeloma (MM) with extramedullary disease (when cancer spreads outside the bone marrow). It was an observational study with 10 patients who received 8 cycles of XVRd for induction and consolidation, followed by maintenance treatment with Selinexor and lenalidomide for at least 2 years or until the disease worsened or they stopped treatment.

The results showed that all 10 patients responded to the treatment, with 2 achieving stringent complete remission, 2 in complete remission, 4 with very good partial response, and 2 with partial response. The median progression-free survival and overall survival were not reached. The most common side effects were low platelet count (thrombocytopenia), nausea, fatigue, and loss of appetite, but most side effects were manageable.

In conclusion, the XVRd treatment showed strong effectiveness and was generally safe for newly diagnosed multiple myeloma patients with extramedullary disease.

 

 

"Clinical characteristics and risk factors of infection in initially treated patients with multiple myeloma during the induction period"

Source

Qianying Pan, Beihui Huang, Junru Liu, Meilan Chen, Jingli Gu, Lifen Kuang, Xiaozhe Li, Juan Li, Clinical characteristics and risk factors of infection in initially treated patients with multiple myeloma during the induction period, Journal of Infection and Chemotherapy, 2024, ISSN 1341-321X, https://doi.org/10.1016/j.jiac.2024.11.012. November 19, 2024. 

People with multiple myeloma (MM)often have weakened immune systems, making them more likely to get infections, which is a major cause of death. The goal of the study was to identify the risk factors for infection and create a tool (called a nomogram) to help predict which patients are more likely to get infections.

The researchers reviewed the medical records of 230 MM patients diagnosed or treated between 2018 and 2021. They found that 37.4% of patients experienced infections, with lung infections being the most common. The highest infection rates were seen during the first treatment. The study identified several risk factors for infection, including having three or more other health conditions, anemia (low red blood cell count), and high levels of certain blood markers (LDH and β2-MG).

A nomogram was created to predict infection risk, and it showed good accuracy. This tool can help doctors monitor patients who are at higher risk of infection, allowing them to take steps to prevent or treat infections more effectively.

 

 

"Monoclonal gammopathy of undetermined significance with multiple paraproteins: A population-based screening study"

Source

Monoclonal gammopathy of undetermined significance with multiple paraproteins: A population-based screening study. HemaSphere, 8: e70046. https://doi.org/10.1002/hem3.70046  November 19, 2024.

Monoclonal gammopathy of undetermined significance (MGUS) is a condition that can lead to multiple myeloma (MM) and other related disorders. It is marked by the presence of abnormal proteins in the blood, but people with MGUS often don’t show symptoms. Sometimes, people with MGUS have multiple abnormal proteins in their blood, but it’s unclear what this means for their health.

In this study, researchers looked at data from a large screening study in Iceland. Out of 75,422 people over 40, 3,389 (4.4%) had at least one abnormal protein in their blood, and 303 (9%) had multiple abnormal proteins. The most common protein in people with multiple paraproteins was IgM, and IgM and non-IgM proteins often appeared together. Two-thirds of the participants were monitored over time, and it was found that only 31% of those with multiple proteins had the same levels over time.

The study also used a special technique to identify different types of abnormal cells in the blood of some patients with multiple proteins. The findings suggest that when people have multiple paraproteins, it often means different diseases are happening at the same time, and each should be monitored separately. However, the management and treatment for these individuals should be similar to those with just one abnormal protein. The study provides new insights into how doctors can better manage this complex group of MGUS patients.

 

 

"The incidence and clinical significance of monoclonal and oligoclonal protein bands in multiple myeloma patients after BCMA–CAR-T cell therapy: A retrospective study based on LEGEND-2"

Source

Liu, R., Gao, G., Chen, H., Dong, R., Zhang, W., Zhao, W., Liu, J., Wang, J., Lei, B., Wang, B., Liu, J., Xu, X., Lin, Z., Yang, R., Wang, Y., He, A., Wang, F. and Bai, J. (2024), The incidence and clinical significance of monoclonal and oligoclonal protein bands in multiple myeloma patients after BCMA–CAR-T cell therapy: A retrospective study based on LEGEND-2. HemaSphere, 8: e70054. https://doi.org/10.1002/hem3.70054 November 19, 2024. 

Abnormal protein bands (APBs), also called oligoclonal protein bands, can appear in patients with multiple myeloma (MM) after treatment, including hematopoietic stem cell transplantation. However, their occurrence and significance are not fully understood, especially in patients treated with BCMA-targeted CAR-T therapy.  

This retrospective study focused on patients with relapsed or refractory MM who received LCAR-B38M CAR-T therapy in the LEGEND-2 trial. Among 47 patients, 48.9% developed APBs after treatment, with IgG being the most common type. APBs typically appeared about 3.6 months after infusion and lasted for an average of 5.8 months.  

Patients with APBs had better responses to therapy, including deeper remission and longer overall and progression-free survival. They also showed improved immune recovery, with higher levels of immunoglobulins, white blood cells, neutrophils, and lymphocytes. However, no major differences were found in T-cell or natural killer cell populations between those with and without APBs.  

These findings suggest that APBs may indicate a stronger humoral immune response and better immune system recovery, contributing to improved outcomes in MM patients treated with CAR-T therapy.

 

 

"Are we there yet? CAR-T therapy in multiple myeloma"

Source

Mirvis E, Benjamin R. Are we there yet? CAR-T therapy in multiple myeloma. Br J Haematol. 2024; 00: 1–15. https://doi.org/10.1111/bjh.19896  November 19, 2024.    

Recent years have brought major advancements in cellular immunotherapy for multiple myeloma (MM), with B-cell maturation antigen (BCMA) emerging as a key target. BCMA-specific CAR-T therapy was approved in 2021 in the U.S. and Europe, showing impressive initial results in heavily treated MM patients. However, challenges like relapses, high manufacturing costs, and weakened T-cell function from prior treatments remain.  

To improve outcomes, researchers are exploring next-generation CAR-T therapies, off-the-shelf CAR-T options, and targeting additional antigens such as GPRC5D, FcRH5, CD19, and SLAMF7. Promising strategies include targeting multiple antigens—such as BCMA-CD19 combinations—and engineering CAR-T cells to overcome resistance pathways like PD-L1 or TGF-β suppression.  

While BCMA CAR-T therapy represents significant progress, achieving a long-term cure for MM continues to be a challenge. Ongoing research is focused on refining these treatments to overcome resistance and improve durability. 

 

 

"The role of daratumumab in complications post-allogeneic hematopoietic stem cell transplantation: a single-center prospective study on PRCA and AIHA"

Source

Giammarco, S., Limongiello, M.A., Di Marino, L. et al. The role of daratumumab in complications post-allogeneic hematopoietic stem cell transplantation: a single-center prospective study on PRCA and AIHA. Bone Marrow Transplant (2024). https://doi.org/10.1038/s41409-024-02479-w  November 20, 2024.    

Recent years have brought major advancements in cellular immunotherapy for multiple myeloma (MM), with B-cell maturation antigen (BCMA) emerging as a key target. BCMA-specific CAR-T therapy was approved in 2021 in the U.S. and Europe, showing impressive initial results in heavily treated MM patients. However, challenges like relapses, high manufacturing costs, and weakened T-cell function from prior treatments remain.  

To improve outcomes, researchers are exploring next-generation CAR-T therapies, off-the-shelf CAR-T options, and targeting additional antigens such as GPRC5D, FcRH5, CD19, and SLAMF7. Promising strategies include targeting multiple antigens—such as BCMA-CD19 combinations—and engineering CAR-T cells to overcome resistance pathways like PD-L1 or TGF-β suppression.  

While BCMA CAR-T therapy represents significant progress, achieving a long-term cure for MM continues to be a challenge. Ongoing research is focused on refining these treatments to overcome resistance and improve durability. 

 

 

"Bortezomib before and after high-dose therapy in transplant-eligible patients with newly diagnosed multiple myeloma: Long-term overall survival after more than 10 years of follow-up from the phase III HOVON-65/GMMG-HD4 trial"

Source

Mai, E.K., Nogai, A., Lokhorst, H.M., van der Holt, B., Zweegman, S., Weisel, K.C., Croockewit, S., Jauch, A., Hillengass, J., Stevens-Kroef, M., Raab, M.S., Broijl, A., Bos, G.M.J., Brossart, P., Ypma, P., Hanoun, C., Bertsch, U., Hielscher, T., Salwender, H.J., Scheid, C., Goldschmidt, H. and Sonneveld, P. (2024), Bortezomib before and after high-dose therapy in transplant-eligible patients with newly diagnosed multiple myeloma: Long-term overall survival after more than 10 years of follow-up from the phase III HOVON-65/GMMG-HD4 trial. HemaSphere, 8: e70052. https://doi.org/10.1002/hem3.70052  November 20, 2024.     

Recent years have brought major advancements in cellular immunotherapy for multiple myeloma (MM), with B-cell maturation antigen (BCMA) emerging as a key target. BCMA-specific CAR-T therapy was approved in 2021 in the U.S. and Europe, showing impressive initial results in heavily treated MM patients. However, challenges like relapses, high manufacturing costs, and weakened T-cell function from prior treatments remain.  

To improve outcomes, researchers are exploring next-generation CAR-T therapies, off-the-shelf CAR-T options, and targeting additional antigens such as GPRC5D, FcRH5, CD19, and SLAMF7. Promising strategies include targeting multiple antigens—such as BCMA-CD19 combinations—and engineering CAR-T cells to overcome resistance pathways like PD-L1 or TGF-β suppression.  

While BCMA CAR-T therapy represents significant progress, achieving a long-term cure for MM continues to be a challenge. Ongoing research is focused on refining these treatments to overcome resistance and improve durability. 

 

"Cell surface marker heterogeneity in human myeloma cell lines for modeling of disease and therapy"

Source

Behsen, A.D., Holien, T., Micci, F. et al. Cell surface marker heterogeneity in human myeloma cell lines for modeling of disease and therapy. Sci Rep 14, 28805 (2024). https://doi.org/10.1038/s41598-024-80263-y  November 20, 2024.       

Multiple myeloma (MM) is a cancer of plasma cells and is classified into two genetic subtypes: hyperdiploid and non-hyperdiploid. Human myeloma cell lines (HMCLs) are critical for studying MM and developing treatments, but their usefulness depends on how well they match the characteristics of patient-derived cells. In this study, researchers used flow cytometry to analyze the protein expression of 24 surface markers, including targets for MM drugs and immunotherapies, across nine HMCLs. RNA sequencing was also performed to compare protein expression with gene activity.  

Results showed five markers (CD47, CD49d, CD138, BCMA, and GPRC5D) were highly expressed across all cell lines, while three (CD19, CD20, and CD117) were low or absent. The expression of 16 other markers varied among cell lines. Comparing these findings to patient data, four out of six in-house HMCLs closely matched patient MM, with hyperdiploid cell lines aligning more closely to hyperdiploid patient samples. The study also introduced three new HMCLs: IH-1, URVIN, and FOLE.  

These findings highlight the importance of carefully selecting cell lines based on specific research goals, as differences in marker expression can impact the relevance of study results. By aligning HMCL characteristics with patient disease profiles, researchers can improve the accuracy and effectiveness of MM studies.

 

 

"CD71+ erythroid cells promote multiple myeloma progression and impair anti-bacterial immune response"

Source

Czubak K, Grzywa TM, Sidor-Dzitkowska K, Pilch Z, Bielak K, Hoser G, et al. CD71+ erythroid cells promote multiple myeloma progression and impair anti-bacterial immune response. Br J Haematol. 2024; 00: 1–6. https://doi.org/10.1111/bjh.19914  November 20, 2024.       

Multiple myeloma (MM) increases the risk of bacterial infections due to weakened immune function from the cancer itself, treatment side effects, and other health conditions. Recent research has identified CD71+ erythroid cells (CECs) as key players in immune suppression in both newborns and cancer patients. Using a mouse model that mimics human MM, scientists found that MM progression is linked to anemia and an increase in immature CECs with high levels of arginase 2 (ARG2). These CECs suppress T-cell activity, weakening the immune response.  

In the study, mice lacking ARG2 showed slower MM progression and lived longer, suggesting that ARG2 contributes to disease severity. Additionally, mice with MM were more vulnerable to bacterial infections, such as *Listeria monocytogenes*, reflecting the infection risks faced by MM patients. These findings highlight the role of ARG2-expressing CECs in immune suppression and infection susceptibility in MM. Targeting ARG2 could improve immune function and lower infection risks in MM patients, offering a promising therapeutic strategy.

 

 

"Resistance to immunomodulatory drugs in multiple myeloma: the cereblon pathway and beyond"

Source

Teoh PJ, Koh MY, Mitsiades C, Gooding S, Chng WJ. Resistance to immunomodulatory drugs in multiple myeloma: the cereblon pathway and beyond. Haematologica; https://doi.org/10.3324/haematol.2024.285636 [Early view].  November 21, 2024.       

In multiple myeloma (MM), resistance to immunomodulatory drugs (IMiDs) remains a major challenge. While the CRBN (cereblon) pathway plays a key role in how these drugs work, it explains only part of the resistance problem.  

New research highlights other ways MM cells develop resistance to IMiDs that don’t rely on the CRBN pathway. This review explores the latest findings on these alternative mechanisms and discusses potential strategies to overcome resistance. The goal is to improve the effectiveness of IMiD-based treatments in the future.  

 

 

"Serum free light chains in a racially diverse population including African Americans and populations from South Africa"

Source

Luca Bertamini, Jean-Baptiste Alberge, David Jungpa Lee, Habib El-Khoury, Sungjae Kim, Grace Fleming, Ciara Suen Marie Murphy, Julia Colchie, Maya I Davis, Jacqueline Perry, Elizabeth D Lightbody, Sabine Allam, Lindokuhle N Goqwana, Vinitha Philip, Natalie Anne Smyth, Dhananjay Sakrikar, Mark C Perkins, Stephen Harding, Derek Troske, Gad Getz, Elizabeth W Karlson, Nikhil C. Munshi, Kenneth C. Anderson, Lorenzo Trippa, Catherine R Marinac, Wenlong Carl Chen, Maureen Joffe, Irene M Ghobrial; Serum free light chains in a racially diverse population including African Americans and populations from South Africa. Blood 2024; blood.2024026078. doi: https://doi.org/10.1182/blood.2024026078  November 21, 2024.       

Diagnosing light chain (LC) monoclonal gammopathy of undetermined significance (MGUS) traditionally uses reference ranges for serum free light chains (FLC) based on mostly White populations. However, a new study highlights the need for updated guidelines to reflect racial diversity.  

Researchers analyzed FLC levels in 10,035 individuals, including 44% who self-identified as Black, from the U.S., South Africa, and the Mass General Brigham Biobank. Using standard reference ranges, 10.7% of participants were diagnosed with LC-MGUS, but rates were significantly higher among Black individuals—14.8% in the U.S. and 27.8% in South Africa—compared to 4% in White participants.  

To reduce overdiagnosis in populations of African descent, researchers propose updated FLC reference ranges: a κ/λ ratio of 0.686 to 2.10, with κ and λ values between 7.97–77.50 mg/L and 6.20–49.20 mg/L, respectively. These adjustments decrease LC-MGUS diagnoses by 91%, aligning rates with actual disease prevalence.  

This study underscores the importance of basing MGUS diagnostic criteria on diverse populations to prevent unnecessary stress, costs, and treatments for Black individuals.

 

 

"UL4A-DDB1-circRFWD2 E3 ligase complex mediates the ubiquitination of p27 to promote multiple myeloma proliferation"

Source

Min, J., Mao, J., Shi, H. et al. CUL4A-DDB1-circRFWD2 E3 ligase complex mediates the ubiquitination of p27 to promote multiple myeloma proliferation. Exp Hematol Oncol 13, 116 (2024). https://doi.org/10.1186/s40164-024-00582-8 November 22, 2024.      

Research shows that multiple myeloma cells can interact with their surroundings using circular RNAs (circRNAs), a type of genetic material that doesn’t code for traditional proteins.  

This study focused on a specific circRNA, **circRFWD2 (hsa_circ_0015361)**, which is produced by MM cells and makes a protein called circRFWD2_369aa. Higher levels of this protein in the blood were linked to worse outcomes for MM patients.  

Researchers discovered that circRFWD2 plays a key role in MM cell growth by breaking down a cell-regulating protein called p27 through the ubiquitination pathway. This happens because circRFWD2 interacts with other genes, **DDB1 and CUL4A**, forming a complex that tags p27 for destruction. Interestingly, the protein created by circRFWD2 also acts as part of this tagging system, called an E3 ligase.  

The findings suggest that circRFWD2 could be a valuable biomarker to improve MM diagnosis and treatment monitoring. This opens the door to new strategies for tackling this challenging disease.  

 

 

"UL4A-DDB1-circRFWD2 E3 ligase complex mediates the ubiquitination of p27 to promote multiple myeloma proliferation"

Source

Hu, Q., Liu, Y., Yue, Q. et al. Lenalidomide-induced pure red cell aplasia is associated with elevated expression of MHC-I molecules on erythrocytes. Nat Commun 15, 10131 (2024). https://doi.org/10.1038/s41467-024-54571-w  November 22, 2024.   

RVd therapy, a combination of lenalidomide, bortezomib, and dexamethasone, is a key treatment for multiple myeloma. However, a patient developed a rare condition called pure red cell aplasia (PRCA) after receiving RVd, even though they had no common risk factors for PRCA.  

Researchers studied the patient’s bone marrow and found overactive CD8+ T cells and problems with red blood cell production (erythropoiesis). Surprisingly, the patient’s red blood cell precursors had unusually high levels of genes linked to antigen presentation, especially major histocompatibility class I (MHC-I) molecules. Lab tests showed that lenalidomide increased MHC-I expression in these cells, worsening the problem.  

Blocking MHC-I or removing T cells improved red blood cell production, suggesting that interactions between T cells and MHC-I-overexpressing erythroid cells in the bone marrow contributed to PRCA. This study highlights how lenalidomide might trigger PRCA and offers insights for managing this rare side effect in cancer patients.

 

 

"Utilization of hematopoietic cell transplantation and cellular therapy technology in Europe and associated Countries. Using the 2022 activity survey data to correlate with economic and demographic factors. A report from the EBMT"

Source

Passweg, J.R., Baldomero, H., Alexander, T. et al. Utilization of hematopoietic cell transplantation and cellular therapy technology in Europe and associated Countries. Using the 2022 activity survey data to correlate with economic and demographic factors. A report from the EBMT. Bone Marrow Transplant (2024). https://doi.org/10.1038/s41409-024-02459-0  November 22, 2024. 

In 2022, 46,143 hematopoietic cell transplants (HCTs) were performed worldwide, including 19,011 allogeneic and 27,132 autologous procedures. Additionally, 4,329 patients received advanced cellular therapies, with 3,205 undergoing CAR-T therapy. However, there were notable differences in how these therapies were used across countries. For allogeneic HCTs, donor types varied significantly: Germany and the Netherlands led in unrelated donor use, while Israel and Lebanon had the highest rates for identical sibling transplants. Haploidentical transplants were most common in Israel and Italy, and cord blood transplants were highest in the Netherlands and the UK.  

The study also linked treatment rates to national income, population demographics, and center density. Italy led in HCT rates, while Switzerland had the highest CAR-T use. In resource-limited countries, HCT procedures were concentrated in fewer centers, reflecting access challenges. These findings reveal global disparities in access to life-saving treatments and provide insights for improving availability and equity in advanced therapies.

 

 

"Therapeutic advantage of combinatorial CAR T cell and chemotherapies"

Source

Meghan B. Ward, Amber B. Jones, Giedre Krenciute, Therapeutic advantage of combinatorial CAR T cell and chemo-therapies, Pharmacological Reviews, 2024, 100011, ISSN 0031-6997, https://doi.org/10.1124/pharmrev.124.001070. November 22, 2024. 

CAR T-cell therapy has revolutionized treatment for blood cancers, but it doesn’t work for everyone and faces challenges in solid and brain tumors. Issues like hostile tumor environments and limited CAR T-cell survival make it unlikely that this approach alone can fully eliminate tumors in all patients.  

Combining CAR T cells with chemotherapy offers a promising solution. Chemotherapy can enhance CAR T-cell activity or work alongside them to clear tumors more effectively. This review highlights efforts to develop successful combinations, focusing on approved chemotherapies for quicker clinical application while also exploring experimental drugs and new drug-screening strategies.  

By addressing the limitations of CAR T-cell therapy and chemotherapy as standalone treatments, these combinations could lead to better outcomes for cancer patients, paving the way for more effective and versatile therapies.

 

"Effects of socioeconomic status and healthcare resource availability on survival in older (≥66 years) non-Hispanic Black patients versus non-Hispanic White patients with multiple myeloma: Socioeconomic factors in multiple myeloma survival"

Source

MegSophia S. Li, Robert Schuldt, Faiza Zafar, Tu My To, Archibong Yellow-Duke, Alina Levine, Allicia Girvan, Shelli Spence, Joseph Mikhael, Effects of socioeconomic status and healthcare resource availability on survival in older (≥66 years) non-Hispanic Black patients versus non-Hispanic White patients with multiple myeloma: Socioeconomic factors in multiple myeloma survival, Clinical Lymphoma Myeloma and Leukemia, 2024, ISSN 2152-2650, https://doi.org/10.1016/j.clml.2024.11.011. November 22, 2024. an B. Ward, Amber B. Jones, Giedre Krenciute, Therapeutic advantage of combinatorial CAR T cell and chemo-therapies, Pharmacological Reviews, 2024, 100011, ISSN 0031-6997, https://doi.org/10.1124/pharmrev.124.001070. November 22, 2024.   

This study examined how socioeconomic status (SES) and healthcare resource (HCR) availability affect survival outcomes in older Black and White patients with multiple myeloma (MM). Researchers analyzed data from 6,609 patients aged 66 and older diagnosed between 2013 and 2017 using SEER-Medicare claims. Among the participants, 15.6% were non-Hispanic Black (NHB).  

NHB patients were generally younger, more often female, and more likely to live in areas with higher poverty and lower education levels than non-Hispanic White (NHW) patients. The unadjusted median overall survival (OS) was slightly shorter for NHB patients (2.76 years) compared to NHW patients (3.01 years), but this difference was not statistically significant. When adjusted for factors like age, sex, comorbidities, SES, and HCR availability, the survival gap by race disappeared (hazard ratio: 0.92; P = 0.12). Factors such as older age, male sex, and higher comorbidity scores were linked to poorer survival, while SES and access to medical care played smaller but notable roles.  

The findings suggest that SES and healthcare access are key drivers of survival disparities in MM. More research with larger datasets is needed to better understand and address these inequities.  

 

 

"RD-driven phase 2 study of daratumumab, carfilzomib, lenalidomide and dexamethasone in newly diagnosed multiple myeloma"

Source

Manisha Bhutani, Myra Robinson, David Foureau, Shebli Atrash, Barry A Paul, Fei Guo, Jason Grayson, Anna Ivanina-Foureau, Mauricio Pineda-Roman, Cindy Varga, Reed Friend, Christopher J Ferreri, Xhevahire Begic, Sarah Norek, Tiffany Drennan, Michelle B Anderson, James T Symanowski, Peter M Voorhees, Saad Z Usmani; MRD-driven phase 2 study of daratumumab, carfilzomib, lenalidomide and dexamethasone in newly diagnosed multiple myeloma. Blood Adv 2024; bloodadvances.2024014417. doi: https://doi.org/10.1182/bloodadvances.2024014417  November 22, 2024. 

In a phase II clinical trial, researchers tested a treatment strategy using daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd) for newly diagnosed multiple myeloma (NDMM) patients. The study aimed to assess how measurable residual disease (MRD) status affects treatment decisions. The primary goal was to determine the rate of complete response (≥CR) after the treatment.  

Out of 39 patients, 54% achieved a complete response, and 59% had MRD-negative results at a 10-5 threshold. Patients who were MRD-negative (group A) continued with lenalidomide maintenance, and 77.8% remained MRD-negative for over 12 cycles. MRD-positive patients who were eligible for a stem cell transplant (group B) had a 62.5% rate of becoming MRD-negative after the transplant. For those ineligible for a transplant (group C), consolidation treatment with KRd improved MRD-negative rates to 77%. The treatment did not present any new safety concerns. With a follow-up of about 30 months, the progression-free survival rate was 82.5%.  

Overall, while the primary endpoint was not met, the Dara-KRd regimen showed high rates of complete response and MRD negativity, with the MRD-adapted strategy further improving outcomes for MRD-positive patients and maintaining long-term control for MRD-negative patients.

 

 

"Outcome of patients with central nervous system multiple myeloma (CNS-MM) treated with CNS-directed radiation therapy: Outcomes of RT for CNS-multiple myeloma"

Source

Gohar S. Manzar, Stephanie O. Dudzinski, Alison K. Yoder, Aaron Seo, Lewis F. Nasr, Hind Rafei, Melody R. Becnel, Krina K. Patel, Hans C. Lee, Gregory P. Kaufman, Mahmoud M. Gaballa, Jing Christine Ye, Neeraj Saini, Sheeba K. Thomas, Behrang Amini, Robert Z. Orlowski, Bouthaina S. Dabaja, Chelsea C. Pinnix, Jillian R. Gunther, Susan Y. Wu, Penny Q. Fang, Outcome of patients with central nervous system multiple myeloma (CNS-MM) treated with CNS-directed radiation therapy: Outcomes of RT for CNS-multiple myeloma, Clinical Lymphoma Myeloma and Leukemia, 2024, ISSN 2152-2650, https://doi.org/10.1016/j.clml.2024.11.010. November 22, 2024. 

Multiple myeloma (MM) involving the central nervous system (CNS-MM) is a rare and serious condition with a poor prognosis. This study looked at patients treated with CNS-directed radiation therapy (RT) from 2015 to 2024. CNS-MM was defined by the presence of disease in the brain or spinal fluid. Treatment responses were categorized as complete response (CR), partial response (PR), or stable disease (SD) based on imaging and cerebrospinal fluid (CSF) findings. 

Out of 45 patients, 62% had high-risk disease, and the median overall survival (OS) after a CNS-MM diagnosis was just 3.7 months. Most patients received craniospinal irradiation, and the average radiation dose was 20 Gy. Of the 21 patients who had follow-up data, 67% achieved a complete response, 24% had a partial response, and 10% had stable disease. Patients with a complete response had a median OS of 7.3 months. Those with focal brain disease had a better chance of long-term survival and achieving CNS control. 

In conclusion, while CNS-MM remains a high-risk condition, aggressive treatment with radiation can provide durable control in a small group of patients.

 

 

"Comprehensive review of bispecific antibody constructs in multiple myeloma: affinities, dosing strategies and future perspectives: Clinical Lymphoma, Myeloma & Leukemia"

Source

Johannes M. Waldschmidt, Leo Rasche, K. Martin Kortüm, Hermann Einsele, Comprehensive review of bispecific antibody constructs in multiple myeloma: affinities, dosing strategies and future perspectives: Clinical Lymphoma, Myeloma & Leukemia (CLML), Clinical Lymphoma Myeloma and Leukemia, 2024, ISSN 2152-2650, https://doi.org/10.1016/j.clml.2024.11.012. November 22, 2024.  

Recent developments in bispecific antibodies (bsAbs), which are designed to target two different molecules at once, have shown promise for treating multiple myeloma (MM), especially in patients who have already tried other therapies. Drugs like teclistamab, elranatamab, and talquetamab are already approved for use in patients with relapsed or refractory MM. These bsAbs target different proteins on MM cells and T cells to help the immune system attack the cancer.

New bsAbs are being developed, including drugs that target different MM-related antigens and offer additional ways to stimulate the immune system. Some promising new drugs are currently in late-stage clinical trials. However, despite the growing number of options, resistance to bsAbs is likely to develop, and the best way to use these treatments alongside other therapies is still being studied. This review looks at the strengths and limitations of the available bsAbs and the challenges that still need to be addressed to improve the effectiveness and safety of these treatments for MM patients.

 

 

"Standardized Flow Cytometry Assays for Enumerating CD34 + Hematopoietic Stem Cells."

Source

Al-Attar, A. and Sutherland, D.R. (2024). Standardized Flow Cytometry Assays for Enumerating CD34 + Hematopoietic Stem Cells. In Manual of Molecular and Clinical Laboratory Immunology (eds J.L. Schmitz, B. Detrick and M.R.G. O'Gorman). https://doi.org/10.1002/9781683674023.ch16  November 22, 2024.  

Flow cytometry, which measures CD34+ cells, is a method used to assess the quality of stem cell grafts. This technique avoids the limitations of older methods like colony-forming unit assays, as it counts the most primitive stem cells as well as developing progenitors. However, at most transplant centers, the collected stem cells are frozen and then directly infused into patients, with no way to assess the quality of the graft once it's collected and before it’s reinfused. Laboratory tests that measure graft quality take time, which means they can't be used in real-time. Ideally, a detailed evaluation of stem cells from collection to reinfusion would ensure their quality. Plerixafor is a drug used to help move hematopoietic stem cells from the bone marrow into the blood for collection and later use in autologous transplants for patients with non-Hodgkin lymphoma and multiple myeloma.

 

 

"The MAPK/ERK signaling pathway involved in Raddeanin A induces apoptosis via the mitochondrial pathway and G2 phase arrest in multiple myeloma"

Source

Jiang, Mz., Li, C., Mao, Cm. et al. The MAPK/ERK signaling pathway involved in Raddeanin A induces apoptosis via the mitochondrial pathway and G2 phase arrest in multiple myeloma. Sci Rep 14, 29061 (2024). https://doi.org/10.1038/s41598-024-76465-z  November 23, 2024.  

Multiple myeloma (MM) is caused by the uncontrolled growth of plasma cells in the bone marrow. Raddeanin A (RA), a natural compound found in Anemone raddeana regel, has shown anti-inflammatory and anti-tumor effects, but most studies have focused on solid tumors, not MM. This study explores how RA affects MM, focusing on its biological activity and how it works at a molecular level. The researchers found that RA affects the MAPK signaling pathway, particularly the MAPK1 gene (also known as ERK2), which plays a role in MM development. 

In lab tests, RA inhibited the growth of MM cells in a dose-dependent and time-dependent way. The study showed that RA stopped the cell cycle in the G2 phase, caused cell death, and changed the mitochondrial membrane potential in MM cells. It also increased the levels of proteins linked to apoptosis (cell death), like Bim, Caspase 3/9, and Cleaved PARP, while decreasing Mcl-1, a protein that helps cells survive. Additionally, RA treatment reduced the activity of proteins involved in the MAPK/ERK signaling pathway, such as p-ERK1/2 and p-MEK1/2. These findings suggest that RA can fight MM by stopping cell growth and triggering cell death through the MAPK/ERK pathway.

 

"Effect of monoclonal gammopathy in the progression of acute kidney injury and chronic kidney disease: a retrospective observational study"

Source

Mitani, K., Horino, T., Terada, Y. et al. Effect of monoclonal gammopathy in the progression of acute kidney injury and chronic kidney disease: a retrospective observational study. Clin Exp Nephrol (2024). https://doi.org/10.1007/s10157-024-02571-x  November 23, 2024.   

This study aimed to evaluate how monoclonal immunoglobulin (MIg) affects kidney function in patients, especially those without a known disease like multiple myeloma. Researchers looked at clinical data from 1,362 patients at Kochi Medical School Hospital between 2017 and 2021, focusing on two main outcomes: the development of acute kidney injury (AKI) and a drop in kidney function (more than 30% decline in the estimated glomerular filtration rate, or eGFR). 

The study found that 119 out of 750 patients tested positive for MIg (15.9%), and these patients were older than those who tested negative. Over the two-year observation period, MIg-positive patients had a significantly lower survival rate than MIg-negative patients. The key factors linked to kidney damage were having MIg, being female, having lower kidney function (eGFR), and lower albumin levels. The study concluded that the presence of MIg is an independent risk factor for kidney damage, and these patients should be carefully monitored for kidney issues, even without a clear underlying disease.

 

 

"A Novel In Silico Approach for Identifying Multi-Target JAK/STAT Inhibitors as Anticancer Agents"

Source

Alessia Bono, Gabriele La Monica, Federica Alamia, Antonino Lauria, Annamaria Martorana, A Novel In Silico Approach for Identifying Multi-Target JAK/STAT Inhibitors as Anticancer Agents, Journal of Molecular Graphics and Modelling, 2024, 108913,ISSN 1093-3263, https://doi.org/10.1016/j.jmgm.2024.108913. November 23, 2024.   

This study focuses on finding new anticancer drugs by targeting the JAK/STAT signaling pathway, which helps control cell death and survival. When this pathway is disrupted, it can lead to diseases like cancer. The researchers used a new approach to screen for drugs that could block JAK/STAT and help treat tumors. They first used a tool to analyze a large database of cancer-related compounds, selecting those that could affect multiple targets. Then, they used molecular docking to test how well different compounds interacted with JAK2, JAK3, and STAT3, which are key parts of the JAK/STAT pathway. The most promising compound identified was 755435, and further testing showed that it was stable and could potentially be used as an anticancer treatment.

 

 

"Pharmacokinetic Positron Emission Tomography Imaging of an Optimized CD38-Targeted 68Ga-Labeled Peptide in Multiple Myeloma: A Pilot Study"

Source

Qi Yang, Lele Song, Zhao Chen, Yongkang Qiu, Tianyao Wang, Xinyao Sun, Wenpeng Huang, Cuicui Li, Zihua Wang, Lei Kang, Pharmacokinetic Positron Emission Tomography Imaging of an Optimized CD38-Targeted 68Ga-Labeled Peptide in Multiple Myeloma: A Pilot Study, Bioconjugate Chemistry,2024, ISSN  

This study focuses on developing a new peptide called PF381, which targets CD38, a protein commonly found on the surface of multiple myeloma (MM) cells. The goal was to explore how PF381 could help diagnose and monitor MM through imaging. The researchers created PF381 and attached it to a radioactive molecule (68Ga) for use in PET scans. They tested it in mice with tumor models and found that the peptide specifically targeted CD38-positive tumors, showing high levels of radioactivity in those areas, but not in tumors that lacked CD38. The peptide also demonstrated good tumor penetration and could be used for sensitive imaging of MM. The study suggests that PF381 could be a useful tool for diagnosing and monitoring MM in patients.

 

 

"Light-chain amyloidosis with concomitant symptomatic myeloma (CRAB-SLiM features): clinical characteristics, cytogenetic abnormalities, and outcomes"

Source

Yu, C., Li, J., Xu, T. et al. Light-chain amyloidosis with concomitant symptomatic myeloma (CRAB-SLiM features): clinical characteristics, cytogenetic abnormalities, and outcomes. BMC Cancer 24, 1449 (2024). https://doi.org/10.1186/s12885-024-13219-0  November 25, 2024.   

This study looked at patients with light-chain (AL) amyloidosis who also have multiple myeloma (MM), a combination known to have a worse prognosis. The researchers compared patients with just MM, just AL amyloidosis, and those with both conditions (MM-AL) to understand their clinical features, genetic abnormalities (cytogenetic abnormalities or CA), and outcomes. They found that patients with MM-AL had the lowest survival rates compared to those with MM or AL alone. Certain genetic changes, like t(11;14), were more common in AL alone, while others, like del13q and gain1q21, were more common in MM-AL. For MM-AL patients, the survival rates were poor, especially for those with t(11;14). The study concluded that MM-AL patients need longer and more aggressive treatment, including extended induction cycles and maintenance therapy, to improve their prognosis.

 

 

"Real-world practitioner perceptions of CARTITUDE-4 results for patients with previously treated multiple myeloma"

Source

Balanean A, Baird S, Dulka B, Jennings-Zhang L, Bone RN, Jeune-Smith Y, et al. Real-world practitioner perceptions of CARTITUDE-4 results for patients with previously treated multiple myeloma. eJHaem. 2024; 1–11. https://doi.org/10.1002/jha2.1047  November 25, 2024.  

The treatment of multiple myeloma has improved significantly in recent years. One of the biggest advancements is chimeric antigen receptor (CAR) T-cell therapy, which targets the B cell maturation antigen (BCMA). This therapy is now approved for patients whose disease has relapsed or is resistant to treatment, and it's being explored for use earlier in treatment. This review discusses the evidence behind current approvals and looks at ways to make CAR-T therapy even more effective. Some of these include addressing problems like BCMA loss, dealing with the tumor environment that suppresses the immune system, improving manufacturing processes, and managing safety issues like cytokine release syndrome and neurotoxicity. The review also highlights the importance of selecting the right patients for this therapy.

 

 

"Clonal hematopoiesis impacts frailty in newly diagnosed multiple myeloma patients: a retrospective multicenter analysis"

Source

Gelli, E., Martinuzzi, C., Soncini, D. et al. Clonal hematopoiesis impacts frailty in newly diagnosed multiple myeloma patients: a retrospective multicenter analysis. Sci Rep 14, 29394 (2024). https://doi.org/10.1038/s41598-024-79748-7  November 26, 2024.   

Clonal hematopoiesis of indeterminate potential (CHIP) refers to genetic mutations in blood cells that are found in healthy individuals. These mutations can increase the risk of developing blood cancers and heart diseases. CHIP has also been observed in multiple myeloma (MM) patients, but its role in the disease is not fully understood. This study analyzed the blood of 76 patients with newly diagnosed multiple myeloma (NDMM) and found that 46% had CHIP. The most common mutations were in the DNMT3A and TET2 genes. Patients with CHIP had more aggressive forms of MM and were more likely to have high-risk disease stages. Over time, some of the mutations showed an increase in their frequency, particularly those in genes related to epigenetics and DNA repair. CHIP patients also had poorer survival outcomes, weaker immune systems, and higher frailty, leading to more toxicity from treatment and shorter survival without disease progression. The study also found that a higher platelet count could be a marker for CHIP in these patients. This research suggests that CHIP may influence the progression of MM, and developing personalized treatments for patients with CHIP could improve outcomes.

 

 

"Ixazomib as consolidation and maintenance versus observation in patients with relapsed multiple myeloma eligible for salvage autologous stem-cell transplantation (Myeloma XII [ACCoRD]): interim analysis of a multicentre, open-label, randomised, phase 3 trial"

Source

Cook, Gordon et al. Ixazomib as consolidation and maintenance versus observation in patients with relapsed multiple myeloma eligible for salvage autologous stem-cell transplantation (Myeloma XII [ACCoRD]): interim analysis of a multicentre, open-label, randomised, phase 3 trial. The Lancet Haematology, Volume 11, Issue 11, e816 - e829. November 2024.  

This clinical trial aimed to determine whether adding consolidation and maintenance therapy after a second autologous stem cell transplant (HSCT) improves outcomes for patients with relapsed multiple myeloma. The treatment involved ixazomib, thalidomide, and dexamethasone, followed by ixazomib alone, compared to simply observing patients without additional treatment.

The trial, known as ACCorD, took place at 79 hospitals in the UK and involved 206 patients. These patients were split into two groups: one group received the consolidation and maintenance treatment, while the other group was monitored without further therapy. The main goal of the study was to measure progression-free survival (how long patients live without the disease worsening).

After about 27 months of follow-up, the group that received consolidation and maintenance treatment had a median progression-free survival of 20 months, compared to 13 months for the observation group. This means the treatment group had better disease control. However, more serious side effects were reported in the treatment group, especially infections, though no deaths were linked to the treatment.

The study concludes that adding ixazomib-based therapy after a second stem cell transplant can improve how long patients live without disease progression, offering a good treatment option for patients who responded well to their first transplant.

 

 

"Accelerating CAR-T Cell Therapies with Small-Molecule Inhibitors"

Source

Mestermann, K., Garitano-Trojaola, A. & Hudecek, M. Accelerating CAR-T Cell Therapies with Small-Molecule Inhibitors. BioDrugs (2024). https://doi.org/10.1007/s40259-024-00688-9   November 26, 2024.   

Chimeric antigen receptor T-cell (CAR-T) therapy has greatly improved survival rates for patients with B-cell cancers like lymphoma. However, it has been less effective for other blood cancers, such as acute myeloid leukemia, and solid tumors. Some challenges include the loss of target markers on cancer cells, difficulty reaching target cells, and the short-lasting effects of these treatments due to the harsh tumor environment. Manufacturing CAR-T cells is also complicated, and patients often experience side effects like cytokine release syndrome and neurotoxicity.

This review discusses how small-molecule inhibitors, some of which are already used in treatment, could help make CAR-T therapy more effective. These inhibitors could improve the production of CAR-T cells, boost their ability to fight tumors, and reduce side effects. Although more research is needed, the promising results from early studies suggest that combining CAR-T therapy with cancer pathway inhibitors may lead to better treatments, offering hope for patients with hard-to-treat cancers.

 

 

"Comparison of outcomes by race among a population-based matched sample of multiple myeloma patients"

Source

Greteman, B.B., Tomasson, M.H., Kahl, A.R. et al. Comparison of outcomes by race among a population-based matched sample of multiple myeloma patients. Cancer Causes Control (2024). https://doi.org/10.1007/s10552-024-01938-5  November 26, 2024.   

This study looked at racial differences in treatment and survival for multiple myeloma (MM) patients in Iowa, where there are known differences in cancer rates and death. The researchers used data from the Iowa Cancer Registry and matched Black patients with White patients based on their age and city of residence to understand why outcomes might differ.

The study included 1,845 patients, with 85 Black patients and 1,760 White patients. When the researchers compared the survival rates of Black and White patients after matching them by age and location, they found no significant differences in survival between the groups. Although Black patients had a lower risk of dying from MM in the overall sample, this difference disappeared when comparing matched groups. There were no major treatment differences between the two groups.

The study found no survival differences between Black and White MM patients in Iowa when matched by age and location, suggesting there are no major treatment barriers based on race in this state. The researchers suggest that future studies should look at other factors that may affect survival, such as specific treatments or differences in rural and urban areas.

 

 

"An emergency medicine review: Multiple myeloma and its complications"

Source

Brit Long, Arleigh McCurdy, Alex Koyfman, Hans Rosenberg, An emergency medicine review: Multiple myeloma and its complications, The American Journal of Emergency Medicine, 2024, ISSN 0735-6757, https://doi.org/10.1016/j.ajem.2024.11.073. November 26, 2024.    

Multiple myeloma (MM) can lead to serious health problems and complications. This review focuses on how MM and its complications are managed in the emergency department (ED). 

MM is the second most common blood cancer and involves the growth of abnormal plasma cells. Symptoms can range from mild to severe, with common issues including anemia, bone pain, kidney problems, fatigue, high calcium levels, and weight loss. While treatments have improved survival, MM can cause many complications. Anemia is common, but other problems like blood thickening, bleeding, and kidney damage can also occur. Bone damage is seen in most patients, which can lead to fractures. Neurological issues, including spinal cord compression and nerve damage, can also happen. Other complications include heart problems from treatment, blood clots, and issues with hormones like adrenal or thyroid dysfunction.

Understanding these complications helps emergency doctors diagnose and treat MM quickly to improve patient outcomes.

 

 

"Daratumumab-based regimen for newly diagnosed multiple myeloma patients with paraskeletal plasmacytomas: a retrospective study in a single center"

Source

Xu, S., Chen, W., & Li, Y. (2024). Daratumumab-based regimen for newly diagnosed multiple myeloma patients with paraskeletal plasmacytomas: a retrospective study in a single center. Hematology, 29(1). https://doi.org/10.1080/16078454.2024.2431958  November 26, 2024.    

This study aimed to compare the effectiveness of daratumumab-based treatments for newly diagnosed multiple myeloma (NDMM) patients with paraskeletal plasmacytomas (PPs) to those who received treatments without daratumumab.

The study analyzed data from 28 patients with NDMM and PPs, dividing them into two groups: one receiving daratumumab-based treatment (group A) and the other receiving treatment without daratumumab (group B). The researchers compared survival rates, efficacy, and risk factors between the two groups.

The findings showed that patients in group A, who received daratumumab, had better survival outcomes and effectiveness. Specifically, group A had a lower risk of death compared to group B, and their overall survival was significantly longer (54 months versus 27 months).

The study concluded that daratumumab-based treatments should be prioritized for patients with multiple myeloma and extramedullary disease (like paraskeletal plasmacytomas), as they improve survival and treatment effectiveness.

 

 

"Splenic T2 signal intensity loss on MRI is associated with disease burden in multiple myeloma"

Source

Neelsen, C., Sachpekidis, C., John, L. et al. Splenic T2 signal intensity loss on MRI is associated with disease burden in multiple myeloma. Eur Radiol (2024). https://doi.org/10.1007/s00330-024-11191-8  November 27, 2024. 

This study looked at how changes in the spleen's signal on different MRI scans could be linked to the level of plasma cell infiltration in the bone marrow, which is an indicator of disease burden in multiple myeloma (MM).

The study analyzed MRI scans from 45 newly diagnosed MM patients. These patients had different types of MRI sequences, including DWI and T2-TSE, to assess spleen signal changes. Additionally, a subgroup of 39 patients also had PET/CT scans. Researchers compared these MRI signals with bone marrow biopsy results and other clinical data, such as lab markers and disease stage.

The results showed that the spleen’s signal intensity on specific MRI sequences (DWI-b50, DWI-b800, and T2-TSE) was negatively linked to the amount of plasma cell infiltration in the bone marrow, meaning that higher infiltration corresponded to lower spleen signal intensity. However, no correlation was found between spleen size, the apparent diffusion coefficient, or PET/CT data with bone marrow plasma cell infiltration.

The study suggests that changes in spleen signal, especially on T2-weighted MRI images, could be useful for assessing the level of tumor burden in MM patients.

 

 

"Phase separation of chimeric antigen receptor promotes immunological synapse maturation and persistent cytotoxicity"

Source

Xinyi Xu, Haotian Chen, Zhengxu Ren, Xiaomin Xu, Wei Wu, Haochen Yang, JinJiao Wang, Yumeng Zhang, Qiuping Zhou, Hua Li, Shaoqing Zhang, Haopeng Wang, Chenqi Xu, Phase separation of chimeric antigen receptor promotes immunological synapse maturation and persistent cytotoxicity, Immunity, 2024, ISSN 1074-7613, https://doi.org/10.1016/j.immuni.2024.11.005. November 27,2024. 

Chimeric antigen receptor (CAR)-T cell therapy faces challenges like poor sensitivity to antigens and limited cell persistence. This study offers a solution by using a technique called CAR phase separation. Researchers added a special T cell receptor motif, EB6I, to traditional CARs, which allowed the CAR-T cells to better recognize and attack tumor cells. The EB6I CAR-T cells formed a stronger immune connection with tumor cells, improving their ability to kill low-antigen tumors and persist in the body for longer. In tests on mice with both blood cancers and solid tumors, EB6I CAR-T cells showed better anti-tumor effects than regular CAR-T cells. This new CAR engineering method could improve the effectiveness of CAR-T cell therapy by enhancing immune signaling.

 

 

"The Prognostic Potential of circRNAs in Multiple Myeloma: Insights From Whole Bone Marrow and Purified Plasma Cells"

Source

Jakobsen, T., Pløen, G.G., Behsen, A.D., Møller, H.J., Plesner, T., Dybkær, K., Andersen, M.N., Misund, K. and Kristensen, L.S. (2024), The Prognostic Potential of circRNAs in Multiple Myeloma: Insights From Whole Bone Marrow and Purified Plasma Cells. J Cell Mol Med, 28: e70215. https://doi.org/10.1111/jcmm.70215 November 27, 2024. 

Multiple myeloma (MM) affects plasma cells in the bone marrow, and patients with rapidly growing plasma cells have a lower chance of survival. Circular RNAs (circRNAs) are molecules that don’t code for proteins but could be useful as cancer markers. In this study, researchers explored the potential of circRNAs as markers for MM and their connection to cell growth. They analyzed RNA from two groups: one with MM patients and one with healthy controls. The results showed that circRNAs were more abundant in MM patients’ bone marrow than in healthy people. In bone marrow samples, high levels of circRNAs linked to low cell growth were linked to a poorer prognosis, while in purified plasma cells, high levels of circRNAs were associated with a better prognosis. These findings suggest that circRNAs could be important markers to predict the outcome of MM.

 

 

 

"Talquetamab in Multiple Myeloma: Efficacy, Safety, and Future Directions"

Source

Labanca, C., Martino, E.A., Vigna, E., Bruzzese, A., Mendicino, F., Lucia, E., Olivito, V., Puccio, N., Neri, A., Morabito, F. and Gentile, M. (2024), Talquetamab in Multiple Myeloma: Efficacy, Safety, and Future Directions. Eur J Haematol. https://doi.org/10.1111/ejh.14353  November 27, 2024. 

Relapsed and refractory multiple myeloma (RRMM) is still difficult to treat, even with new immunotherapies. Talquetamab, a novel bispecific antibody (BsAb), has shown promising results, especially in patients who have not responded to several treatments. Recently approved by the FDA and EMA, talquetamab is used for patients who have already tried at least three or four treatment lines. After a step-up dosing phase to manage side effects like cytokine release syndrome (CRS), talquetamab showed an overall response rate (ORR) of about 70%, even in patients who had received prior T-cell therapies. Its safety profile is similar to other BsAbs, with common side effects like anemia and neutropenia, and some unique issues such as taste changes and skin problems. Infections are less common than with other BsAbs. Research is ongoing to determine the best way to combine talquetamab with other therapies, including CAR-T cell treatments. The real-world data confirms its effectiveness, making it an important treatment option for RRMM.

 

 

"High level of circulating cell-free tumor DNA at diagnosis correlates with disease spreading and defines multiple myeloma patients with poor prognosis"

Source

Martello, M., Solli, V., Mazzocchetti, G. et al. High level of circulating cell-free tumor DNA at diagnosis correlates with disease spreading and defines multiple myeloma patients with poor prognosis. Blood Cancer J. 14, 208 (2024). https://doi.org/10.1038/s41408-024-01185-6  November 28, 2024. 

Multiple myeloma (MM) affects plasma cells and often involves the bones. Recent research shows that cell-free DNA (cfDNA) can provide important information about the disease and its spread. In this study, 162 newly diagnosed MM patients were analyzed using imaging and whole genome sequencing to understand the role of cfDNA. The results showed that patients with higher levels of cfDNA at diagnosis were more likely to have active tumors in the bones and outside the bone marrow. The study also found that inflammation in the tumor environment might contribute to the release of cfDNA. High cfDNA levels at diagnosis were linked to a worse prognosis and could help identify high-risk patients when added to the current risk-scoring system. Overall, cfDNA can be a useful and less invasive tool for understanding MM and predicting patient outcomes.

 

 

"Novel CCL3-HMGB1 signaling axis regulating osteocyte RANKL expression in multiple myeloma"

Source

Anloague A, Sabol HM, Kaur J, Khan S, Ashby C, Schinke C, Barnes CL, Alturkmani F, Ambrogini E, Gundesen MT, Lund T, Amstrup AK, Andersen TL, Diaz-delCastillo M, Roodman GD, Bellido T, Delgado-Calle J. Novel CCL3-HMGB1 signaling axis regulating osteocyte RANKL expression in multiple myeloma. Haematologica; https://doi.org/10.3324/haematol.2024.286484 [Early view]. November 28, 2024.  

Multiple myeloma (MM) is a cancer that affects plasma cells and causes serious bone problems. A key feature of MM is osteolytic destruction, where bones are broken down too quickly due to the overproduction of a protein called RANKL, which stimulates bone-destroying cells called osteoclasts. This study focuses on how MM affects osteocytes, the cells in bones that regulate RANKL production. The researchers found that a substance called CCL3, produced by MM cells, causes osteocytes to produce more RANKL, leading to bone loss. They also discovered that blocking CCL3 can reduce the amount of RANKL made by osteocytes and prevent bone damage. This process involves another protein, HMGB1, which is also triggered by CCL3. These findings reveal a new way MM affects bone health and suggest that targeting CCL3 could help reduce bone damage in MM patients.

 

 

"Allocation and validation of the second revision of the International Staging System in the ICARIA-MM and IKEMA studies"

Source

Richardson, P.G., Perrot, A., Mikhael, J. et al. Allocation and validation of the second revision of the International Staging System in the ICARIA-MM and IKEMA studies. Blood Cancer J. 14, 209 (2024). https://doi.org/10.1038/s41408-024-01149-w  November 28, 2024. 

The International Staging System (ISS) for multiple myeloma was recently updated to better predict patient outcomes by including genetic changes, like the gain of the 1q21 chromosome, and other high-risk features. This study looked at two large clinical trials (ICARIA-MM and IKEMA) to see how well the updated staging system (R2-ISS) worked for patients with relapsed or refractory multiple myeloma. The study included 609 patients and found that those reclassified into higher stages of the R2-ISS had shorter progression-free survival, meaning their cancer worsened faster. Adding a treatment called isatuximab improved survival compared to double therapy, and this effect was seen across all R2-ISS stages. This is the first study to confirm that the R2-ISS system works well with newer treatments, including anti-CD38 monoclonal antibodies, in patients whose cancer has returned or is resistant to treatment.

 

 

"Multiple myeloma long-term survivors exhibit sustained immune alterations decades after first-line therapy"

Source

Lutz, R., Grünschläger, F., Simon, M. et al. Multiple myeloma long-term survivors exhibit sustained immune alterations decades after first-line therapy. Nat Commun 15, 10396 (2024). https://doi.org/10.1038/s41467-024-54543-0  November 29, 2024. 

This study looks at the long-term effects of multiple myeloma and its treatments on the immune system, even many years after patients are cancer-free. The researchers studied the bone marrow of long-term survivors, ranging from the time of diagnosis up to 17 years later. They found that even after surviving cancer with no detectable disease, patients still had changes in their bone marrow that weakened their immune system. These changes were linked to ongoing inflammation caused by remaining myeloma cells, even if they couldn't be detected. This study shows that cancer and its treatment can leave lasting effects on the immune system, some of which may be permanent.

 

 

"Bispecific antibodies in clinical practice: Understanding recent advances and current place in cancer treatment landscape"

Source

Verma, V., Sharma, G. Bispecific antibodies in clinical practice: Understanding recent advances and current place in cancer treatment landscape. Clin Exp Med 25, 11 (2025). https://doi.org/10.1007/s10238-024-01520-y  November 28, 2024.  

Immunotherapy has changed cancer treatment in recent years, and manipulating T cells has shown promise. Two common ways to manipulate T cells are CAR-T cell therapy and bispecific antibodies (BiTEs). Both have been studied for treating blood cancers that haven't responded to other treatments. While these therapies haven’t been directly compared in controlled trials, available evidence suggests that BiTEs are just as effective as CAR-T cells but have fewer side effects. A major advantage of BiTEs is that they can be used for all patients, regardless of certain genetic factors, making them easier to administer. This article reviews the recent approvals and uses of bispecific antibodies, their effectiveness, and side effects, providing helpful information for doctors on how to use these treatments in current cancer care.

 

 

"Isatuximab–dexamethasone–pomalidomide combination effects on serum M protein and PFS in myeloma: Development of a joint model using phase I/II data"

Source

Pitoy A, Desmée S, Riglet F, et al. Isatuximab–dexamethasone–pomalidomide combination effects on serum M protein and PFS in myeloma: Development of a joint model using phase I/II data. CPT Pharmacometrics Syst Pharmacol. 2024; 00: 1-15. doi:10.1002/psp4.13206  November 28, 2024. 

This study used data from clinical trials to create a model that connects changes in serum M-protein levels (a marker of multiple myeloma) with progression-free survival (PFS) in patients treated with isatuximab (Isa), pomalidomide (Pom), and dexamethasone (Dex). The data came from 203 patients with relapsed or refractory multiple myeloma. The researchers first developed separate models for serum M-protein levels and PFS, and then combined them into a joint model to understand how changes in M-protein levels relate to PFS. The model showed that serum M-protein levels were influenced by the treatment drugs, and PFS was linked to factors like age, baseline beta-2 microglobulin levels, and the use of dexamethasone. The model supported the dosing schedule used in the ICARIA-MM phase III trial, which was also validated with the same trial data.

 

 

"A Phase 1/2 study of teclistamab, a humanized BCMA × CD3 bispecific Ab in Japanese patients with relapsed/refractory MM"

Source

Ishida, T., Kuroda, Y., Matsue, K. et al. A Phase 1/2 study of teclistamab, a humanized BCMA × CD3 bispecific Ab in Japanese patients with relapsed/refractory MM. Int J Hematol (2024). https://doi.org/10.1007/s12185-024-03884-z  November 28, 2024. 

This study looked at the safety and effectiveness of the bispecific antibody teclistamab in Japanese patients with relapsed or refractory multiple myeloma (RRMM). Patients had previously been treated with a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody. In phase 1, patients received weekly injections of teclistamab in varying doses, with no severe side effects. In phase 2, patients received the recommended dose of 1.5 mg/kg per week. After about 14 months, the treatment showed a high overall response rate of 76.9%, with many patients achieving a very good partial response or complete response. Common side effects included cytokine release syndrome, neutropenia, and infections, but there were no cases of severe neurotoxicity. The results suggest that teclistamab could become an effective treatment for RRMM in Japan, similar to global findings in the MajesTEC-1 study.

 

 

"Optimizing treatment sequencing in multiple myeloma: a novel model to predict survival outcomes"

Source

Petrucci, M. T., Bringhen, S., Entrala Cerezo, C., Mendes, J., & Armeni, P. (2024). Optimizing treatment sequencing in multiple myeloma: a novel model to predict survival outcomes. Hematology, 29(1). https://doi.org/10.1080/16078454.2024.2432815  November 29, 2024. 

This study developed a model to compare different treatment sequences for multiple myeloma (MM) patients, helping doctors choose the best treatment plan. The model looked at both transplant-eligible (TE) and transplant-ineligible (TIE) patients over four treatment lines, starting from first-line (FL) treatment to fourth-line (4L). The results showed that starting with daratumumab-containing regimens led to the best outcomes. For TE patients, overall survival (OS) ranged from 11.8 to 18.1 years, and progression-free survival (PFS) ranged from 4.8 to 13.4 years in the first line. For TIE patients, starting with daratumumab also gave the best OS and PFS. The study concluded that using daratumumab early on in treatment helps improve outcomes for MM patients.

 

 

"BCMA CAR-T therapy combined with pomalidomide is a safe and effective treatment for relapsed/refractory multiple myeloma"

Source

Yan, Y., Tu, Y., Cheng, Q. et al. BCMA CAR-T therapy combined with pomalidomide is a safe and effective treatment for relapsed/refractory multiple myeloma. J Transl Med 22, 1087 (2024). https://doi.org/10.1186/s12967-024-05772-w  November 29, 2024. 

This study looked at the combination of BCMA-targeted CAR T-cell therapy and long-term pomalidomide treatment in patients with relapsed or refractory multiple myeloma (R/R MM). The researchers found that the combination therapy was very effective. In patients who received pomalidomide after the CAR T-cell infusion, 100% had a good response, with most achieving either a very good partial response (VGPR) or complete response (CR) after three months. In comparison, fewer patients who did not receive pomalidomide achieved the same results. The study also showed that the combination therapy helped patients live longer without disease progression, with longer progression-free survival (TTP) and overall survival (OS). Importantly, the treatment was well tolerated, with no significant long-term side effects like hematological toxicity or liver damage. The study concluded that combining BCMA CAR T-cell therapy with pomalidomide is a promising treatment option for patients with R/R MM.

 

 

"Characteristics and outcomes in patients with lenalidomide-refractory multiple myeloma treated with 1-3 prior lines of therapy: analysis of individual patient-level data from daratumumab clinical trials"

Source

Kwee Yong, Hermann Einsele, Jordan M Schecter, Tito Roccia, William Deraedt, Nikoletta Lendvai, Ana Slaughter, Carolina Lonardi, Kaitlyn Connors, Keqin Qi, Anil Londhe, Robin Carson, Akshay Kharat, Patricia Cost, Satish Valluri, João Mendes, Lida Pacaud, Nitin Patel, Erika Florendo, Binod Dhakal, Characteristics and outcomes in patients with lenalidomide-refractory multiple myeloma treated with 1-3 prior lines of therapy: analysis of individual patient-level data from daratumumab clinical trials, European Journal of Cancer, 2024, 115157, ISSN 0959-8049, https://doi.org/10.1016/j.ejca.2024.115157. November 29, 2024.  

This study looked at patients with multiple myeloma (MM) who were resistant to lenalidomide and had already received one to three prior treatments. The goal was to understand the outcomes and effectiveness of current treatments for these patients, who are harder to treat. Data from several studies involving the drug daratumumab were analyzed, including information on time to next treatment, progression-free survival (PFS), and overall survival (OS). 

The study found that out of 4764 patients, 915 met the criteria for the study. The overall response rate to treatment was 55.4%. On average, patients had 9.7 months before needing another treatment, 10 months of PFS, and 27.5 months of OS. However, response rates and survival times decreased as patients had more previous treatments. Key factors affecting treatment outcomes included the stage of the disease, whether the patient had any bone lesions, their hemoglobin levels, and certain genetic markers. 

The results show that patients who are resistant to lenalidomide and have had multiple treatments still have poor survival rates, underlining the need for better treatment options for this challenging group.

 

 

"Autologous stem cell transplantation for multiple myeloma patients whose myeloma-defining event was SLiM"

Source

Vaxman I, Kumar S, Cohen I, Simony S, Dispenzieri A, Buadi F, et al. Autologous stem cell transplantation for multiple myeloma patients whose myeloma-defining event was SLiM. Br J Haematol. 2024; 00: 1–8. https://doi.org/10.1111/bjh.19936  November 29, 2024.  

The findings of the study indicate that ASCT is safe and effective for SLiM patients, with a 0% transplant-related mortality (TRM) in this cohort. The overall response rate was 100%, with 30% of patients achieving a complete response (CR) or stringent CR (sCR) and 30% achieving minimal residual disease (MRD) negativity. The 36-month progression-free survival (PFS) was 91.61%, and overall survival (OS) was 100%. SLiM patients also experienced significantly shorter times to neutrophil and platelet engraftment compared to a matched cohort. Notably, 53% of patients did not require hospitalization during ASCT, and among those who did, the median duration of hospitalization was 6 days.

In conclusion, ASCT is a safe and effective treatment for patients diagnosed based on SLiM criteria, with high response rates and minimal complications. However, early intervention did not lead to superior MRD negativity or longer PFS compared to patients diagnosed with CRAB criteria. The findings suggest that while SLiM patients may benefit from early treatment, the expected survival advantage from early intervention did not materialize in this cohort, possibly due to the shorter follow-up period and the limited number of patients studied.
 

 

 

 

"FaMMily Affairs: Dissecting Inherited Contributions to Multiple Myeloma Risk"

Source

Saoirse Bodnar, Tehilla Brander, Julie Gold, Ayuko Iverson, Alessandro Lagana, Kenan Onel, Sundar Jagannath, Samir Parekh, Santiago Thibaud, FaMMily Affairs: Dissecting Inherited Contributions to Multiple Myeloma Risk,Seminars in Hematology,2024,ISSN 0037-1963, https://doi.org/10.1053/j.seminhematol.2024.11.006. November 30, 2024. 

The cause of multiple myeloma (MM) is not fully understood, but growing evidence suggests that genetics play a major role. This review looks at current research on inherited factors that may increase the risk of MM, combining both population studies and genetic data. It discusses patterns of MM in families, genetic variants found in genome-wide studies, and rare mutations in important genes linked to MM risk. The review also suggests that people at high risk for MM—especially those with a family history of cancer, personal cancer history, or early-onset disease—should undergo genetic screening. The goal is to better understand genetic influences on MM and improve risk assessments for these individuals.