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 September 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 September 2024) 

"Mosaic chromosomal alterations in hematopoietic cells and clinical outcomes in patients with multiple myeloma"

Source

Husby, S., Tulstrup, M., Harsløf, M. et al. Mosaic chromosomal alterations in hematopoietic cells and clinical outcomes in patients with multiple myeloma. Leukemia (2024). https://doi.org/10.1038/s41375-024-02396-3 September 2, 2024. 

Overview

Highlights from the article:

• "Mosaic chromosomal alterations (mCAs) are found in the hematopoietic cells in 16% of patients with multiple myeloma undergoing ASCT. 
• Female patients with loss of chromosome X have a significant superior response to ASCT and improved overall survival despite being older." 

 

 

"Current status of BAFF targeting immunotherapy in B-cell neoplasm"

Source

Tagami, N., Yuda, J. & Goto, Y. Current status of BAFF targeting immunotherapy in B-cell neoplasm. Int J Clin Oncol (2024). https://doi.org/10.1007/s10147-024-02611-2  September 2, 2024 

Overview

BAFF, or B-cell activating factor, is important for the growth and survival of B cells, which are a type of immune cell. BAFF works through different receptors, including BCMA, TACI, and BAFF-R, and helps B cells multiply and produce antibodies. Too much or too little BAFF can lead to problems: too little weakens the immune response, while too much can cause diseases like autoimmune disorders or certain types of blood cancers. High BAFF levels are linked to diseases like multiple myeloma and chronic lymphocytic leukemia (CLL).

Researchers are studying treatments that target BAFF, such as belimumab, atacicept, and tabalumab. Belimumab is being tested with other drugs for CLL, while atacicept showed promise in early trials. However, tabalumab didn’t work well in a trial for multiple myeloma. BAFF-targeting therapies, including CAR-T cells, are showing potential in early research for treating B-cell cancers. The study highlights the importance of understanding how BAFF affects these diseases and how it can be targeted for new treatments.

 

 

"Novel potent molecular glue degraders against broad range of hematological cancer cell lines via multiple neosubstrates degradation"

Source

Li, P., Hu, X., Fan, Z. et al. Novel potent molecular glue degraders against broad range of hematological cancer cell lines via multiple neosubstrates degradation. J Hematol Oncol 17, 77 (2024). https://doi.org/10.1186/s13045-024-01592-z  September 2, 2024.  

Overview

This study focuses on improving treatments for blood cancers, like multiple myeloma (MM), using a strategy called targeted protein degradation. Current drugs, called IMiDs, can help but often lead to drug resistance and harmful side effects, limiting their effectiveness.

Researchers screened different small molecules to find new ones that could break down harmful proteins in cancer cells. They identified two promising compounds, MGD-4 and MGD-28, which target key proteins (Ikaros proteins and CK1α) that are important in MM. MGD-28, in particular, showed strong ability to stop cancer cell growth, both in MM and other solid cancers. These compounds worked well alone and even better when combined with standard treatments.

The study also found that a protein called BRD9 is linked to resistance against IMiD drugs and may play a role in the progression of MM. By blocking BRD9 along with MGD-28, the treatment was even more effective.

The research highlights a potential new approach to treating blood cancers and other cancers by breaking down multiple cancer-related proteins. This strategy could improve current treatments and help overcome drug resistance.

 

 

"Exploring the promise of regulator of G Protein Signaling 20: insights into potential mechanisms and prospects across solid cancers and hematological malignancies"

Source

Wang, Y., Qin, J., Sharma, A. et al. Exploring the promise of regulator of G Protein Signaling 20: insights into potential mechanisms and prospects across solid cancers and hematological malignancies. Cancer Cell Int 24, 305 (2024). https://doi.org/10.1186/s12935-024-03487-y  September 3, 2024 

Overview

RGS proteins, especially RGS20, play important roles in cell signaling and have been linked to various cancers. Researchers have been interested in RGS20 because it may be involved in the development of hepatocellular carcinoma (a type of liver cancer). This study looks at mutations in the RGS20 gene and how it interacts with other proteins, which could help explain its role in cancer.

The researchers are now focusing on how RGS20 affects blood cancers, like multiple myeloma and follicular lymphoma. By studying RGS20 in these cancers, they hope to find new treatment strategies. They are also exploring RGS20’s potential role in diseases of the central nervous system, showing that it may have effects beyond cancer.

 

 

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

Source

Xavier Deschenes-Simard, Bianca D. Santomasso, Parastoo B. Dahi; Clinical features, pathophysiology, and management of acute myelopathy following CAR T-cell therapy. Blood 2024; blood.2024025679. doi: https://doi.org/10.1182/blood.2024025679  September 3, 2024 

Overview

CAR T-cell therapy has changed the way we treat patients with certain blood cancers that have come back or are hard to treat. However, this therapy can lead to serious side effects, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). As more people receive CAR T-cell therapy, some rare neurological problems are being noticed, including acute myelopathy, which is a type of spinal cord dysfunction.

Although there are guidelines for managing ICANS, there isn’t much information on how to handle this specific complication. This study looks at the symptoms, causes, and best ways to treat acute myelitis after CAR T-cell therapy by reviewing cases reported in medical literature. The goal is to improve understanding and management of this rare side effect.

 

 

"Effects of consolidation therapy with autologous hematopoietic stem cell transplantation after BCMA-CAR T-cell therapy on the survival of patients with relapsed or refractory multiple myeloma. Transplantation and Cellular Therapy"

Source

Xavier Deschenes-Simard, Bianca D. Santomasso, Parastoo B. Dahi; Clinical features, pathophysiology, and management of acute myelopathy following CAR T-cell therapy. Blood 2024; blood.2024025679. doi: https://doi.org/10.1182/blood.2024025679  September 3, 2024 

Overview

Highlights from the study:

• "CAR T-cell therapy is effective and safe for relapsed or refractory MM (RRMM). 
• However, an effective treatment is needed for relapse after CAR T-cell therapy. 
• We tested the efficacy of autologous hematopoietic stem cell transplantation (AHCT). 
• Consolidation ACHT after CAR T-cell therapy improved the prognosis of RRMM patients. 
• Thus, consolidation AHCT after CAR T-cell therapy is a promising option for RRMM." 

 

 

"A phase Ib trial of isatuximab, bendamustine, and prednisone in relapsed/refractory multiple myeloma"

Source

Goldsmith, S.R., Slade, M.J., Fiala, M. et al. A phase Ib trial of isatuximab, bendamustine, and prednisone in relapsed/refractory multiple myeloma. Ann Hematol (2024). https://doi.org/10.1007/s00277-024-05975-7 September 4, 2024. 

Overview

This study investigated a treatment combination for patients with triple-class refractory multiple myeloma (TCR MM), who often require quick control of their disease. The researchers tested a regimen that included isatuximab, an anti-CD38 antibody, bendamustine, a chemotherapy drug, and prednisone, to see if it would be safe and effective.

Fifteen patients participated in the trial. They received isatuximab weekly during the first cycle and then every two weeks, while bendamustine was given in different doses over two days. The researchers monitored for any side effects and treatment responses.

The results showed that the treatment was generally safe, with only one severe side effect (low platelet count and bleeding) reported. There were no life-threatening side effects. The overall response rate was 20%, meaning three out of fifteen patients showed some improvement, including one who achieved a complete response. The average time until the disease progressed (progression-free survival) was about 2.5 months.

Although the study was stopped due to slow enrollment, the findings suggest that the isatuximab-bendamustine-prednisone combination can be tolerated by patients. Some patients did respond positively, even those who had limited options left for treatment. "This study was registered on clinicaltrials.gov as NCT04083898 on 9/6/2019."

 

 

"Gene therapy for polygenic or complex diseases. Biomark Res 12, 99"

Source

Wu, T., Hu, Y. & Tang, L.V. Gene therapy for polygenic or complex diseases. Biomark Res 12, 99 (2024). https://doi.org/10.1186/s40364-024-00618-5  September 4, 2024. 

Overview

Gene therapy uses drugs made from nucleic acids to treat various diseases by adding, replacing, silencing, or editing genes. This approach is different from traditional medications and offers new ways to address genetic disorders. In the last twenty years, gene therapy has made great progress, leading to the approval of several gene therapy drugs. 

Initially, gene therapy was mainly used for rare genetic diseases and certain cancers, which are often caused by a single faulty gene. However, common diseases caused by multiple genes (called polygenic or complex diseases) affect more people and have become a focus for research. Scientists have discovered new targets for treating these diseases, expanding the possibilities for gene therapy.

This review looks at different strategies in gene therapy, particularly the CRISPR-Cas9 gene editing method, and the carriers that deliver gene therapies. It also highlights how gene therapy is being applied to polygenic diseases, focusing on treatments that are either in clinical use or currently being tested in clinical trials.

 

 

"Enhanced platelet function through CAR-T cell therapy in relapsed/refractory multiple myeloma"

Source

Ma, R., Zhang, Q., Liu, Y. et al. Enhanced platelet function through CAR-T cell therapy in relapsed/refractory multiple myeloma. Clin Exp Med 24, 210 (2024). https://doi.org/10.1007/s10238-024-01477-y  September 4, 2024. 

Overview

This study looked at how CAR-T cell therapy affects platelet function in patients with relapsed or refractory multiple myeloma (R/R MM). It involved 50 patients treated with CAR-T cells. Researchers measured the mean platelet closure time (PCT), which indicates how well platelets are working.

Before treatment, the average PCT was significantly longer, meaning platelet function was poorer (about 195 seconds). After CAR-T therapy, this time decreased to about 128 seconds, showing a significant improvement. The post-treatment PCT was similar to that of healthy individuals.

Patients who responded better to the CAR-T therapy (more than partial remission) showed even greater improvements in PCT compared to their pre-treatment levels. However, a longer PCT (over 240.5 seconds) was linked to worse outcomes, including shorter progression-free survival (PFS). Patients with a PCT over 240.5 seconds had a median PFS of 10.2 months, while those with a lower PCT had a median PFS of 22.0 months.

The study concluded that CAR-T cell therapy improves platelet function in R/R MM patients, and PCT could serve as a useful prognostic marker to predict the effectiveness of the treatment.

 

 

"Phase II trial of elotuzumab with pomalidomide and dexamethasone for daratumumab-refractory multiple myeloma"

Source

Parrondo, R.D., LaPlant, B.R., Elliott, J. et al. Phase II trial of elotuzumab with pomalidomide and dexamethasone for daratumumab-refractory multiple myeloma. Blood Cancer J. 14, 152 (2024). https://doi.org/10.1038/s41408-024-01134-3  September 5, 2024. 

Overview

Recent advancements in treatments like immunomodulatory agents (IMiDs), proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (MoAbs) have significantly improved survival rates for patients with multiple myeloma (MM). Elotuzumab, an anti-CD38 MoAb, targets myeloma cells and helps activate natural killer (NK) cells to destroy them. In the ELOQUENT 2 and ELOQUENT 3 trials, combining elotuzumab with standard treatments showed better response rates and survival compared to those treatments alone.

However, patients previously treated with daratumumab, another anti-CD38 therapy, may have reduced effectiveness with elotuzumab, as daratumumab can deplete NK cells. This study evaluates the effectiveness of elotuzumab combined with pomalidomide and dexamethasone (EPd) in patients whose MM progressed after daratumumab treatment.

Thirty-seven patients were enrolled, with a median of four prior treatment lines. The overall response rate (ORR) was 35%, but no complete responses were observed. The median progression-free survival (PFS) was about 3.7 months, and the median overall survival (OS) was 56.7 months. Interestingly, the timing of daratumumab treatment before starting EPd did not significantly affect the outcomes, suggesting that EPd can still be effective even shortly after daratumumab therapy.

The study also highlighted a diverse patient population, including a notable number of African American patients, aligning with efforts to increase diversity in clinical trials. Although other treatments are available for patients with heavily pre-treated or refractory MM, EPd remains a viable option, potentially serving as a bridging therapy for patients awaiting CAR-T cell therapy.

 

 

"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

Parrondo, R.D., LaPlant, B.R., Elliott, J. et al. Phase II trial of elotuzumab with pomalidomide and dexamethasone for daratumumab-refractory multiple myeloma. Blood Cancer J. 14, 152 (2024). https://doi.org/10.1038/s41408-024-01134-3  September 5, 2024. 

Overview

This study explored the effectiveness of consolidation and maintenance therapy following salvage autologous hematopoietic stem-cell transplantation (HSCT) in patients with relapsed multiple myeloma. Researchers aimed to determine if a treatment regimen involving ixazomib, thalidomide, and dexamethasone, followed by maintenance with ixazomib alone, would outperform simple observation after treatment. The interim analysis was part of the Myeloma XII trial, which included 206 patients who were randomly assigned to receive either the combination therapy or observation after HSCT. The main goal was to measure progression-free survival, which is the duration during which the disease does not worsen.

The results indicated that patients receiving the consolidation and maintenance therapy experienced a median progression-free survival of 20 months, compared to just 13 months for those who were observed. While the treatment group showed significant improvement in disease control, they also experienced higher rates of serious side effects (32% compared to 7% in the observation group), with infections being the most common adverse event. Overall, the findings suggest that this treatment regimen can extend the duration of disease control for patients with relapsed multiple myeloma after salvage HSCT, offering a promising oral alternative to ongoing intravenous therapies.

 

 

"CCL17, CCL22 and their receptor CCR4 in hematologic malignancies"

Source

Zou, S., Liu, B. & Feng, Y. CCL17, CCL22 and their receptor CCR4 in hematologic malignancies. Discov Onc 15, 412 (2024). https://doi.org/10.1007/s12672-024-01210-x  September 6, 2024. 

Overview

Hematological malignancies (HM), which include conditions like lymphoma, leukemia, and multiple myeloma, are serious cancers that significantly impact health and often come with high rates of recurrence and treatment-related side effects. Researchers are focusing on developing targeted therapies that are more precise and safer than traditional chemotherapy. One key area of investigation is the interaction between C–C chemokine ligands CCL17 and CCL22 and their receptor CCR4. This interaction has been linked to how tumors evade the immune system and can affect the development and outcomes of hematological cancers. The review discusses the roles of these chemokines and receptor interactions, particularly in multiple myeloma, and highlights the potential of therapies targeting this pathway, including humanized anti-CCR4 antibodies.

In multiple myeloma specifically, CCL17 levels are notably high, while CCL22 levels can decrease in patients who respond well to certain treatments, suggesting that CCL22 may serve as a useful biomarker. Despite advances in treatments like IMiDs and proteasome inhibitors, multiple myeloma remains incurable. The ongoing research into the CCL17/CCL22-CCR4 axis suggests it could become a significant target for new therapies, moving beyond conventional methods like chemotherapy and radiotherapy. As studies continue, the hope is that targeting these chemokines and their receptor will lead to more effective treatments for hematological malignancies.

 

 

"Plasma cell disorders supress mucosal anti-bacterial immunity: another dimension of immunoparesis in plasma cell neoplasms"

Source

Faustini, S., Chan, Y.L.T., Evans, L. et al. Plasma cell disorders supress mucosal anti-bacterial immunity: another dimension of immunoparesis in plasma cell neoplasms. Leukemia (2024). https://doi.org/10.1038/s41375-024-02398-1  September 7, 2024. 

Overview

Multiple myeloma (MM) is a cancer of plasma cells that leads to weakened immune systems and a high risk of infection. In the first three months after diagnosis, about one-third of MM patients develop serious bacterial infections, with half of early deaths linked to infections. Streptococcus pneumoniae is a common infection in MM, with a significantly increased risk of serious pneumococcal disease. Most MM patients also have reduced levels of important antibodies at diagnosis, which worsens during treatment, leaving them vulnerable to infections even in remission. Recent research has highlighted the importance of mucosal immunity, especially salivary antibodies, in defending against infections, but pathogen-specific salivary antibody levels in MM patients have not been well studied until now.

This study explored the levels of serum and salivary antibodies against pneumococcus in patients with MM, smoldering multiple myeloma (SMM), and monoclonal gammopathy of unknown significance (MGUS). Results showed that both serum and salivary antibody levels were lowest in patients with active MM and those in remission, compared to healthy controls. While there are no clinical guidelines for salivary antibody levels, the findings suggest a potential new area of immunoparesis (antibody deficiency) that could impact infection risk in MM patients. More research is needed to determine if salivary antibody levels can help predict infection risk and guide treatment strategies, including vaccination against pneumococcal infections.

 

 

"Self-perceived oral health in hemato-oncological patients and the relation to quality of life"

Source

Laheij, A.M., Dillen, L.M., Nur, E. et al. Self-perceived oral health in hemato-oncological patients and the relation to quality of life. Support Care Cancer 32, 643 (2024). https://doi.org/10.1007/s00520-024-08849-w  September 7, 2024.  

Overview

This study aimed to evaluate the oral health and quality of life in patients with hematologic cancers, such as lymphoma, leukemia, and multiple myeloma. Researchers used digital surveys to gather data from 705 patients, assessing their oral health and related quality of life.

Key findings:

• About 40% of patients had dry mouth (xerostomia), and other common complaints included mouth soreness, sensitivity, gum pain, and bleeding, as well as issues with dentures.
• Despite these problems, most patients reported a relatively good oral health-related quality of life (OH-QoL). However, those with more severe dry mouth had a lower quality of life.
• Xerostomia was more common in women, those who had received stem cell transplants, head and neck radiation, or used multiple medications.

The study concluded that dry mouth and other oral issues are common in patients with hematologic cancers, especially after cancer treatments, but these problems do not always lead to a poor quality of life. Health professionals should regularly assess and address oral health concerns in these patients to improve their well-being. Further research is needed to explore the long-term effects of cancer treatments on oral health.

 

 

"Modest survival benefits of autologous stem cell transplantation in multiple myeloma with renal impairment: a critical appraisal of the pre-antibody era"

Source

Li, Y., Zhang, X., Zou, Z. et al. Modest survival benefits of autologous stem cell transplantation in multiple myeloma with renal impairment: a critical appraisal of the pre-antibody era. Clin Exp Med 24, 215 (2024). https://doi.org/10.1007/s10238-024-01481-2  September 9, 2024.  

Overview

This study reviewed the safety and effectiveness of high-dose melphalan followed by autologous stem cell transplantation (HDM-ASCT) in multiple myeloma (MM) patients with kidney problems (renal insufficiency, RI). Researchers analyzed 26 studies and compared MM patients with RI to those with normal kidney function (NRF). 

Key findings:

• The risk of death related to the transplant was similar between MM patients with RI and those with NRF.
• Both groups had similar rates of complete response (full cancer remission) after the transplant.
• While progression-free survival (time without cancer worsening) was also similar, patients with RI had shorter overall survival compared to those with normal kidney function.

The study concluded that with a reduced dose of melphalan, HDM-ASCT is safe and effective for MM patients with RI. However, these patients have worse overall survival, suggesting more research is needed to improve outcomes.

 

 

"Bortezomib, lenalidomide, and dexamethasone versus bortezomib, doxorubicin, and dexamethasone in newly diagnosed multiple myeloma"

Source

Liang, D., Bai, S., Feng, D. et al. Bortezomib, lenalidomide, and dexamethasone versus bortezomib, doxorubicin, and dexamethasone in newly diagnosed multiple myeloma. BMC Cancer 24, 1123 (2024). https://doi.org/10.1186/s12885-024-12880-9  September 9, 2024. 

Overview

This study compared two treatments, VRD (bortezomib, lenalidomide, and dexamethasone) and PAD (bortezomib, doxorubicin, and dexamethasone), for newly diagnosed multiple myeloma (NDMM) in China. A total of 390 patients were included, with 195 receiving each treatment. 

Key findings:

• VRD had better five-year survival rates than PAD, with 74% of VRD patients alive after five years, compared to 59% for PAD.
• Progression-free survival (PFS), meaning the time patients lived without the cancer getting worse, was also better with VRD (67% vs. 37%).
• VRD showed especially strong results for patients with standard-risk genetic factors and those who had stem cell transplants, with higher five-year survival and PFS.
•  In patients with high-risk genetics, VRD did not show a significant advantage over PAD.

Although VRD showed better results overall, the study cautioned that differences in transplant rates and other factors between the two groups may affect the conclusions.

 

 

"The American Society of Hematology Health Equity Compendium: examining health equity across the Blood journals"

Source

Warren B. Fingrut, James Troyer, Eddrika Russell, Melanie Aviles, Sherraine Della-Moretta, Dre’Von Dobson, Zainul Hasanali, Bei Hu, Ajibike Lapite, Pallavi M. Pillai, Joseph W. Schramm, Lynda M. Villagomez, Phuong Vo, Ruth Wang’ondu, Jennifer Yui, Angela C. Weyand; The American Society of Hematology Health Equity Compendium: examining health equity across the Blood journals. Blood Adv 2024; 8 (17): 4616–4624. doi: https://doi.org/10.1182/bloodadvances.2024013633 September 10, 2024. 

Overview

This study, led by the American Society of Hematology (ASH) Health Equity Task Force, aimed to compile a collection of research articles focused on health equity in hematology. The researchers reviewed papers from several ASH journals published between January 2018 and June 2023 to identify those that mentioned health equity in their content.

Key findings:

• A total of 57 articles were included, with most focusing on patients rather than blood donors or healthcare workers. The majority of the articles looked at racial and ethnic disparities, particularly affecting Black and Hispanic patients.
• The articles mainly discussed health disparities in hematologic cancers and bone marrow transplants. Fewer articles addressed other diseases like sickle cell anemia or blood clotting disorders.
• Most studies were retrospective, meaning they looked back at existing data, and only a few were prospective or clinical trials that collect new data over time.
• Few studies explored ways to reduce disparities, and none included collaboration with patient or community advocates.

The study highlighted an increase in health equity research in hematology journals over time but noted a need for more research on underserved populations and interventions to address disparities. This work serves as a benchmark for future studies and emphasizes the need for collaboration with communities to improve health equity.

 

 

"Clinical outcomes after idecabtagene vicleucel in older patients with multiple myeloma: a multicenter real-world experience"

Source

Nilesh M. Kalariya, Michelle A. T. Hildebrandt, Doris K. Hansen, Surbhi Sidana, Jack Khouri, Christopher J. Ferreri, William N. Doyle, Omar Castaneda-Puglianini, Ciara L. Freeman, Vanna Hovanky, Hitomi Hosoya, Leyla O. Shune, Krina K. Patel; Clinical outcomes after idecabtagene vicleucel in older patients with multiple myeloma: a multicenter real-world experience. Blood Adv 2024; 8 (17): 4679–4688. doi: https://doi.org/10.1182/bloodadvances.2024013540  September 10, 2024. 

Overview

This study looked at the safety and effectiveness of CAR T-cell therapy (ide-cel) in older patients, a group that often has more health issues. Researchers compared younger patients (under 65) with older patients (65 and up). Out of 156 patients, 75 were older, with a median age of 69. Most older patients were frail and had multiple health problems. Despite this, the overall response rate (ORR) for older patients was 86.7%, similar to the 73% seen in previous studies. Median survival times were 9.1 months without disease worsening and 26.5 months overall. Serious side effects were rare, with severe cytokine-release syndrome in 1% of older patients and neurotoxicity in 4%. Older patients had more frailty, were on multiple medications, and had more organ problems than younger patients, but these factors didn’t worsen their outcomes. Overall, ide-cel was effective and safe in both younger and older patients.

 

 

 

"Functional multiomics reveals genetic and pharmacologic regulation of surface CD38 in multiple myeloma"

Source

Priya Choudhry, Corynn Kasap, Bonell Patiño-Escobar, Olivia Gugliemini, Huimin Geng, Vishesh Sarin, Amrik Kang, Audrey Kishishita, Sham Rampersaud, Letitia Sarah, Yu-Hsiu T. Lin, Neha Paranjape, Poornima Ramkumar, Jonathan C. Patton, Makeba Marcoulis, Donghui Wang, Paul Phojanakong, Veronica Steri, Byron Hann, Benjamin G. Barwick, Martin Kampmann, Arun P. Wiita; Functional multiomics reveals genetic and pharmacologic regulation of surface CD38 in multiple myeloma. Blood Neoplasia 2024; 1 (3): 100025. doi: https://doi.org/10.1016/j.bneo.2024.100025  Sept. 16, 2024 

Overview

CD38 is a protein found at high levels on myeloma cells and is the target for treatments like daratumumab and isatuximab. The amount of CD38 on tumor cells affects how well these treatments work. Some small molecules can increase CD38 levels on the surface of cancer cells to make these treatments more effective. Other CD38-targeting therapies are also being developed. In this study, researchers used advanced techniques to find new factors that control CD38 levels, including two key proteins, XBP1 and SPI1. They found that reducing CD38 didn't significantly change other proteins on the cell surface. The study also confirmed that all-trans retinoic acid specifically increases CD38 levels, while other drugs had broader effects. Additionally, they discovered that blocking a certain cell pathway (MAP kinase) happens after daratumumab treatment. This research helps guide future strategies to improve CD38-targeting therapies for multiple myeloma.

 

 

"BCMA x CD3 T-cell engager in a patient with pentarefractory multiple myeloma and HIV: a clinical and immunological report"

Source

Cords L, Schaefers C, Kamili A, Hoffmann C, Cichutek S, Haag F, Polywka S, Bokemeyer C, Leypoldt L, Alsdorf W, Wiesch JS zur, Weisel KC. BCMA x CD3 T-cell engager in a patient with pentarefractory multiple myeloma and HIV: a clinical and immunological report. Haematologica 2024;109(9):3071-3077; https://doi.org/10.3324/haematol.2023.284917.  September 2024.  

Overview

T-cell therapies have revolutionized treatment for multiple myeloma. One such treatment, teclistamab, targets BCMA and CD3, and is approved for patients with relapsed or refractory multiple myeloma (RRMM) after multiple treatments. However, there is little data on the use of T-cell therapies in people with HIV (PWH), as they are often excluded from clinical trials due to safety concerns. This case involves a 54-year-old man with both HIV and RRMM who had undergone various cancer treatments, including stem cell transplant and chemotherapy, with limited success. After multiple relapses, the patient was treated with teclistamab, despite the limited experience with this therapy in PWH.

The patient responded well to teclistamab, achieving a very good partial response with manageable side effects. His HIV remained under control throughout the treatment, and his immune system showed signs of recovery. While there were concerns about the impact of HIV on T-cell therapy, this case suggests that teclistamab can be a safe and effective option for PWH with RRMM. The success of this treatment highlights the need for more studies on T-cell therapies in HIV-positive patients and for making such treatments available to underserved populations like PWH.

 

 

"Non-viral approaches in CAR-NK cell engineering: connecting natural killer cell biology and gene delivery"

Source

McErlean, E.M., McCarthy, H.O. Non-viral approaches in CAR-NK cell engineering: connecting natural killer cell biology and gene delivery. J Nanobiotechnol 22, 552 (2024). https://doi.org/10.1186/s12951-024-02746-4 September 10, 2024. 

Overview

Natural Killer (NK) cells are promising for cancer immunotherapy due to their natural ability to kill cancer cells and advantages over T cells in CAR (Chimeric Antigen Receptor) therapy. Concerns about the safety, cost, and scalability of using viruses to modify NK cells have led researchers to explore non-viral methods. This review looks at recent progress and challenges in using non-viral techniques, like electroporation and nanoparticles, to genetically modify NK cells for CAR-NK therapies. It also highlights how understanding NK cell biology is important for designing these new methods. The review offers insights into advancing non-viral CAR-NK therapies for cancer treatment.

 

 

"ISB 2001 trispecific T cell engager shows strong tumor cytotoxicity and overcomes immune escape mechanisms of multiple myeloma cells"

Source

Carretero-Iglesia, L., Hall, O.J., Berret, J. et al. ISB 2001 trispecific T cell engager shows strong tumor cytotoxicity and overcomes immune escape mechanisms of multiple myeloma cells. Nat Cancer (2024). https://doi.org/10.1038/s43018-024-00821-1  September 11, 2024. 

Overview

Despite advances in immunotherapies, multiple myeloma patients often relapse. ISB 2001 is a new T cell engager (TCE) that targets both BCMA and CD38, improving the ability to kill cancer cells. By focusing on two antigens, ISB 2001 shows stronger and more effective tumor-killing power across different tumor types and in patient samples and mouse models. It also triggers less T cell activation in healthy tissues compared to TCEs targeting CD38 alone. To determine the best dose for human trials, researchers used a special model based on preclinical data to minimize patient exposure to ineffective doses. The clinical trial (NCT05862012) is ongoing.

 

 

"Belantamab mafodotin, pomalidomide, and dexamethasone for triple class exposed/refractory relapsed multiple myeloma: a subgroup analysis of the ALGONQUIN trial"

Source

McCurdy, A., Reece, D., Louzada, M.L. et al. Belantamab mafodotin, pomalidomide, and dexamethasone for triple class exposed/refractory relapsed multiple myeloma: a subgroup analysis of the ALGONQUIN trial. Blood Cancer J. 14, 155 (2024). https://doi.org/10.1038/s41408-024-01135-2  September 11, 2024.  

Overview

Most patients with multiple myeloma eventually become resistant to common treatments like PIs, IMiDs, and anti-CD38 mAbs, making effective options for this group crucial. In a subgroup analysis of the ALGONQUIN study, patients who were triple class exposed (TCE) or refractory (TCR) received belantamab mafodotin plus pomalidomide-dexamethasone (belamaf-Pd). The study included 69 TCE and 56 TCR patients. The overall response rate was 86.4% in TCE and 84.9% in TCR patients, with good remission rates. Median progression-free survival was around 18-19 months. The most common serious side effects were eye issues, neutropenia, and infections. Overall, the treatment showed strong results with lasting remissions.

 

 

"Association of ADAM family members with proliferation signaling and disease progression in multiple myeloma"

Source

Evers, M., Stühmer, T., Schreder, M. et al. Association of ADAM family members with proliferation signaling and disease progression in multiple myeloma. Blood Cancer J. 14, 156 (2024). https://doi.org/10.1038/s41408-024-01133-4  September 11, 2024. 

Overview

Multiple myeloma (MM) is a type of blood cancer that is hard to cure due to frequent relapses and resistance to treatment. This study looked at the roles of proteins called ADAM8, ADAM9, and ADAM15 in MM. High levels of these proteins were linked to more aggressive forms of the disease and were found more often in patients with relapsed or resistant MM. The study found that when ADAM8, ADAM9, or ADAM15 levels were high, MM cells grew faster and had more markers of cell growth. Reducing these proteins in lab tests slowed down the growth of MM cells. This suggests that ADAM8, ADAM9, and ADAM15 could be important in MM progression and may be used as markers to predict how aggressive the disease will be.

 

 

"Acute respiratory distress syndrome in patients with hematological malignancies: a one-year retrospective nationwide cohort study"

Source

Bris, PN., Pauly, V., Orleans, V. et al. Acute respiratory distress syndrome in patients with hematological malignancies: a one-year retrospective nationwide cohort study. Ann. Intensive Care 14, 141 (2024). https://doi.org/10.1186/s13613-024-01373-4  September 11, 2024. 

Overview

This study looked at patients with acute respiratory distress syndrome (ARDS) and blood cancers (hematological malignancies) admitted to French intensive care units (ICUs) in 2017. The goal was to understand their outcomes and risk factors for death. Out of 12,846 ARDS patients, 990 had blood cancers like non-Hodgkin lymphoma (NHL), acute myeloid leukemia (AML), or multiple myeloma. The 90-day death rate for patients with blood cancers was 64.4%, which was higher than patients without cancer (46.6%) but similar to patients with solid cancers (61.4%).

Patients with blood cancers were less likely to be intubated compared to the other groups. Factors that increased the risk of death included having lymphoma or leukemia, being older, needing kidney treatment, fungal infections, and septic shock. On the other hand, bacterial pneumonia, infections outside the lungs, and non-invasive ventilation were linked to better outcomes.

Patients with blood cancers and ARDS have a high death rate, and certain factors can help predict their chances of survival.

 

 

"Bispecific antibodies in the treatment of multiple myeloma"

Source

Devasia, A.J., Chari, A. & Lancman, G. Bispecific antibodies in the treatment of multiple myeloma. Blood Cancer J. 14, 158 (2024). https://doi.org/10.1038/s41408-024-01139-y  September 12, 2024. 

Overview

The treatment for multiple myeloma is continuously evolving. New therapies, such as monoclonal antibodies like daratumumab, proteasome inhibitors (PIs), and immune modulators (IMiDs), have improved patient survival and outcomes. However, these treatments can create challenges when the disease relapses. 

To address relapsed multiple myeloma, therapies like chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies are becoming important. Bispecific antibodies target two different antigens, connecting T cells to plasma cells through specific targets like BCMA, GPRC5D, and FcRH5. These treatments have shown strong and lasting responses in patients who have already undergone multiple therapies, and they are easy to use because they can be stored and used when needed.

Research is ongoing to tackle issues such as T cell exhaustion, changes in target antigens, and high disease levels. Some studies are also exploring the use of these therapies as first-line treatments for newly diagnosed patients. Overall, these agents are crucial for treating relapsed myeloma, and researchers are working to improve how they are used in treatment plans.

 

 

"Updates on CAR T cell therapy in multiple myeloma"

Source

Nasiri, F., Asaadi, Y., Mirzadeh, F. et al. Updates on CAR T cell therapy in multiple myeloma. Biomark Res 12, 102 (2024). https://doi.org/10.1186/s40364-024-00634-5  September 12, 2024. 

Overview

Multiple myeloma (MM) is a type of blood cancer where plasma cells grow abnormally. Common initial treatments include immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies (mAbs). Despite advances in diagnosis and treatment, the average life expectancy for MM patients is still only four to five years after starting treatment.

Recent developments in immunotherapy, particularly chimeric antigen receptor (CAR) T-cells, show promise in treating MM. Ide-cel and cilta-cel are the only FDA-approved CAR T-cells that target BCMA for MM patients. However, there are challenges with CAR T-cell therapy, including difficulties in manufacturing and administering the cells. These processes can be expensive, time-consuming, and limit access for patients.

Other issues arise from the characteristics of MM, such as varied tumor antigens, changes in how antigens are presented, and complex tumor environments, which can lead to T-cell exhaustion and treatment failure. Adverse events, including cytokine release syndrome and neurotoxicity, also pose risks.

This review discusses the effectiveness of current CAR T-cell treatments for MM, examines the main reasons for treatment resistance, and suggests ways to improve long-lasting remissions. It also looks into the potential for combining CAR T-cells with other therapies.

 

 

"Racial and Ethnic Disparities in Autologous Hematopoietic Cell Transplant Utilization in Multiple Myeloma Have Persisted Over Time even after Referral to a Transplant Center"

Source

Wu, James F. et al. Racial and Ethnic Disparities in Autologous Hematopoietic Cell Transplant Utilization in Multiple Myeloma Have Persisted Over Time even after Referral to a Transplant Center. Transplantation and Cellular Therapy, Volume 0, Issue 0. September 12, 2024. 

Overview

Key Highlights from this article:

• "Non-Hispanic Black patients had the lowest stem cell transplant utilization 
• Racial/ethnic utilization disparities have improved over time but remain 
• Younger consult age and shorter diagnosis to consult associated with transplant 
• Lack of heart or kidney disease associated with transplant 
• Patient preference and lack of caregiver were common reasons for no transplant" 

 

 

"Function of NLRP3 inflammasome activation in multiple myeloma"

Source

Zhu, X., Yu, J., Hua, M., Xu, N., Wang, L., Chen, L., … Zhao, X. (2024). Function of NLRP3 inflammasome activation in multiple myeloma. Hematology, 29(1). https://doi.org/10.1080/16078454.2024.2399367 September 13, 2024. 

Overview

This study investigates the mechanisms behind drug resistance in multiple myeloma (MM) cells, a significant factor contributing to relapse and disease progression. Researchers utilized various techniques, including Western blot analysis and RT-qPCR, to assess the expression levels of specific proteins and genes associated with inflammation and cell survival in MM cells. They focused on NLRP3, ASC, pro-IL-1β, and cleaved IL-1β, measuring their protein and mRNA levels. Additionally, the levels of IL-1β and IL-18 in the supernatants of activated cells were evaluated to understand how MM cells respond to activation.

The findings revealed that the protein and mRNA levels of NLRP3 and cleaved IL-1β were significantly higher in both bone marrow mononuclear cells (BMMCs) and the KM3 cell line compared to control groups. Furthermore, the study demonstrated that the combination of LPS, ATP, and dexamethasone reduced early apoptosis rates in MM cells, indicating that the activation of the NLRP3 inflammasome offers protection against drug-induced cell death. This suggests that the NLRP3 inflammasome activation contributes to the resistance of MM cells to treatments like dexamethasone and bortezomib, highlighting a potential target for improving therapeutic strategies in MM.

 

 

"Quadruplet therapy for newly diagnosed myeloma: comparative analysis of sequential cohorts with triplet therapy lenalidomide, bortezomib and dexamethasone (RVd) versus daratumamab with RVD (DRVd) in transplant-eligible patients"

Source

Joseph, N.S., Kaufman, J.L., Gupta, V.A. et al. Quadruplet therapy for newly diagnosed myeloma: comparative analysis of sequential cohorts with triplet therapy lenalidomide, bortezomib and dexamethasone (RVd) versus daratumamab with RVD (DRVd) in transplant-eligible patients. Blood Cancer J. 14, 159 (2024). https://doi.org/10.1038/s41408-024-01120-9  September 13, 2024. 

Overview

This study examines the effectiveness of two treatment regimens for newly diagnosed multiple myeloma (NDMM): the standard treatment of lenalidomide, bortezomib, and dexamethasone (RVd), and a newer regimen that adds daratumumab (Dara-RVd). Previous research has shown that adding daratumumab to RVd improves the depth of treatment responses and extends progression-free survival (PFS) for patients. The authors compare data from a historical group of 1,000 NDMM patients treated with RVd to a more recent group of 326 patients who received the Dara-RVd treatment with the intent to undergo a transplant.

The results from this analysis highlight the effectiveness of the Dara-RVd regimen in real-world clinical settings, showing that it can be beneficial for different patient groups that might not have been well-represented in clinical trials. Additionally, the study explores how daratumumab impacts maintenance therapy for NDMM patients, providing valuable insights into its role in improving patient outcomes.

 

 

"Efficacy of daratumumab on multiple myeloma patients with renal insufficiency: a systematic review and meta-analysis"

Source

Jiang, H., Li, L., Guo, M., Li, M., Wu, H., Chen, X., … Fu, W. (2024). Efficacy of daratumumab on multiple myeloma patients with renal insufficiency: a systematic review and meta-analysis. Hematology, 29(1). https://doi.org/10.1080/16078454.2024.2399430  September 13, 2024. 

Overview

This study investigates the effectiveness of daratumumab in treating multiple myeloma (MM) patients who have renal insufficiency (RI). Renal insufficiency is known to impact the prognosis for these patients, and the researchers wanted to determine how well daratumumab works for them. They conducted a systematic search of various medical databases and reviewed ten randomized controlled trials (RCTs) that included 5,003 patients. The analysis focused on outcomes like progression-free survival (PFS), overall survival (OS), complete response rates, and minimal residual disease (MRD) negativity.

The findings showed that adding daratumumab to the treatment regimen significantly improved both PFS and OS for newly diagnosed MM patients with RI and for those with relapsed/refractory MM. The effectiveness of daratumumab in patients with RI was comparable to that in patients with normal kidney function. The benefits of daratumumab appeared to increase over time, particularly in relapsed/refractory patients. Overall, the results suggest that MM patients with RI can benefit from daratumumab treatment, but further high-quality RCTs are needed to confirm these results.

 

 

"Circular RNA_0003489 reflects unfavorable treatment response and shortened survival in newly diagnosed multiple myeloma patients who receive bortezomib-based induction therapy"

Source

Song, S., Xie, J., Xu, B., & Ran, Q. (2024). Circular RNA_0003489 reflects unfavorable treatment response and shortened survival in newly diagnosed multiple myeloma patients who receive bortezomib-based induction therapy. Hematology, 29(1). https://doi.org/10.1080/16078454.2024.2399419  September 13, 2024. 

Overview

This study aimed to explore the role of circular RNA_0003489 (Circ_0003489) as a potential biomarker in newly diagnosed multiple myeloma (NDMM) patients undergoing bortezomib-based treatment. Researchers collected bone marrow samples from 85 NDMM patients and 15 healthy controls. They found that Circ_0003489 levels were significantly higher in NDMM patients compared to the controls. Increased levels of Circ_0003489 were linked to various factors, including higher tumor burden and poorer outcomes. Specifically, higher expression was associated with a lower chance of achieving complete or partial responses to treatment and was linked to shorter progression-free survival (PFS) and overall survival (OS).

Overall, the findings suggest that higher Circ_0003489 levels in NDMM patients indicate a worse response to treatment and shorter survival times after receiving bortezomib-based therapy. This indicates that Circ_0003489 could be a valuable biomarker for assessing treatment outcomes in these patients.

 

 

"Single-cell sequencing analysis of multiple myeloma heterogeneity and identification of new theranostic targets"

Source

Wang, Y., Peng, Y., Yang, C. et al. Single-cell sequencing analysis of multiple myeloma heterogeneity and identification of new theranostic targets. Cell Death Dis 15, 672 (2024). https://doi.org/10.1038/s41419-024-07027-4  September 14, 2024.  

Overview

Multiple myeloma (MM) is a complex and incurable cancer caused by the uncontrolled growth of plasma cells. To better understand the differences in MM and identify new treatment targets, researchers created a detailed profile of bone marrow cells from 48,293 samples, including those from MM patients and healthy donors. They found that the way B lymphocyte cells communicate was disrupted in MM patients compared to healthy individuals, with unique signaling molecules present in the MM group.

Using advanced analysis techniques, the researchers discovered that the main differences between MM patients and healthy donors were seen in the plasma cells, particularly relating to processes involving mitochondria. They identified a specific group of cells linked to the growth of malignant plasma cells. This group showed strong growth potential, high scores for genetic changes, increased expression of commonly mutated genes, and active glucose metabolism.

Additionally, the study highlighted WNK1 as a promising target for therapy in MM. Overall, this research offers new insights into the development of B cells and the diversity of plasma cells in MM, suggesting that WNK1 could be an effective treatment target.

 

 

"Impact of comorbidity on health-related quality of life in newly diagnosed patients with lymphoma or multiple myeloma: results from the PROFILES-registry"

Source

Ekels, A., van de Poll-Franse, L.V., Issa, D.E. et al. Impact of comorbidity on health-related quality of life in newly diagnosed patients with lymphoma or multiple myeloma: results from the PROFILES-registry. Ann Hematol (2024). https://doi.org/10.1007/s00277-024-06006-1   September 16, 2024.  

Overview

As the population ages, many people are facing multiple health issues (comorbidities) alongside their diagnosis of lymphoma or multiple myeloma (MM). This study looked at how comorbidities affect health-related quality of life (HRQoL) in 261 newly diagnosed patients from October 2020 to March 2023. Researchers used specific questionnaires to measure both general and disease-related HRQoL, classifying patients based on the level of comorbidity: no comorbidity, mild (like joint pain), or moderate to severe (like heart or lung disease).

At the time of diagnosis, the average age of participants was 64, with 63% being male. Among these patients, 38% reported no comorbidity, 33% had mild comorbidity, and 29% had moderate to severe comorbidity. Those with mild or moderate-severe comorbidities experienced significantly worse HRQoL compared to those without any comorbidities. 

One year after diagnosis, most patients showed improvement in HRQoL, regardless of their comorbidity status. However, patients with comorbidities reported less improvement in areas like physical functioning, overall health, bone pain, muscle/joint pain, and muscle weakness. The differences in HRQoL between those with and without comorbidities continued over time. 

Overall, the findings highlight that patients with comorbidities start with a worse quality of life and recover more slowly after a lymphoma or MM diagnosis. This suggests that both prognosis and HRQoL should be considered when making treatment decisions.

 

 

"Lipid levels and multiple myeloma risk: insights from Meta-analysis and mendelian randomization"

Source

Zhu, W., Charwudzi, A., li, Q. et al. Lipid levels and multiple myeloma risk: insights from Meta-analysis and mendelian randomization. Lipids Health Dis 23, 299 (2024). https://doi.org/10.1186/s12944-024-02289-5  September 16, 2024.  

Overview

This study explored the relationship between lipid levels (fats in the blood) and the risk of developing multiple myeloma (MM). Researchers conducted a thorough analysis using literature from databases like PubMed and Embase, focusing on data related to lipid levels from the IEU group and MM data from the FinnGen database. Their findings from observational studies revealed that higher levels of LDL (bad cholesterol), HDL (good cholesterol), total cholesterol (TC), and triglycerides were associated with a lower risk of MM. Specifically, the analysis showed significant hazard ratios (HRs) indicating that increases in these lipid levels correlated with reduced MM risk. Moreover, the Mendelian randomization (MR) analysis confirmed that higher triglyceride levels might causally lower the risk of MM, independent of body mass index (BMI). 

The study identified two potential mediators, X-11,423-O-sulfo-L-tyrosine and neuropilin-2, which could help explain the biological mechanisms linking lipid metabolism to MM development. These findings suggest that managing lipid levels, particularly triglycerides, could be a promising strategy for MM prevention. Additionally, the identification of neuropilin-2 as a therapeutic target is significant, especially with ongoing clinical trials for drugs like Efzofitimod. Overall, the study advocates for further research into how triglycerides relate to MM and emphasizes the need for well-designed clinical trials to assess the therapeutic potential of targeting neuropilin-2 in treating MM.

 

 

"Evaluation of Drug–Drug Interaction Potential of Talquetamab, a T-Cell-Redirecting GPRC5D × CD3 Bispecific Antibody, as a Result of Cytokine Release Syndrome in Patients with Relapsed/Refractory Multiple Myeloma in MonumenTAL-1, Using a Physiologically Based Pharmacokinetic Model"

Source

Willemin, ME., Gong, J., Hilder, B.W. et al. Evaluation of Drug–Drug Interaction Potential of Talquetamab, a T-Cell-Redirecting GPRC5D × CD3 Bispecific Antibody, as a Result of Cytokine Release Syndrome in Patients with Relapsed/Refractory Multiple Myeloma in MonumenTAL-1, Using a Physiologically Based Pharmacokinetic Model. Targ Oncol (2024). https://doi.org/10.1007/s11523-024-01093-6  September 16, 2024.  

Overview

This study focused on cytokine release syndrome, a condition often linked with T-cell immunotherapies, which was observed in the MonumenTAL-1 study with talquetamab, a bispecific antibody designed to redirect T-cells. Researchers noted that this syndrome led to increased levels of interleukin-6 (IL-6), a cytokine that can suppress the activity of certain enzymes known as cytochrome P450 (CYP) enzymes. The objective was to assess how elevated IL-6 levels might affect the metabolism of drugs that rely on these CYP450 enzymes, considering both typical and peak IL-6 levels following talquetamab treatment.

To carry out this analysis, the team developed a pharmacokinetic model using data from patients in the MonumenTAL-1 study who received recommended doses of talquetamab. They found that while the average IL-6 levels were not expected to affect drug metabolism significantly, the highest IL-6 levels could moderately impact the metabolism of specific CYP450 substrates, particularly CYP2C19, CYP3A4, and CYP3A5. The study concluded that while IL-6 release due to talquetamab treatment could have some effect on drug interactions, these impacts would likely be limited and would occur mainly within the first 7 to 9 days after treatment begins.

 

 

"Post-thaw CD34+ cell recovery likely degraded under extreme graft platelet concentrations. Bone Marrow Transplant"

Source

Duarte, G.C., Ladvanszky, L., Atkinson, G. et al. Post-thaw CD34+ cell recovery likely degraded under extreme graft platelet concentrations. Bone Marrow Transplant (2024). https://doi.org/10.1038/s41409-024-02409-w  September 16, 2024.  

Overview

This study investigated how platelet concentration affects the viability of CD34 cells after thawing in patients undergoing autologous hematopoietic stem cell transplant (ASCT). Impaired viability of these cells can indicate delayed engraftment, but the relationship between platelets and CD34 cell viability has not been well understood. Researchers analyzed data from 82 ASCT patients in New Zealand, with a total of 150 collections of peripheral blood stem cells. They found a significant negative correlation between platelet concentration and CD34 cell recovery, meaning that as platelet levels increased or decreased beyond a certain range, the recovery of CD34 cells was reduced. This trend was most notable in patients whose platelet levels were between 1500 and 2000 × 10^9/L.

The results showed that patients with either very low or very high platelet concentrations had poorer CD34 recovery. The lowest platelet subgroup included many patients with Hodgkin or non-Hodgkin lymphoma, while the highest subgroup mainly consisted of patients with multiple myeloma, with a notable male majority in both groups. The researchers proposed that the concentration of graft platelets may reflect the state of CD34 cells, such as their cell cycle and adhesion, which are related to platelet functions. When platelet concentrations were within a certain range, CD34 cell viability was maintained, but levels outside this range negatively impacted recovery.

 

 

"Lenalidomide, Ixazomib or Daratumumab Maintenance Therapy in Multiple Myeloma"

Source

Eunice Lai, Yu Yang Soon, Ainsley Ryan Yan Bin Lee, Shi Yin Wong, Cinnie Yentia Soekojo, Melissa Ooi, Wee Joo Chng, Sanjay de Mel; Lenalidomide, Ixazomib or Daratumumab Maintenance Therapy in Multiple Myeloma. Blood Neoplasia 2024; 100042. doi: https://doi.org/10.1016/j.bneo.2024.100042  September 16, 2024. 

Overview

This study examined the effectiveness of three maintenance therapies—lenalidomide, ixazomib, and daratumumab—for patients with newly diagnosed multiple myeloma (NDMM). Although these treatments have been suggested for maintenance, there were no previous randomized trials directly comparing them. The researchers conducted a network meta-analysis of nine studies that included 4,115 transplant-eligible patients (TEMM) and 1,689 non-transplant-eligible patients (NTEMM). They used a Bayesian model to evaluate the treatments' impacts on progression-free survival (PFS) and overall survival (OS) compared to a placebo.

The results showed that both lenalidomide and daratumumab significantly improved PFS in both TEMM and NTEMM patients, while ixazomib did not show similar benefits. For example, lenalidomide had a hazard ratio (HR) of 0.46, indicating a much lower risk of disease progression compared to placebo. However, none of the treatments showed an improvement in overall survival. Additionally, patients with high-risk cytogenetics did not experience PFS benefits from any of the therapies. The study also noted safety concerns, with lenalidomide linked to second malignancies, ixazomib to low platelet counts, and daratumumab to pneumonia. Based on these findings, the researchers concluded that lenalidomide should remain the preferred maintenance therapy for patients with NDMM.

 

 

"Use of Hematopoietic Cell Transplant for Hematologic Cancers by Race, Ethnicity, and Age"

Source

Hahn T, Herr MM, Brazauskas R, et al. Use of Hematopoietic Cell Transplant for Hematologic Cancers by Race, Ethnicity, and Age. JAMA Netw Open. 2024;7(9):e2433145. doi:10.1001/jamanetworkopen.2024.33145 September 18, 2024. 

Overview

This study investigated the use of hematopoietic cell transplantation (HCT) for treating hematologic cancers, focusing on whether disparities based on race, ethnicity, and age still exist over time. Researchers analyzed data from patients who received transplants in the U.S. between January 2009 and December 2018. They looked at how many patients received HCT and categorized them into different groups based on race and ethnicity, including Hispanic, non-Hispanic White, non-Hispanic Black, and non-Hispanic Other (Asian and American Indian).

The results showed that from 2009 to 2018, a total of 136,280 HCTs were performed, with 16.7% of the patients being children or young adults (ages 0-39) and 83.3% being adults (ages 40-84). Overall, HCT utilization increased across all groups. However, the study found persistent disparities for non-Hispanic Black patients, particularly in adult allogeneic transplants for acute myeloid leukemia and myelodysplastic syndrome, where their rates were lower compared to Hispanic and non-Hispanic White patients. In contrast, Hispanic and non-Hispanic Other groups showed increased utilization rates that matched those of non-Hispanic White patients in the most recent data. For younger patients (ages 0-39), Hispanic patients had the highest rates of allogeneic transplants for acute lymphoblastic leukemia. The findings suggest that while some disparities have improved, significant differences remain for non-Hispanic Black patients.

 

 

"Pomalidomide for Epistaxis in Hereditary Hemorrhagic Telangiectasia"

Source

Hanny Al-Samkari, Raj S. Kasthuri, Vivek N. Iyer, et al. Pomalidomide for Epistaxis in Hereditary Hemorrhagic Telangiectasia. N Engl J Med 2024;391:1015-1027 VOL. 391 NO. 11. September 18, 2024. 

Overview

This study focused on hereditary hemorrhagic telangiectasia (HHT), a genetic condition that causes abnormal blood vessel formations and frequent nosebleeds (epistaxis). These nosebleeds can lead to iron-deficiency anemia and significantly impact patients' quality of life. Researchers conducted a randomized, placebo-controlled trial to assess the safety and effectiveness of a drug called pomalidomide in treating HHT. They randomly assigned 144 patients to receive either 4 mg of pomalidomide daily or a placebo for 24 weeks. The main goal was to measure changes in the Epistaxis Severity Score, which rates the severity of nosebleeds, with a reduction of 0.71 points or more considered clinically important.

The trial was halted early after a planned analysis showed significant benefits from pomalidomide. Of the participants, 95 received pomalidomide while 49 received a placebo. At the end of the 24 weeks, the pomalidomide group showed a 0.94-point greater reduction in the Epistaxis Severity Score compared to the placebo group, indicating a meaningful improvement in nosebleed severity. Additionally, the quality-of-life scores for HHT patients also improved in the pomalidomide group. However, some side effects, such as low white blood cell counts (neutropenia), constipation, and rashes, were more common in those taking pomalidomide. Overall, the study concluded that pomalidomide effectively reduces the severity of nosebleeds in HHT patients without any unexpected safety issues.

 

 

"Characterization of MYC Rearrangements in Multiple Myeloma: an Optical Genome Mapping Approach"

Source

Yoon, J., Jeon, T., Kwon, JA. et al. Characterization of MYC Rearrangements in Multiple Myeloma: an Optical Genome Mapping Approach. Blood Cancer J. 14, 165 (2024). https://doi.org/10.1038/s41408-024-01147-y September 20, 2024. 

Overview

Multiple myeloma (MM) is a blood cancer marked by various genetic changes that influence how the disease progresses and how patients respond to treatment. Common genetic alterations in MM include structural variations in immunoglobulin heavy chains (IGH) and hyperdiploidy, which are primary changes, along with secondary changes like 1q gain and 17p deletion that occur as the disease worsens. Certain genetic factors, like specific IGH translocations and mutations in TP53, can indicate a higher risk for patients.

MYC rearrangements are another potential risk factor in newly diagnosed MM, but their impact on patient outcomes isn’t fully understood. Earlier studies suggested that MYC rearrangements might lead to worse outcomes, but recent research shows that only certain types of MYC translocations are consistently linked to poor prognosis. The frequency of MYC rearrangements varies significantly based on the detection method used, with whole genome sequencing (WGS) identifying higher rates than fluorescence in situ hybridization (FISH).

This study aimed to analyze MYC rearrangements in MM using advanced optical genome mapping (OGM) alongside traditional methods like FISH and next-generation sequencing (NGS). Researchers examined bone marrow samples from patients diagnosed with MM and found that OGM detected MYC rearrangements in 43.3% of the cases, significantly more than other methods.

The results indicated that many MYC translocations clustered around specific chromosomal regions, suggesting common breakpoints in MM that may help in detecting these alterations more effectively. Importantly, MYC expression levels were typically higher in cases with translocations involving immunoglobulin loci compared to those with other genetic partners.

In conclusion, this study highlights the importance of using OGM to detect MYC rearrangements in MM and suggests that targeting specific chromosomal regions could improve diagnostic accuracy. The findings also underline the need for further research to better understand the relationship between MYC rearrangements and clinical outcomes in MM. Integrating RNA expression data with protein analysis could enhance the understanding of how these genetic changes affect the disease.

 

 

"Colesevelam for lenalidomide-associated diarrhea in patients with multiple myeloma"

Source

Hultcrantz, M., Hassoun, H., Korde, N. et al. Colesevelam for lenalidomide associated diarrhea in patients with multiple myeloma. Blood Cancer J. 14, 164 (2024). https://doi.org/10.1038/s41408-024-01136-1 September 19, 2024.  

Overview

Lenalidomide is a drug commonly used to treat multiple myeloma (MM), but it can cause diarrhea during the maintenance phase, which can lower the quality of life and sometimes leads to stopping the treatment. This study looked at using colesevelam, a bile acid binder, to treat lenalidomide-related diarrhea. Twenty-five MM patients with diarrhea were treated with colesevelam for 12 weeks. 

Most patients (88%) saw improvement, and 68% had complete relief from diarrhea. Side effects of colesevelam included constipation, flatulence, and acid reflux, but they were manageable. Importantly, colesevelam did not affect the way lenalidomide worked in the body. Patients reported fewer symptoms and a better quality of life after starting colesevelam. The study shows that colesevelam can effectively manage lenalidomide-related diarrhea, helping patients continue their treatment without compromising its benefits.

 

 

"Anti-BCMA–engineered exosomes for bortezomib-targeted delivery in multiple myeloma"

Source

Shushu Yuan, Qi Li, Chuan He, Mengli Bing, Xinyun Zhang, Hao Xu, Zhiming Wang, Meifang Zhao, Yucheng Zhang, Yali Chai, Bingzong Li, Wenzhuo Zhuang; Anti-BCMA–engineered exosomes for bortezomib-targeted delivery in multiple myeloma. Blood Adv 2024; 8 (18): 4886–4899. doi: https://doi.org/10.1182/bloodadvances.2023012464  September 24, 2024.  

Overview

Exosomes, small particles naturally released by cells, are being explored as new ways to deliver drugs because they are better at targeting specific cells and cause fewer immune reactions than standard methods. This study created a system using exosomes from modified monocytes to deliver the cancer drug bortezomib (Btz) to multiple myeloma (MM) cells. The exosomes were altered to carry an antibody (anti-BCMA) that specifically targets MM cells. These modified exosomes loaded with Btz worked better at killing MM cells compared to regular Btz in lab tests and in mice with MM. The treatment also caused little damage to healthy cells. The study shows that using targeted exosomes could be a promising new way to treat MM with fewer side effects.

 

 

"Rates of Hematopoietic Stem Cell Transplantation, Racism, and the Aging Face of America"

Source

Rosanwo TO. Rates of Hematopoietic Stem Cell Transplantation, Racism, and the Aging Face of America. JAMA Netw Open. 2024;7(9):e2433124. doi:10.1001/jamanetworkopen.2024.33124.  September 18, 2024. 

Overview

Hematopoietic stem cell transplantation (HSCT) is a life-saving treatment for cancer patients, where healthy stem cells are used to rebuild damaged bone marrow. This therapy has become a key part of cancer treatment since the 1980s, improving survival rates for diseases like leukemia. However, access to HSCT varies based on race, age, and socioeconomic status.

A recent study by Hahn and colleagues looked at over 130,000 transplants from 2009 to 2018. It showed that while HSCT use has increased across all groups, Hispanic and Black patients still face challenges. Hispanic patients improved their access to HSCT over time, but Black patients continue to have lower HSCT rates, especially as they age. For example, Black patients with multiple myeloma (MM) are less likely to receive HSCT even though MM is more common in Black individuals.

These disparities are partly due to factors like structural racism, healthcare bias, and a lack of matching donors for Black patients. The study suggests that healthcare providers should work to overcome these barriers by offering more referrals and providing support to help all patients access this crucial treatment.

 

 

"Measurable Residual Disease by Mass Spectrometry and Next-Generation Flow to Assess Treatment Response in Myeloma"

Source

Noemi Puig, Cristina Agullo Roca, Teresa Contreras Sanfeliciano, M Teresa Cedena, Joaquín Martínez-López, Albert Oriol, María-Jesús Blanchard, Rafael Ríos-Tamayo, Belén Iñigo Rodríguez, Anna Sureda, Sunil Lakhwani, Javier de la Rubia Comos, Veronica Gonzalez-Calle, Valentín Cabañas, Luis Palomera, José María M Moraleda, Joan Bargay, Sergio Castro, Laura Rosiñol, Joan Bladé, Jesús F. San-Miguel, Juan-Jose Lahuerta, Bruno Paiva, Maria-Victoria Mateos; Measurable Residual Disease by Mass Spectrometry and Next-Generation Flow to Assess Treatment Response in Myeloma. Blood 2024; blood.2024024995. doi: https://doi.org/10.1182/blood.2024024995  September 18, 2024. 

Overview

Quantitative immunoprecipitation mass-spectrometry (QIP-MS) is a method used to detect small amounts of cancer (MRD) in multiple myeloma patients who seem to be in complete remission. In two clinical trials (GEM2012MENOS65 and GEM2014MAIN), researchers compared QIP-MS in blood with next-generation flow (NGF) cytometry in bone marrow to monitor MRD after different stages of treatment.

Both methods successfully identified groups of patients with different survival outcomes, showing that patients who stayed or became MRD-negative lived longer than those who stayed or became MRD-positive. When MRD reappeared in blood using QIP-MS, it was linked to a high risk of the disease coming back soon. Since QIP-MS is less invasive than bone marrow tests, it offers a promising new way to track MRD and assess treatment response in multiple myeloma.

 

 

"NK cells with adhesion defects and reduced cytotoxic functions are associated with a poor prognosis in multiple myeloma"

Source

Eve Blanquart, Rüçhan Ekren, Bineta Rigaud, Marie-Véronique Joubert, Virginie Baylot, Hélène Daunes, Marine Cuisinier, Marine Villard, Nadège Carrié, Céline Mazzotti, Liliana E. Lucca, Aurore Perrot, Jill Corre, Thierry Walzer, Hervé Avet-Loiseau, Pierre-Paul Axisa, Ludovic Martinet; NK cells with adhesion defects and reduced cytotoxic functions are associated with a poor prognosis in multiple myeloma. Blood 2024; 144 (12): 1271–1283. doi: https://doi.org/10.1182/blood.2023023529  September 19, 2024. 

Overview

Immunotherapy has shown promising results in treating multiple myeloma (MM), and better ways to group patients based on their immune system, especially natural killer (NK) cells, are needed. In this study, researchers used single-cell RNA sequencing to analyze NK cells from 10 MM patients and 10 healthy individuals. They found significant changes in NK cells in both the bone marrow and blood of MM patients.

The number of mature, cytotoxic NK cells was lower in MM patients, and instead, they had more late-stage NK cells with inflammatory markers but poor ability to kill cancer cells. These defective NK cells also had issues with cell adhesion and movement, which may further reduce their effectiveness.

In a group of 177 MM patients, those with higher levels of these faulty NK cells (low in CD16 and CD226 markers) had shorter overall survival. This research highlights the need to develop better therapies targeting NK cells to improve MM treatment outcomes.

 

 

"Not so natural, not so killers"

Source

Bruno Paiva, José-Angel Martinez-Climent; Not so natural, not so killers. Blood 2024; 144 (12): 1238–1240. doi: https://doi.org/10.1182/blood.2024025597  September 19, 2024 

Overview

This article highlights how dysfunctional natural killer (NK) cells affect the survival of patients with multiple myeloma (MM). MM often develops from precursor conditions, but some patients never progress to active disease, suggesting the role of the immune system in controlling cancer growth. Immunotherapy has reshaped MM treatment, but little is known about the role of NK cells in this process.

The study used advanced techniques to compare NK cells from MM patients and healthy donors. MM patients had fewer cytotoxic NK cells and more dysfunctional NK cells, which could not effectively kill cancer cells. The accumulation of these altered NK cells was linked to worse survival outcomes in MM patients.

The research also found that NK cells with low levels of two key proteins, CD16 and CD226, had reduced function, and higher numbers of these cells were associated with shorter survival in MM patients. These findings highlight the need for more research to improve immunotherapy by targeting NK cell dysfunction in MM.

 

 

"Multiomics analysis of IgM monoclonal gammopathies reveals epigenetic influence on oncogenesis via DNA methylation"

Source

Karan Chohan, Jonas Paludo, Surendra Dasari, Patrizia Mondello, Joseph P. Novak, Jithma P. Abeykoon, Kerstin Wenzl, Zhi-Zhang Yang, Shahrzad Jalali, Vaishali Bhardwaj, Jordan E. Krull, Esteban Braggio, Michelle K. Manske, Aneel Paulus, Craig B. Reeder, Sikander Ailawadhi, Asher Chanan-Khan, Prashant Kapoor, Robert A. Kyle, Morie A. Gertz, Anne J. Novak, Stephen M. Ansell; Multiomics analysis of IgM monoclonal gammopathies reveals epigenetic influence on oncogenesis via DNA methylation. Blood 2024; 144 (12): 1284–1289. doi: https://doi.org/10.1182/blood.2023023639  September 19, 2024. 

Overview

A recent study examined the role of DNA methylation in IgM monoclonal gammopathies, focusing on Waldenström macroglobulinemia (WM) and IgM monoclonal gammopathy of undetermined significance (MGUS). Researchers analyzed DNA methylation, RNA sequencing, and whole-exome sequencing in 34 participants (23 with WM, 6 with IgM-MGUS, and 5 healthy controls). They found significant differences in DNA methylation between these groups, suggesting that epigenetic changes may regulate important pathways like cell cycle, metabolism, and immune signaling. Notably, pathways like CXCR4 and interleukin signaling were more active in WM than in IgM-MGUS. Key genes such as CCND1 and CD79B also showed changes in methylation and gene expression, indicating that DNA methylation plays a role in the development of these conditions.

 

 

"The epigenetic spectrum of IgM gammopathies"

Source

Benjamin G. Barwick; The epigenetic spectrum of IgM gammopathies. Blood 2024; 144 (12): 1240–1241. doi: https://doi.org/10.1182/blood.2024025698  September 19, 2024  

Overview

A recent study by Chohan and colleagues analyzed immunoglobulin M (IgM) gammopathies, which include conditions like Waldenström macroglobulinemia (WM) and IgM monoclonal gammopathy of undetermined significance (MGUS). These conditions can evolve into more serious diseases, such as multiple myeloma or lymphomas, and this study aimed to better understand their biological differences.

Using high-tech methods, the researchers looked at gene expression and DNA methylation in IgM gammopathies. DNA methylation is a process that can control gene activity. They found that as these diseases progress, there is a loss of DNA methylation, which reflects the normal changes B-cells go through as they turn into plasma cells. Key genes involved in immune signaling and cell growth, like CXCR4 and CD79B, were found to be more active in these conditions compared to healthy cells, even without genetic mutations.

The study also identified three subtypes of IgM gammopathies. Cluster 1, which includes only WM cases, is thought to be more aggressive, with cells showing fewer signs of DNA methylation. Cluster 2, a mix of WM and MGUS cases, showed more immune-related activity, while Cluster 3 included both diseased and healthy controls. These findings suggest that different forms of WM may need different treatments.

The study highlights the importance of understanding the unique biological characteristics of these diseases. In the future, researchers hope to find easy-to-detect markers to identify these subtypes, which could help doctors provide more personalized treatments.

 

 

"Chemokine Receptor 4-Targeted PET/CT with [68Ga]pentixather in Newly Diagnosed Multiple Myeloma: a Comparative Study with [68Ga]pentixafor PET/CT"

Source

Yang, Q., Zhang, F., Hao, Z. et al. Chemokine Receptor 4-Targeted PET/CT with [68Ga]pentixather in Newly Diagnosed Multiple Myeloma: a Comparative Study with [68Ga]pentixafor PET/CT. Mol Imaging Biol (2024). https://doi.org/10.1007/s11307-024-01953-7  September 20, 2024. 

Overview

This study compared two types of PET/CT scans, [68Ga]pentixather and [68Ga]pentixafor, to see which one is better at detecting cancer in newly diagnosed multiple myeloma (NDMM) patients. It also looked at how well these scans could measure the amount of cancer in the body (tumor load).

Nineteen patients with NDMM were given both types of PET/CT scans. A positive scan meant finding cancer in the form of bone lesions or abnormal growths outside the bone. The researchers compared the number of lesions and how active the cancer was in both scans, using a measurement called SUVmax (which shows how much cancer is in a lesion). They also analyzed how these scans related to other ways doctors assess cancer risk.

The study found that [68Ga]pentixather PET/CT detected cancer in 94.7% of patients, while [68Ga]pentixafor PET/CT detected it in 78.9%. Among 14 patients with bone lesions, [68Ga]pentixather PET/CT found more or equal lesions in 13 patients and showed higher SUVmax, meaning it detected more active cancer. This scan also showed a higher total cancer burden than [68Ga]pentixafor PET/CT, especially in patients with more advanced disease.

In conclusion, [68Ga]pentixather PET/CT was just as good as [68Ga]pentixafor PET/CT at finding cancer in NDMM patients. It was also better at measuring the total amount of cancer in the body, which could help doctors understand a patient’s cancer load more accurately.

 

 

"Steroid-free combination of 5-azacytidine and venetoclax for the treatment of multiple myeloma"

Source

Flanagan L, Coughlan A, Cosgrove N, Roe A, Wang Y, Gilmore S, Drozdz I, Comerford C, Ryan J, Minihane E, Parvin S, O’Dwyer M, Quinn J, Murphy P, Furney S, Glavey S, Chonghaile TN, Foundation LR, Ireland SF, Research BC. Steroid-free combination of 5-azacytidine and venetoclax for the treatment of multiple myeloma. Haematologica 2024;109(9):2930-2943; https://doi.org/10.3324/haematol.2023.283771.  September 2024  

Overview

Multiple myeloma (MM) is a cancer of plasma cells that is currently incurable, though treatments have improved survival rates. Some MM patients depend on a protein called BCL-2 for their cancer cells' survival, and a drug called venetoclax, which targets BCL-2, has been effective for patients with specific genetic traits (like t(11;14)) and those who overexpress BCL-2. However, only about 20% of MM patients respond to venetoclax, so researchers are looking for ways to expand its use.

In this study, researchers screened various epigenetic modifiers to find a way to make more MM cells sensitive to venetoclax. They found that a drug called 5-azacytidine, which inhibits DNA demethylation, could enhance the effectiveness of venetoclax in MM cells that don’t rely on BCL-2. This combination worked by increasing the expression of a protein called NOXA, which promotes cell death.

The study showed that adding a steroid to the combination did not improve results and even caused more immune cell death, suggesting that a steroid-free approach might be better, especially for elderly patients. The combination of venetoclax and 5-azacytidine was also effective in MM patient samples with different genetic backgrounds and anti-apoptotic dependencies (BCL-2 or MCL-1).

The study identified the venetoclax and 5-azacytidine combination as a promising treatment, especially for patients who can’t tolerate steroids.

 

 

"Tocilizumab administration in cytokine release syndrome is associated with hypofibrinogenemia after chimeric antigen receptor T-cell therapy for hematologic malignancies"

Source

Perl M, Herfeld K, Harrer DC, Höpting M, Schweiger M, Sterz U, Knödler L, Heimerl S, Hansmann L, Herr W, Poeck H, Wolff D, Edinger M, Hart C, Fante MA. Tocilizumab administration in cytokine release syndrome is associated with hypofibrinogenemia after chimeric antigen receptor T-cell therapy for hematologic malignancies. Haematologica 2024;109(9):2969-2977; https://doi.org/10.3324/haematol.2023.284564.  September 2024.   

Overview

CAR T-cell therapy, a treatment for blood cancers, can cause serious side effects, including cytokine release syndrome (CRS). One of these effects is hypofibrinogenemia, a condition where there are low levels of fibrinogen, a protein important for blood clotting. Until now, this was thought to be caused by conditions like disseminated intravascular coagulation (DIC) and liver problems.

In this study, researchers looked at 41 patients who received CAR T-cell therapy. Almost all (93%) developed CRS, and hypofibrinogenemia was seen even in mild cases of CRS. DIC and liver dysfunction mainly appeared in more severe cases of CRS. After patients received the drug tocilizumab to treat CRS, their fibrinogen levels dropped, while those who didn't receive tocilizumab had increased fibrinogen levels. The study identified tocilizumab as a key factor in causing low fibrinogen levels.

The researchers believe that during CRS, the body increases fibrinogen production to compensate for the loss of clotting factors. However, tocilizumab disrupts this process, leading to prolonged low fibrinogen levels. This highlights the importance of monitoring fibrinogen levels closely after tocilizumab treatment.

 

 

"Clonal CD8+ T-cell expansion is associated with complete response to elranatamab in refractory multiple myeloma"

Source

Krzysiek R, Bitoun S, Belkhir R, Hacein-Bey-Abina S, Mariette X. Clonal CD8+ T-cell expansion is associated with complete response to elranatamab in refractory multiple myeloma. Haematologica 2024;109(9):3078-3080; https://doi.org/10.3324/haematol.2023.284942. September 2024.   

Overview

This study focuses on bispecific T-cell engagers (TCEs) that target BCMA and CD3, which are used to treat refractory multiple myeloma (MM). TCEs have shown good clinical response rates, but researchers are still trying to understand how they work and why some patients develop resistance. 

In this study, a 74-year-old patient with relapsed MM received a TCE treatment called elranatamab. After starting treatment, the patient's immune system responded with a large increase in certain types of T cells (CD8+). This response included a significant expansion of specific T-cell clones, which are thought to help control the cancer. Despite the strong immune reaction and high levels of T cells, the patient did not experience any severe side effects like cytokine release syndrome (CRS) or neurotoxicity. The treatment led to a complete remission within two months, and the patient's condition remained stable for eight months.

Researchers observed that the patient's T cells were highly activated and showed markers that indicated they were fighting the cancer. Interestingly, this patient’s CD8+ T cells expanded dramatically, while CD4+ T cells displayed signs of exhaustion. This case demonstrates the potential role of T-cell clonal expansion in TCE-based treatments and suggests that monitoring T-cell behavior could help predict the success of treatment. However, more research is needed to confirm these findings in larger groups of MM patients.

 

 

"Optimizing individualized therapy decision-making in multiple myeloma (MM): integration and impact of the Revised Myeloma Comorbidity Index in the MM-tumor board"

Source

Dreyling, E., Ihorst, G., Reinhardt, H. et al. Optimizing individualized therapy decision-making in multiple myeloma (MM): integration and impact of the Revised Myeloma Comorbidity Index in the MM-tumor board. Ann Hematol (2024). https://doi.org/10.1007/s00277-024-06010-5  September 21, 2024. 

Overview

Multiple Myeloma (MM) often affects older adults, making individualized treatment plans necessary. This study looked at how well the Revised Myeloma Comorbidity Index (R-MCI), a tool used to assess patient health, was used in treatment decisions at a cancer center. 

Researchers studied 565 patients presented at an MM-tumor board over three years. They found that the R-MCI was used in 94% of cases to help guide treatment, while in 6%, it was not applied, which may have missed important treatment changes. Patients were presented multiple times to the tumor board, with a median of 3 presentations per patient.

Among patients with multiple presentations, 55% had their treatment doses reduced, especially those presented four or more times. Most patients either maintained or improved their health status, as measured by the R-MCI. The study showed that the R-MCI is highly useful for making treatment decisions, offering valuable insights beyond just the patient’s age.

 

 

"Beyond Conventional Treatments: Exploring CAR-T Cell Therapy for Cancer Stem Cell Eradication"

Source

Rabie, L.E., Mohran, A.A., Gaber, K.A. et al. Beyond Conventional Treatments: Exploring CAR-T Cell Therapy for Cancer Stem Cell Eradication. Stem Cell Rev and Rep (2024). https://doi.org/10.1007/s12015-024-10786-4  September 23, 2024. 

Overview

This study focuses on CAR-T cell therapy, a promising cancer treatment. CAR-T cells are special immune cells modified to target cancer cells. The study reviews how CAR-T cells are made, their structure, and improvements over time. Researchers also discuss the potential of using these cells to target cancer stem cells, which can help make treatments more precise.

However, CAR-T cell therapy has limitations. One issue is "antigen loss," where cancer cells stop showing the proteins CAR-T cells are designed to attack, making them hard to detect. Solutions like using multiple CAR-T cells to target different antigens are being explored. Another problem is cytokine release syndrome (CRS), which causes dangerous inflammation in the body. Tocilizumab is often used to control severe cases of CRS without reducing the therapy's effectiveness.

While CAR-T cells show great promise, especially for blood cancers, their success in solid tumors is limited due to issues with targeting cancer cells accurately and overcoming the tumor's defenses. Scientists are working on ways to improve CAR-T cell therapy, such as enhancing its ability to recognize cancer cells and reducing side effects. Despite its challenges, CAR-T therapy could become a major cancer treatment in the future with more research.

 

 

"Response to daratumumab-retreatment in patients with multiple myeloma"

Source

Souren, L., Ihorst, G., Greil, C. et al. Response to daratumumab-retreatment in patients with multiple myeloma. Ann Hematol (2024). https://doi.org/10.1007/s00277-024-05991-7  September 23, 2024. 

Overview

This study looked at whether retreatment with daratumumab, a drug for multiple myeloma (MM), is effective and safe. Researchers analyzed 293 patients who had received daratumumab between 2016 and 2023, with a focus on 22 patients who were treated with daratumumab more than once. Most of these patients were older, had advanced stages of MM, and had been through at least three prior treatments.

The results showed that daratumumab retreatment worked well, with response rates only slightly decreasing over time: 64% after the first treatment, 46% after the first retreatment, and 43% after the second retreatment. Patients had similar survival times between treatments, and side effects did not increase with retreatment.

The study suggests that carefully selected MM patients can benefit from retreatment with daratumumab, especially when combined with other treatments and with breaks between treatment rounds. Further studies are needed to confirm these findings.

 

 

"Pomalidomide in patients with multiple myeloma: potential impact on the reconstitution of a functional T-cell immunity"

Source

Shen, J., Senes, F., Wen, X. et al. Pomalidomide in patients with multiple myeloma: potential impact on the reconstitution of a functional T-cell immunity. Immunol Res (2024). https://doi.org/10.1007/s12026-024-09546-w September 24, 2024. 

Overview

This study looked at how the drug pomalidomide affects the immune system in patients with relapsed or refractory multiple myeloma (RRMM). Pomalidomide is an oral drug used when other treatments, like bortezomib and lenalidomide, no longer work.

Researchers used flow cytometry to track changes in T-cells during treatment. At the start, they noticed that patients had lower CD4+ (helper) T-cells and higher CD8+ (killer) T-cells compared to healthy people. Over time, most T-cell levels stayed stable, except for CD4+ cells, which decreased further as treatment continued.

One key finding was an increase in CD4+ T-cell expansions, especially in patients who were still responding to pomalidomide at later stages of treatment. This suggests that pomalidomide may influence immune cells, particularly CD4+ cells, which could play a role in fighting the cancer.

Overall, the study shows that pomalidomide may help adjust the immune system in RRMM patients, potentially aiding in antitumor immunity.

 

 

"Proposal for harmonizing the reporting of infections during treatment with bispecific antibodies in multiple myeloma"

Source

Heinz Ludwig, Nikhil C. Munshi, Evangelos Terpos, Ilvy Schweitzer, Noopur Raje, Philippe Moreau, Ajay Nooka; Proposal for harmonizing the reporting of infections during treatment with bispecific antibodies in multiple myeloma. Blood Adv 2024; 8 (18): 4979–4982. doi: https://doi.org/10.1182/bloodadvances.2024013461  September 24, 2024.  

Overview

Infections are a major concern for patients with multiple myeloma who are treated with new immunotherapies, particularly bispecific antibodies (BsAbs). In fact, infections are the second leading cause of death for these patients, after the disease itself. Understanding how often infections occur in patients treated with BsAbs is important for managing their care, including adjusting treatment doses and implementing preventive measures. However, infection rates reported in different studies can vary significantly, making it hard to compare results.

This study reviewed existing data on infections in patients treated with BsAbs and proposed a standardized way to report these infections due to inconsistencies in current reporting practices. The researchers looked at studies involving at least 50 patients published by the end of 2023 and excluded studies that combined BsAbs with other therapies known to increase infection risk.

They found nine studies with varying infection rates—ranging from 42.5% to 80%—which were influenced by how long patients were followed. The risk of infection was lower with certain newer BsAbs, as they caused less severe side effects like neutropenia (low white blood cell count). The researchers adjusted the data to show infection rates per 100 patients per month, which ranged from 3.5 to 10.7 infections.

They also analyzed data from the MajesTEC-1 study to see how infection rates changed over time. They found that infections were more common in the first month of treatment but remained relatively stable after that. This suggests that the risk of infections is mainly due to the immunosuppressive effects of the BsAbs rather than uncontrolled myeloma. Additionally, the way infections were reported in studies often led to underreporting, with 123 infections reported in a trial when counting the highest grade of infection, compared to 436 when counting each infection.

The study argues for a new reporting method that counts each infection as a separate event over the treatment period, rather than just the highest one per patient. This would provide a clearer picture of infection risks and help guide treatment. They also acknowledged that diagnosing infections can be tricky and might have been influenced by COVID-19.

The researchers recommend a standardized approach for reporting infections in patients treated with BsAbs. This could improve understanding of the infection risks associated with these therapies and help doctors manage patient care better. They created a Myeloma Infection Score calculator to help track infections and visualize their frequency over time. Further research is needed to refine strategies for monitoring and addressing infection risks after treatment with BsAbs.

 

 

"PVR (CD155) epigenetic status mediates immunotherapy response in multiple myeloma"

Source

Martinez-Verbo, L., Veselinova, Y., Llinàs-Arias, P. et al. PVR (CD155) epigenetic status mediates immunotherapy response in multiple myeloma. Leukemia (2024). https://doi.org/10.1038/s41375-024-02419-z  September 24, 2024. 

Overview

The immune system is complex and needs careful regulation to function properly. If it becomes unbalanced, it can lead to serious health issues. Epigenetics involves changes to the structure of DNA that do not alter the DNA sequence itself. These changes can affect how genes are expressed, playing a crucial role in immune responses, such as the activation of cells that can kill tumors.

Cytotoxic cells must undergo specific interactions to become activated, known as immune checkpoint (IC) events. These interactions can either encourage or inhibit immune responses. Over time, repeated inhibitory signals can lead to cell exhaustion. One inhibitory marker, the poliovirus receptor (PVR or CD155), interacts with another protein called TIGIT, which can dampen immune activation. Cancer cells, including those in multiple myeloma (MM), often exploit changes in DNA methylation to regulate these markers, leading to tumor growth.

MM is a type of blood cancer characterized by the accumulation of plasma cells in the bone marrow, which makes it difficult to treat and often leads to relapses. The authors of this study focus on how epigenetic changes in PVR affect immune activation and sensitivity to immunotherapy in MM.

They found that about 15% of primary MM samples had high levels of methylation at the PVR gene, which was not present in healthy plasma cells. This methylation was linked to lower PVR expression. When they inhibited methylation, PVR expression returned, suggesting that this epigenetic change silences the gene.

To explore how PVR impacts immune responses in MM, researchers created models that decreased PVR expression. They found that reducing PVR made MM cells more vulnerable to T cell attacks. They also tested different immunotherapy strategies, including bispecific T cell engagers and CAR-T therapies, and found that lowering PVR improved the effectiveness of these treatments.

Analysis of data from the CoMMpass project, which includes cases of newly diagnosed MM, showed that patients with low PVR levels had better overall survival than those with high levels. Furthermore, lower PVR levels were linked to less aggressive cancer features, while higher levels were associated with high-risk genetic changes.

These findings suggest that low PVR expression may lead to better immune engagement in MM, making targeting PVR a potential therapeutic strategy. While immune checkpoint inhibitors alone haven't been very effective for MM, combining them with other therapies like bispecific antibodies and cellular treatments might enhance their effectiveness by addressing issues like cytotoxic cell exhaustion.

 

 

"Defining infection risk of bispecific antibodies for myeloma"

Source

Martinez-Verbo, L., Veselinova, Y., Llinàs-Arias, P. et al. PVR (CD155) epigenetic status mediates immunotherapy response in multiple myeloma. Leukemia (2024). https://doi.org/10.1038/s41375-024-02419-z  September 24, 2024. 

Overview

In this issue of *Blood Advances*, Ludwig and colleagues suggest a new way to report infections in patients with relapsed/refractory multiple myeloma who are treated with bispecific antibody therapy. Current reporting practices often miss the full picture because they only document the highest grade of infection per patient and do not consider how long patients are followed in studies. The authors analyzed data from studies with at least 50 participants treated with bispecific antibodies and calculated the number of infections per 100 patients per month to address these limitations.

Their findings showed that infection rates were consistent throughout an 18-month follow-up period, challenging the belief that infection risk is highest in the first few months of treatment. Instead, they suggest that the risk of infections is more closely related to the bispecific antibody therapy itself rather than to uncontrolled myeloma.

Since these therapies were approved, it has become evident that infections are a significant risk. Early clinical trials indicated high infection rates, with some differences depending on the specific bispecific antibody used. This has led to calls for clearer and more accurate infection reporting in ongoing studies.

Studies have shown that bacterial and respiratory viral infections are common among these patients. Additionally, some patients may experience opportunistic infections, such as reactivation of cytomegalovirus (CMV) and severe adenovirus infections, which are more typical with other intensive cancer treatments.

Research has identified several infection risk factors. For example, corticosteroid use for managing side effects increased the risk of initial infections. Patients receiving intravenous immunoglobulin (IVIG) therapy experienced significantly fewer infections compared to those who were not on this treatment.

Despite the known risks, many questions about infections in patients receiving bispecific antibodies remain. It’s essential to explore when specific opportunistic infections, like CMV reactivation and severe adenovirus infections, occur and identify which patients are most at risk so they can be monitored or given preventive treatment.

Adopting Ludwig et al.'s reporting model will help improve our understanding of infection risks in patients receiving bispecific antibody therapy. Better tracking of infection occurrences and risk factors will lead to better strategies for protecting patients from both common and opportunistic infections while allowing them to benefit from this effective treatment.

 

 

"LocoMMotion: a study of real-life current standards of care in triple-class exposed patients with relapsed/refractory multiple myeloma – 2-year follow-up (final analysis)"

Source

Mateos, MV., Weisel, K., De Stefano, V. et al. LocoMMotion: a study of real-life current standards of care in triple-class exposed patients with relapsed/refractory multiple myeloma – 2-year follow-up (final analysis). Leukemia (2024). https://doi.org/10.1038/s41375-024-02404-6  September 25, 2024.  

Overview

Treating relapsed/refractory multiple myeloma (RRMM) is difficult, especially when patients have already tried many therapies and the disease no longer responds to standard treatments. This abstract presents the final results of the LocoMMotion study, which looked at real-world treatment practices for patients with RRMM who had been exposed to multiple drug classes. 

The study included 248 patients who had received an average of four previous treatments. Researchers followed these patients for about 26 months. They found that 31.9% of patients responded to the treatments, with a median progression-free survival (PFS) of 4.6 months and a median overall survival of 13.8 months. 

Of the patients, 61.3% went on to receive additional treatments, using a total of 134 different regimens. The median PFS from the start of the study through the first subsequent treatment was 10.8 months. Unfortunately, 158 patients died during the study, with 67.7% of those deaths due to the disease worsening.

The results showed a wide variety of treatment regimens used and poor clinical outcomes, indicating that there is no standard treatment for these patients. This highlights the urgent need for new therapies with different approaches to improve outcomes for those with RRMM.

 

 

"Dexamethasone dose intensity does not impact outcomes in newly diagnosed multiple myeloma: a secondary SWOG analysis)"

Source

Rahul Banerjee, Rachael Sexton, Andrew J. Cowan, Aaron S. Rosenberg, Sikander Ailawadhi, S. Vincent Rajkumar, Shaji K Kumar, Angela Dispenzieri, Sagar Lonial, Brian G.M. Durie, Paul G. Richardson, Saad Z Usmani, Antje Hoering, Robert Z Orlowski; Dexamethasone dose intensity does not impact outcomes in newly diagnosed multiple myeloma: a secondary SWOG analysis. Blood 2024; blood.2024025939. doi: https://doi.org/10.1182/blood.2024025939  September 25, 2024. 

Overview

Dexamethasone is an important medication used in the initial treatment of newly diagnosed multiple myeloma (NDMM), but it often causes side effects like high blood sugar and trouble sleeping. In the ECOG E4A03 trial, giving patients 40 milligrams (mg) of dexamethasone once a week resulted in lower death rates compared to higher doses. However, it’s not clear how reducing the dose below this amount affects progression-free survival (PFS) and overall survival (OS) in NDMM.

To explore this, researchers conducted a secondary analysis of two studies (S0777 and S1211) that looked at treatment combinations involving lenalidomide and dexamethasone, with or without bortezomib or elotuzumab. They categorized patients into two groups: those who received full-dose dexamethasone (FD-DEX) and those who had lower doses or stopped taking it due to severe side effects (LD-DEX). Out of 541 patients analyzed, 373 were in the LD-DEX group.

The results showed no differences in PFS or OS between the two groups, even though they were similar in terms of age, disease stage, and health status. Factors that affected PFS and OS included the treatment group, being over 70 years old, and having low platelet counts; however, full-dose dexamethasone did not significantly improve outcomes.

This study indicates that dose reductions of dexamethasone are common in multiple myeloma treatment, even in clinical trials. Given the side effects of dexamethasone and the unclear benefits at lower doses, further research on its dosage during initial treatment for NDMM is needed.

 

 

"Impact of soluble BCMA and non-T-cell factors on refractoriness to BCMA-targeting T-cell engagers in multiple myeloma)"

Source

Holly Lee, Michael A. Durante, Sheri Skerget, Deeksha Vishwamitra, Sacha Benaoudia, Sungwoo Ahn, Mansour Poorebrahim, Elie Barakat, David Jung, Noémie Leblay, Bachisio Ziccheddu, Benjamin T. Diamond, Marios Papadimitriou, Adam D. Cohen, Ola Landgren, Paola Neri, Francesco Maura, Nizar J. Bahlis; Impact of soluble BCMA and non-T-cell factors on refractoriness to BCMA-targeting T-cell engagers in multiple myeloma. Blood 2024; blood.2024026212. doi: https://doi.org/10.1182/blood.2024026212  September 25, 2024.

Overview

Adoptive T cell therapy shows promise for treating multiple myeloma (MM), but its success depends on understanding certain biological markers that predict how well patients will respond. One important target in MM is B cell maturation antigen (BCMA), and there are many therapies being developed that focus on targeting BCMA, including anti-BCMA T cell engagers (TCEs) and chimeric antigen receptor T cell (CAR T) therapies.

Recent research has explored how MM cells regulate the expression of surface BCMA, leading to the release of soluble BCMA (sBCMA) into the bloodstream. This has raised questions about whether sBCMA can be used as a reliable marker to predict treatment outcomes. The study used whole genome sequencing and laboratory tests to show that high levels of sBCMA can independently predict resistance to anti-BCMA therapies.

In addition to sBCMA, factors like the overall tumor burden and the amount of surface BCMA on cancer cells also affect how well TCEs work against the cancer. An analysis of 163 patients treated with the anti-BCMA TCE teclistamab confirmed that patients with elevated baseline sBCMA levels (greater than 400 ng/mL) were more likely to be resistant to treatment.

Importantly, the study found that increasing the TCE dose, using TCEs that target other proteins (like GPRC5D), or using gamma secretase inhibitors can help overcome the challenges posed by high levels of sBCMA. These findings emphasize the need to consider baseline sBCMA levels, the extent of disease, and the intensity of TCE dosing when planning treatments. This research provides valuable insights into improving treatment strategies for patients with MM who have high-risk features or show resistance to anti-BCMA therapies.

 

 

"Optimal cut-off values and diagnostic significance of clinical laboratory indicators in newly diagnosed multiple myeloma"

Source

Li, M., Wu, H., Shou, C. et al. Optimal cut-off values and diagnostic significance of clinical laboratory indicators in newly diagnosed multiple myeloma. Discov Onc 15, 477 (2024). https://doi.org/10.1007/s12672-024-01254-z  September 27, 2024. 

Overview

The study aimed to find clinical laboratory tests that can help diagnose newly diagnosed multiple myeloma (NDMM) and establish the best cutoff values for early screening. Researchers analyzed data from 279 NDMM patients and 553 healthy individuals at Zhejiang Province People’s Hospital from January 2008 to June 2023.

Using multifactor logistic regression (LR), they identified key laboratory indicators for diagnosing NDMM. The study found that hemoglobin (Hb), albumin (Alb), and platelet distribution width (PDW) were important diagnostic factors. The optimal cutoff values for these indicators were determined as follows: Alb below 39.3 g/L, Hb below 11.6 g/dL, and PDW below 14.1 fL significantly increased the likelihood of an NDMM diagnosis.

The researchers developed a diagnostic model based on these findings, which showed a high accuracy rate, with an area under the receiver operating characteristic curve (ROC) of 0.960, indicating good sensitivity (86%) and specificity (95%). In an external validation group, the model had an even higher ROC value of 0.979, confirming its effectiveness in diagnosing NDMM.

The study established valuable cutoff values for Hb, Alb, and PDW and created a diagnostic model that accurately screens for NDMM, offering a reliable method for early diagnosis.

 

 

 

"Daratumumab with lenalidomide as maintenance after transplant in newly diagnosed multiple myeloma: the AURIGA study"

Source

Ashraf Z Badros, Laahn Foster, Larry D. Anderson, Chakra P. Chaulagain, Erin M Pettijohn, Andrew J Cowan, Caitlin L. Costello, Sarah Larson, Douglas W Sborov, Kenneth H Shain, Rebecca Silbermann, Nina Shah, Alfred Chung, Maria Krevvata, Huiling Pei, Sharmila Patel, Vipin Khare, Annelore Cortoos, Robin Carson, Thomas Lin, Peter M Voorhees; Daratumumab with lenalidomide as maintenance after transplant in newly diagnosed multiple myeloma: the AURIGA study. Blood 2024; blood.2024025746. doi: https://doi.org/10.1182/blood.2024025746  September 27, 2024

Overview

The AURIGA study compared the effectiveness of daratumumab and lenalidomide (D-R) maintenance therapy with standard lenalidomide (R) alone for patients with newly diagnosed multiple myeloma (NDMM) who had a very good partial response and were positive for minimal residual disease (MRD) after a stem cell transplant. 

In this phase 3 trial, 200 patients were randomly assigned to receive either D-R (99 patients) or R (101 patients) maintenance therapy for up to 36 cycles. The main goal was to see how many patients became MRD-negative (meaning there were no detectable cancer cells) within 12 months. The results showed that a higher percentage of patients in the D-R group became MRD-negative compared to the R group (50.5% vs. 18.8%). This difference was statistically significant. 

At a median follow-up of about 32 months, the D-R group continued to show better results, with 60.6% achieving MRD-negative status compared to 27.7% in the R group. The D-R group also had a higher rate of complete responses (75.8% vs. 61.4%) and longer progression-free survival (PFS) at 30 months (82.7% for D-R vs. 66.4% for R).

While there were slightly higher rates of severe side effects and infections in the D-R group compared to R, no new safety issues were identified. Overall, the study concluded that D-R maintenance therapy leads to better outcomes than R alone after a transplant, making it a promising option for NDMM patients.