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 December 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 December 2024)
"Advancements in the Treatment of Multiple Myeloma"
Source
Zavaleta-Monestel E, Quesada-Villaseñor R, Barrantes-López M, et al. (December 02, 2024) Advancements in the Treatment of Multiple Myeloma. Cureus 16(12): e74970. doi:10.7759/cureus.74970. December 2, 2024.
Overview
Multiple myeloma (MM), the second most common blood cancer worldwide, was once considered highly aggressive and fatal. However, recent advancements in treatment have brought new hope to patients. Over the last decade, innovative therapies with fewer side effects have transformed how MM is treated.
Key treatments include proteasome inhibitors (like bortezomib, carfilzomib, and ixazomib), monoclonal antibodies (such as daratumumab, isatuximab, and elotuzumab), immunomodulators (like thalidomide, lenalidomide, and pomalidomide), and corticosteroids (like dexamethasone). Combining these treatments has proven even more effective by attacking the disease from multiple angles.
These advancements have improved quality of life, extended remission periods, and slowed disease progression for many patients. While MM is not yet curable, ongoing research and innovative drug combinations offer hope for turning MM into a manageable, and possibly curable, disease in the future.
"Advancements in the Treatment of Multiple Myeloma"
Source
Zavaleta-Monestel E, Quesada-Villaseñor R, Barrantes-López M, et al. (December 02, 2024) Advancements in the Treatment of Multiple Myeloma. Cureus 16(12): e74970. doi:10.7759/cureus.74970. December 2, 2024.
Overview
Multiple myeloma (MM), the second most common blood cancer worldwide, was once considered highly aggressive and fatal. However, recent advancements in treatment have brought new hope to patients. Over the last decade, innovative therapies with fewer side effects have transformed how MM is treated.
Key treatments include proteasome inhibitors (like bortezomib, carfilzomib, and ixazomib), monoclonal antibodies (such as daratumumab, isatuximab, and elotuzumab), immunomodulators (like thalidomide, lenalidomide, and pomalidomide), and corticosteroids (like dexamethasone). Combining these treatments has proven even more effective by attacking the disease from multiple angles.
These advancements have improved quality of life, extended remission periods, and slowed disease progression for many patients. While MM is not yet curable, ongoing research and innovative drug combinations offer hope for turning MM into a manageable, and possibly curable, disease in the future.
"Health care Systems as Determinants of Outcomes in Multiple Myeloma: Final Results from the Latin American MYLACRE Study"
Source
Vania Tietsche de Moraes Hungria, Rafael D Gaiolla, Kenny Galvez, Guillermina Remaggi, Natalia Schutz, Rosane Isabel Bittencourt, Angelo Maiolino, Guillermo Enrique Quintero-Vega, Maria Silvana Cugliari, Walter Moises Tobias Braga, Carolina Colaco Villarim, Edvan de Queiroz Crusoé, Alicia Ines Ines Enrico, Gaston Caeiro, Jandey Gloria Bigonha, Fernanda Lemos Moura, Jair Figueroa Emiliani, Claudia Sossa-Melo, Milton Lombana, Huiling Pei, Mariana Fernandez, Jaqueline Saes, Damila Cristina Trufelli; Health care Systems as Determinants of Outcomes in Multiple Myeloma: Final Results from the Latin American MYLACRE Study. Blood Adv 2024; bloodadvances.2024013838. doi: https://doi.org/10.1182/bloodadvances.2024013838
Overview
Immune checkpoints help the body balance its immune responses, preventing it from attacking itself (autoimmunity) while also allowing cancer cells to evade detection. This review focuses on two important immune checkpoint molecules: PSGL-1 and VISTA.
Both molecules are found in high levels on blood-forming cells like T cells and myeloid cells. VISTA acts in two ways: on myeloid cells, it controls the release of signaling proteins, cell movement, and immune cell development into a tolerogenic (tolerance-promoting) state; on T cells, it helps keep them inactive when necessary. PSGL-1 partners with VISTA to further suppress T-cell activation, especially in acidic environments like those found in tumors.
This review highlights how these molecules work, their structures, and their roles in the immune system. It also explores their potential for treating cancer, autoimmune diseases, and transplant rejection. The dual role of PSGL-1 and VISTA in controlling immune responses offers exciting opportunities to improve cancer immunotherapy and develop better treatments for immune-related conditions.
"Elotuzumab in combination with pomalidomide, bortezomib, and dexamethasone in relapsed and refractory multiple myeloma"
Source
Andrew J. Yee, Jacob P Laubach, Erica L. Campagnaro, Brea C. Lipe, Omar Nadeem, Robb S Friedman, Craig E. Cole, Elizabeth O'Donnell, Giada Bianchi, Andrew R Branagan, Robert L. Schlossman, Samantha J. Shaprio, Cynthia C. Harrington, Jill N. Burke, Marilyn T. Gammon, Kathleen J. Lively, Cassandra A. Reimonn, Danielle X. Andrade, Robert A Redd, Jens G. Lohr, Kenneth C. Anderson, Paul G. Richardson, Noopur Raje; Elotuzumab in combination with pomalidomide, bortezomib, and dexamethasone in relapsed and refractory multiple myeloma. Blood Adv 2024; bloodadvances.2024014717. doi: https://doi.org/10.1182/bloodadvances.2024014717 December 3, 2024. Peng, M., Lu, X., Guo, J. et al. A pair of promising immune checkpoints PSGL-1 and VISTA from immunotolerance to immunotherapy. Biomark Res 12, 151 (2024). https://doi.org/10.1186/s40364-024-00693-8 December 2, 2024
Overview
Elotuzumab, a monoclonal antibody targeting SLAMF7 on plasma and immune cells, has been shown to boost the effects of other myeloma drugs like lenalidomide, pomalidomide, and bortezomib. A phase 2 trial tested adding elotuzumab to the pomalidomide, bortezomib, and dexamethasone (PVd) regimen—creating "elo-PVd"—for patients with relapsed or refractory multiple myeloma (MM).
The study included 48 patients, median age 64, who had received at least one prior treatment (median 3). About 25% had high-risk genetic features. The trial showed a 56.3% overall response rate (ORR) and a median progression-free survival (PFS) of 10 months. Patients with only one prior therapy had better outcomes, with a 73.7% ORR and 23.4 months PFS.
Common serious side effects included low white blood cells (33%), infections (33%), lung infections (27%), low phosphate levels (19%), and low platelets (15%).
This study is among the first to successfully use a four-drug regimen including a monoclonal antibody in heavily pretreated MM patients, offering hope for those with prior exposure to multiple drug classes.
"Impact of the number of administered systemic treatment lines on local response to radiation therapy for multiple myeloma"
Source
Andrea Emanuele Guerini, Eneida Mataj, Paolo Borghetti, Luca Triggiani, Ludovica Pegurri, Stefania Nici, Stefano Riga, Alessandra Tucci, Angelo Belotti, Marco Lorenzo Bonù, Giorgio Facheris, Stefano Maria Magrini, Luigi Spiazzi, Michela Buglione, Impact of the number of administered systemic treatment lines on local response to radiation therapy for multiple myeloma. Advances in Radiation Oncology, 2024, 101696,ISSN 2452-1094, https://doi.org/10.1016/j.adro.2024.101696. December 3, 2024.
Overview
A study examined whether prior systemic treatments for multiple myeloma (MM) impact the effectiveness of radiotherapy (RT). Researchers analyzed data from 366 patients treated with RT at a single center between 2005 and 2023.
The study evaluated 665 MM lesions, focusing on local response six months after RT and any side effects during treatment. Among 217 lesions with available data, 13.4% showed complete response, 65% had partial response, 19.4% had stable disease, and only 2.3% showed disease progression. Importantly, the number of prior systemic treatments did not affect RT outcomes. However, a higher radiotherapy dose (measured as BED10) significantly improved responses.
Side effects were minimal, with serious events occurring in less than 1% of cases.
This study suggests that radiotherapy remains an effective and safe option for MM, even in patients who have undergone multiple prior treatments. It challenges concerns about treatment resistance raised by earlier pre-clinical studies.
"Doxorubicin synergizes bortezomib-induced multiple myeloma cell death by inhibiting aggresome formation and augmenting endoplasmic reticulum/Golgi stress and apoptosis"
Source
Yu, CT.R., Liao, YT.A., Chiang, CY.N. et al. Doxorubicin synergizes bortezomib-induced multiple myeloma cell death by inhibiting aggresome formation and augmenting endoplasmic reticulum/Golgi stress and apoptosis. J Transl Med 22, 1095 (2024). https://doi.org/10.1186/s12967-024-05920-2 December 3, 2024.
Overview
Bortezomib, a key treatment for multiple myeloma (MM), kills cancer cells by building up toxic misfolded proteins. However, some MM cells develop resistance by forming "aggresomes," structures that help remove these misfolded proteins. Aggresomes rely on proteins like Vimentin, HDAC6, and Dynein to function, reducing bortezomib's ability to kill cancer cells.
In this study, researchers tested several anticancer drugs to find one that works with bortezomib to block aggresome formation and increase cell death. They found that doxorubicin enhanced bortezomib’s effectiveness by preventing aggresome formation. It did this by lowering levels of Vimentin, HDAC6, and Dynein, causing misfolded proteins to accumulate. This triggered stress in the cell’s endoplasmic reticulum (ER) and Golgi, leading to stronger cell death through apoptosis (programmed cell death) and necroptosis (inflammatory cell death).
Doxorubicin’s effects only worked in cells capable of forming aggresomes, suggesting its benefits depend on this specific mechanism. Combining doxorubicin with bortezomib could be a promising strategy to overcome resistance in MM treatment.
"Impact of T cell characteristics on CAR-T cell therapy in hematological malignancies"
Source
Tao, Z., Chyra, Z., Kotulová, J. et al. Impact of T cell characteristics on CAR-T cell therapy in hematological malignancies. Blood Cancer J. 14, 213 (2024). https://doi.org/10.1038/s41408-024-01193-6 December 3, 2024.
Overview
CAR T-cell therapy has transformed the treatment of blood cancers, but it doesn't work long-term for more than half of patients. One reason is that CAR T cells sometimes lack the power to completely destroy cancer cells.
This review explores key T-cell traits that affect the success of CAR T-cell therapy. Factors like T-cell exhaustion, memory cell types, aging (senescence), regulatory T-cells, the balance between CD4+ and CD8+ cells, metabolism, and the diversity of T-cell receptors all play important roles.
By studying these T-cell characteristics, researchers aim to improve CAR T-cell therapy, making it more effective and safer for patients in the future.
"Quadruplet regimens for patients with newly diagnosed multiple myeloma: a systematic review and meta-analysis"
Source
Mohammad S. Ebraheem, Rajshekhar Chakraborty, Bram Rochwerg, Alissa Visram, Ghulam Rehman Mohyuddin, Christopher P. Venner, Irwindeep Sandhu, Arleigh McCurdy, Thierry Facon, Maria-Victoria Mateos, Hira Mian; Quadruplet regimens for patients with newly diagnosed multiple myeloma: a systematic review and meta-analysis. Blood Adv 2024; 8 (23): 5993–6002. doi: https://doi.org/10.1182/bloodadvances.2024014139 December 10, 2024.
Overview
A new analysis highlights the benefits of four-drug regimens (quadruplets) for treating newly diagnosed multiple myeloma (NDMM). These combinations, which include an anti-CD38 monoclonal antibody (mAb), a proteasome inhibitor (PI), and an immunomodulatory drug (IMiD), were compared to three-drug regimens (triplets) in seven clinical trials involving 3,716 patients. The findings revealed that quadruplets significantly improve treatment outcomes, offering higher overall response rates (ORR), longer progression-free survival (PFS), and better overall survival (OS). Additionally, patients treated with quadruplets had increased rates of minimal residual disease (MRD) negativity, a key marker of treatment success.
Despite these benefits, quadruplets were associated with a slight increase in serious infections (grade 3–4), with a 22% higher risk compared to triplets. However, the overall improvements in survival and disease control make quadruplets a compelling option, particularly for patients eligible for stem cell transplants. This study underscores the potential of quadruplet therapy to become the new standard of care in NDMM, offering patients a better chance at long-term disease control and survival.
"Febrile neutropenia in patients with Duffy-null–associated neutrophil counts and multiple myeloma or AL amyloidosis"
Source
Maya Abdallah, Frances Arters, Jasmine Patel, Camille Edwards, Adam Lerner, Fabio Petrocca, Margaux Dockerty, Brittany Fuller, Alicia Godfrey, Andrew Staron, Vaishali Sanchorawala, J. Mark Sloan, Kimberly Bertrand, Raphael Szalat; Febrile neutropenia in patients with Duffy-null–associated neutrophil counts and multiple myeloma or AL amyloidosis. Blood Adv 2024; 8 (23): 5935–5938. doi: https://doi.org/10.1182/bloodadvances.2024013453 December 10, 2024.
Overview
Duffy-null–associated neutrophil counts (DANCs) are a biological variation common in individuals of sub-Saharan African and Arabian Peninsula ancestry. People with DANC have naturally lower absolute neutrophil counts (ANC) due to a genetic variation, but their neutrophil function remains normal, and they do not face higher risks of infection. In the U.S., DANC is present in about 70% of Black individuals and less than 1% of White individuals. However, standard definitions for conditions like neutropenia may not apply to those with DANC, raising concerns about how this condition impacts treatment outcomes in patients with hematologic malignancies.
A study at Boston Medical Center examined the role of Duffy status in patients with multiple myeloma (MM) or systemic light chain (AL) amyloidosis treated with the drug daratumumab. Among 136 patients, 38% had DANC, most of whom self-identified as Black. The study found no significant differences in disease stage or the incidence of febrile neutropenia based on Duffy status. However, it highlighted the need for more research to determine how Duffy status affects treatment responses and complications, particularly for conditions like MM and AL amyloidosis.
While limited by its retrospective design and small sample size, the study emphasizes the importance of considering Duffy status when managing neutropenia in hematologic malignancies. Including Duffy status in clinical trials could lead to more accurate treatment criteria and better subgroup analyses, ultimately improving care for patients with this genetic variation.
"CD38-CAR human NK cells in combination with ATRA enhance cytotoxicity against CD38-expressing hematologic malignancies"
Source
Ella Troy, Joseph Caporale, Yasemin Sezgin, Marcelo S. F. Pereira, Gregory Behbehani, Justin Lyberger, Dean A. Lee, Meisam Naeimi Kararoudi; CD38-CAR human NK cells in combination with ATRA enhance cytotoxicity against CD38-expressing hematologic malignancies. Blood Neoplasia 2024; 1 (4): 100032. doi: https://doi.org/10.1016/j.bneo.2024.100032 December 16, 2024.
Overview
CD38 is a key enzyme found on many normal and cancerous blood cells, making it a target for therapies like anti-CD38 monoclonal antibodies (mAbs). However, these treatments can be limited by a phenomenon called natural killer (NK) cell fratricide, where NK cells attack each other. Researchers developed fratricide-resistant CD38-chimeric antigen receptor (CAR) NK cells using advanced genetic engineering techniques. These modified cells not only resist fratricide but also have improved metabolism and stronger cancer-fighting abilities.
The study tested these CAR NK cells against multiple CD38+ blood cancers, including multiple myeloma and acute myeloid leukemia. The cells became even more effective when combined with all-trans retinoic acid (ATRA), which increases CD38 expression on cancer cells. Compared to similarly engineered CAR T cells, the CAR NK cells showed superior ability to kill cancer cells. These findings suggest that CD38-CAR NK cells, especially when combined with ATRA, could be a powerful new approach for treating CD38+ blood cancers.
"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; 1 (4): 100042. doi: https://doi.org/10.1016/j.bneo.2024.100042 December 16, 2024.
Overview
Lenalidomide, ixazomib, and daratumumab are potential maintenance treatments for newly diagnosed multiple myeloma (NDMM), but no direct comparisons exist. A network meta-analysis of nine clinical trials, involving over 5,800 patients, evaluated these therapies against placebo. The study found that lenalidomide and daratumumab improved progression-free survival (PFS) in both transplant-eligible and non–transplant-eligible patients. Ixazomib, however, did not show a significant PFS benefit in either group. Importantly, none of the therapies improved overall survival (OS), and the PFS benefits were not observed in patients with high-risk cytogenetics.
Each therapy was associated with specific side effects: lenalidomide increased the risk of second cancers, ixazomib caused low platelet counts, and daratumumab was linked to pneumonia. Based on these findings, lenalidomide remains the preferred maintenance treatment for NDMM, offering the best balance of efficacy and safety.
"Phase 1b study of the anti-CD38 antibody mezagitamab in patients with relapsed/refractory multiple myeloma"
Source
Amrita Y. Krishnan, Krina K. Patel, Meera Mohan, Sundar Jagannath, Ruben Niesvizky, Rebecca W. Silbermann, Ziji Yu, Tao Long, Scott R. P. McDonnell, Deborah Berg, Keith E. Stockerl-Goldstein; Phase 1b study of the anti-CD38 antibody mezagitamab in patients with relapsed/refractory multiple myeloma. Blood Neoplasia 2024; 1 (4): 100043. doi: https://doi.org/10.1016/j.bneo.2024.100043 December 16, 2024
Overview
A phase 1b trial tested mezagitamab, a subcutaneous anti-CD38 antibody, in patients with relapsed/refractory multiple myeloma (RRMM) who had undergone multiple prior treatments. Fifty patients participated, with 44 receiving mezagitamab alone at varying doses and 6 receiving it alongside pomalidomide and dexamethasone. Mezagitamab was well-tolerated, with no dose-limiting toxicities observed, and a recommended phase 2 dose of 600 mg was established. The most common side effects were mild fatigue in the monotherapy group and neutropenia in the combination group, with no infusion reactions reported.
Among the 22 patients receiving 600 mg of mezagitamab, nearly half (47%) responded to treatment, with responses lasting a median of 22.1 months. These results are comparable to other anti-CD38 therapies for heavily pretreated myeloma patients. Despite promising outcomes, further development of mezagitamab for myeloma is not planned, though it is being investigated for autoimmune diseases.
"Recent advances in targeted drug delivery systems for multiple myeloma"
Source
Ashruti Pant, Aayushi Laliwala, Sarah A. Holstein, Aaron M. Mohs, Recent advances in targeted drug delivery systems for multiple myeloma, Journal of Controlled Release, Volume 376,2024, Pages 215-230, ISSN 0168-3659, https://doi.org/10.1016/j.jconrel.2024.10.003. December 2024.
Overview
Multiple myeloma (MM) remains an incurable blood cancer, despite recent advances in therapy. Many current treatments are limited by significant side effects, which can reduce their effectiveness. Nanotherapeutics, an innovative approach in cancer treatment, has the potential to bypass these limitations by improving how drugs are delivered to cancer cells.
This review explores the latest developments in nanoparticle-based and immunotherapy-focused drug delivery systems for MM. It highlights how these technologies target cancer cells more precisely, enable controlled drug release, and minimize harm to healthy cells. While promising, challenges remain in designing and implementing these advanced systems. Continued research in this area could lead to more effective and less toxic treatments for MM.
"Potential mechanisms for predicting comorbidity between multiple myeloma and femoral head necrosis based on multiple bioinformatics"
Source
Jie Li, Jing Dong, Ming Li, Hongbo Zhu, Peicheng Xin, Potential mechanisms for predicting comorbidity between multiple myeloma and femoral head necrosis based on multiple bioinformatics, Computational Biology and Chemistry, Volume 113, 2024, 108220, ISSN 1476 9271, https://doi.org/10.1016/j.compbiolchem.2024.108220. December 2024.
Overview
This study used advanced bioinformatics to explore the shared mechanisms behind multiple myeloma (MM) and osteonecrosis of the femoral head (ONFH), two diseases that may co-occur. Researchers analyzed gene expression data from public databases, identifying 418 immune-related genes linked to both conditions. These genes showed involvement in processes like protein synthesis and ribosome activity, which may play a role in disease progression.
Key genes, including *RPS19*, *RPL35*, *RPL24*, *RPL36*, and *EIF3G*, were highlighted through network analysis and validated with high accuracy. The immune microenvironment analysis revealed plasma cell infiltration as a common factor, pointing to potential immune-related therapeutic targets. This study provides valuable insights for future research into the shared biology and targeted treatments for MM and ONFH.
"Palmitic acid inhibits macrophage-mediated chemotherapy resistance in multiple myeloma via ALOX12 signaling, International Immunopharmacology"
Source
He Dong, Jintong Chen, Hua Zhang, Munan Zhao, Ying Yue, Siqing Wang, Palmitic acid inhibits macrophage-mediated chemotherapy resistance in multiple myeloma via ALOX12 signaling, International Immunopharmacology, Volume 143, Part 1, 2024,113320,ISSN 15675769, https://doi.org/10.1016/j.intimp.2024.113320. December 25,2024.
Overview
Researchers explored how tumor-associated macrophages (tMΦs) promote chemotherapy resistance in multiple myeloma (MM) and identified a potential solution. They discovered that tMΦs have reduced levels of enzymes (*FASN* and *SCD2*) involved in producing palmitic acid, a fatty acid. Adding palmitic acid to MM cells reversed the protective effect of tMΦs against chemotherapy drugs like bortezomib and melphalan. In animal models, combining palmitic acid with these drugs further reduced tumor growth.
The study revealed that palmitic acid increases the activity of a protein called ALOX12 in macrophages, disrupting their protective effects on MM cells. It also inhibits the AMPK signaling pathway, which plays a role in chemotherapy resistance. The findings suggest that targeting tMΦs with palmitic acid could enhance the effectiveness of chemotherapy in MM, offering a promising avenue for future treatments.
"Outcomes in randomized controlled trials of therapeutic interventions for multiple myeloma: A systematic review"
Source
Maria Mainou, Kalliopi Tsapa, Theodoros Michailidis, Konstantinos Malandris, Thomas Karagiannis, Ioannis Avgerinos, Aris Liakos, Maria Papaioannou, Evangelos Terpos, Vinay Prasad, Apostolos Tsapas, Outcomes in randomized controlled trials of therapeutic interventions for multiple myeloma: A systematic review, Critical Reviews in Oncology/Hematology, Volume 204, 2024, 104529, ISSN 1040-8428, https://doi.org/10.1016/j.critrevonc.2024.104529. December 2024.
Overview
This study reviewed randomized controlled trials (RCTs) in multiple myeloma to explore the outcomes most commonly used in evaluating treatments. Researchers found 624 eligible trials, including 448 focused on anti-myeloma treatments and 176 on supportive care. The most common outcomes measured were disease response, progression-free survival (PFS), and overall survival (OS). PFS was the most frequently used primary endpoint, especially in studies funded by pharmaceutical companies, while OS was often listed as a secondary endpoint. Quality of life was rarely prioritized, appearing as a primary endpoint in only 1% of trials.
The study concluded that while PFS is commonly used as a main measure of treatment success, OS should also be considered an important outcome in future trials to better reflect the long-term benefits for patients with multiple myeloma.
"Enhanced cytotoxicity in multiple myeloma via T cells armed with bispecific T cell engager targeting B-cell maturation antigen on cancer cells and CD3 on T cells"
Source
Kamonlapat Supimon, Thanich Sangsuwannukul, Piriya Luangwattananun, Pa-thai Yenchitsomanus, Enhanced cytotoxicity in multiple myeloma via T cells armed with bispecific T cell engager targeting B-cell maturation antigen on cancer cells and CD3 on T cells, International Immunopharmacology, Volume 143, Part 2, 2024,113480,ISSN 1567-5769, https://doi.org/10.1016/j.intimp.2024.113480. December 25, 2024.
Overview
Multiple myeloma (MM) is a tough-to-treat cancer of plasma cells, with high rates of recurrence and limited long-term cures. New immunotherapies like CAR T cells and bispecific antibodies (BITEs) targeting BCMA have helped treat relapsed MM, but they come with challenges such as complex manufacturing, high costs, and severe side effects. In this study, researchers developed a new approach using BITE-armed T cells (BATs) that target BCMA, a protein found on MM cells. These BATs were able to activate and grow T cells, improving their ability to kill MM cells. The BATs worked better than unarmed T cells, even at lower doses, and showed a strong, specific attack on BCMA-expressing cells. Importantly, the BATs triggered T cell expansion and cytokine release without increasing the risk of severe side effects like cytokine release syndrome (CRS). This method is simpler, faster, and cheaper to produce, making it a promising new treatment option for MM.
This study reviewed randomized controlled trials (RCTs) in multiple myeloma to explore the outcomes most commonly used in evaluating treatments. Researchers found 624 eligible trials, including 448 focused on anti-myeloma treatments and 176 on supportive care. The most common outcomes measured were disease response, progression-free survival (PFS), and overall survival (OS). PFS was the most frequently used primary endpoint, especially in studies funded by pharmaceutical companies, while OS was often listed as a secondary endpoint. Quality of life was rarely prioritized, appearing as a primary endpoint in only 1% of trials.
The study concluded that while PFS is commonly used as a main measure of treatment success, OS should also be considered an important outcome in future trials to better reflect the long-term benefits for patients with multiple myeloma.
"Engineering next-generation chimeric antigen receptor-T cells: recent breakthroughs and remaining challenges in design and screening of novel chimeric antigen receptor variants"
Source
Anna Mei, Kevin P Letscher, Sai Reddy, Engineering next-generation chimeric antigen receptor-T cells: recent breakthroughs and remaining challenges in design and screening of novel chimeric antigen receptor variants, Current Opinion in Biotechnology, Volume 90, 2024,103223, ISSN 0958-1669, https://doi.org/10.1016/j.copbio.2024.103223. December 2024.
Overview
Chimeric Antigen Receptor (CAR) T cells are a powerful treatment for blood cancers, but there are still challenges in designing and improving these therapies. CAR-T cells work by modifying a patient’s T cells to recognize and kill cancer cells. The effectiveness of CAR-T cells depends on the different parts of the synthetic receptor used, like the extracellular domain (ECD), hinge, and intracellular domains (ICD). So far, only a few protein domains have been tested in clinical studies. New methods, like high-throughput technologies, allow researchers to test many different combinations of these domains to improve CAR-T cell function.
However, one major challenge is that there is no standardized way to compare different CAR-T cell designs across research labs and clinical studies. This review discusses how high-throughput technologies and computational tools can help accelerate the development of CAR-T cells by testing more combinations and finding the best ones. It also highlights the need for a scoring system to better compare CAR-T cells and predict which ones will work best in clinical trials.
The CAR-T field has been slow to adopt a standardized scoring system for evaluating new CAR designs. Currently, researchers use different tests to assess CAR-T cells, but they often don’t know which tests best predict clinical success. New tools, including machine learning, can help analyze more CAR-T cell variants and predict their effectiveness. By combining high-throughput methods with computational tools like machine learning and graph theory, researchers can find the best CAR-T cell designs for clinical use, especially for challenging tumors like solid cancers. Standardizing this process could improve the development of CAR-T therapies and lead to better treatments for patients.
"AURKA targeting: a NEAT approach to halt myeloma"
Source
Solimando AG, Botta C. AURKA targeting: a NEAT approach to halt myeloma. Haematologica 2024;109(12):3847-3849; https://doi.org/10.3324/haematol.2024.286085. December 2024.
Overview
Multiple myeloma (MM) is a complex and challenging cancer to treat, as it often relapses despite improvements in treatment. Recent research has focused on the role of long non-coding RNA (lncRNA), which regulate important processes in cells. One lncRNA, NEAT1, has been found to influence cell growth, resistance to treatment, and other factors involved in MM. In this study, researchers looked at how NEAT1 interacts with a protein called AURKA, which helps control cell division. They found that NEAT1 regulates genes that affect the cell’s structure and division, and when NEAT1 was silenced, the process of cell division was disrupted.
They also discovered that combining NEAT1 silencing with AURKA inhibition caused more cancer cell death in lab experiments, suggesting that targeting both could be an effective treatment strategy. AURKA is already being tested in clinical trials for MM and has shown manageable side effects, which makes it a promising therapy. Moreover, NEAT1 and AURKA expression levels were linked to a worse prognosis in MM patients, particularly those with high-risk genetic features, pointing to a population that could benefit from targeted treatments.
The study suggests that by blocking NEAT1 and AURKA together, we could disrupt MM cell survival and avoid some resistance mechanisms. This approach may be especially useful for aggressive forms of the disease. Additionally, the research highlights the need for further studies into the role of NEAT1, AURKA, and other related genes, as this could lead to better treatment options and help overcome some of the challenges in treating MM.
"Combinatorial strategies targeting NEAT1 and AURKA as new potential therapeutic options for multiple myeloma"
Source
Puccio N, Manzotti G, Mereu E, Torricelli F, Ronchetti D, Cumerlato M, Craparotta I, Di Rito L, Bolis M, Traini V, Manicardi V, Fragliasso V, Torrente Y, Amodio N, Bolli N, Taiana E, Ciarrocchi A, Piva R, Neri A. Combinatorial strategies targeting NEAT1 and AURKA as new potential therapeutic options for multiple myeloma. Haematologica 2024;109(12):4040-4055; https://doi.org/10.3324/haematol.2024.285470. December 2024.
Overview
Multiple myeloma (MM) is a complex disease with many different genetic changes that contribute to its progression and resistance to treatment. Long non-coding RNAs (lncRNAs), which play a role in gene regulation, are often altered in MM. One such lncRNA, NEAT1, has been found to help MM cells grow, making it a potential target for therapy.
In this study, researchers used a combination of gene analysis and drug screening to identify drugs that work well with NEAT1 inhibition. They found that AURKA inhibitors, which target a protein important for cell division, were particularly effective when combined with NEAT1 silencing. This combination disrupted the structure of the cell and led to its death.
The study also found that high levels of AURKA in MM patients were linked to poorer survival outcomes. Additionally, they discovered that the protein TPX2, which interacts with AURKA, is also influenced by NEAT1, helping explain why targeting both NEAT1 and AURKA together works so well. These findings suggest that targeting NEAT1 and AURKA could be an effective strategy for treating MM.
"Single-point and kinetics of peripheral residual disease by mass spectrometry to predict outcome in patients with high-risk smoldering multiple myeloma included in the GEM-CESAR trial"
Source
Puig N, Agulló C, Contreras T, Pérez J-J, Aires I, Calasanz M-J, García-Sanz R, Castro S, Martínez-López J, Rodríguez-Otero P, González-Calle V, González MS, Oriol A, Gutiérrez NC, Ríos-Tamayo R, Rosiñol L, Álvarez M- Ángel, Bargay J, González-Rodríguez A-P, Alegre A, Escalante F, Iñigo M-B, de la Rubia J, Teruel A-I, de Arriba F, Palomera L, Hernández MT, López-Jiménez J, Reinoso M, García-Mateo A, Ocio EM, Bladé J, Lahuerta J-J, Cedena M-T, Paiva B, Miguel JFS, Mateos M-V. Single-point and kinetics of peripheral residual disease by mass spectrometry to predict outcome in patients with high-risk smoldering multiple myeloma included in the GEM-CESAR trial. Haematologica 2024;109(12):4056-4066; https://doi.org/10.3324/haematol.2024.285742. December 2024.
Overview
This study explored using quantitative immunoprecipitation mass spectrometry (QIP-MS) to track the M-protein in patients with high-risk smoldering myeloma (HRsMM), a stage before active multiple myeloma. The researchers tested QIP-MS in 62 patients enrolled in the GEM-CESAR trial after 24 cycles of treatment. They found that detecting the M-protein with mass spectrometry (MS) or clonal plasma cells using next-generation flow cytometry (NGF) helped identify patients who had a shorter progression-free survival (PFS), meaning their disease worsened faster.
The study showed that standard response categories used in myeloma treatment were not helpful for monitoring HRsMM patients. However, both MS and NGF were valuable tools for predicting patient outcomes. The combination of MS and NGF had a high negative predictive value (NPV), meaning that if both tests were negative, the chances of disease progression were low. Additionally, patients who showed sustained negative results for either MS or NGF had a very favorable outcome.
The findings suggest that MS can be a useful, non-invasive tool for monitoring HRsMM and guiding treatment decisions, helping doctors detect potential disease progression early. The study also highlights the importance of combining MS and NGF results for better long-term disease control.
"A multicenter, phase Ib study of subcutaneous administration of isatuximab in combination with pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma"
Source
Quach H, Parmar G, Ocio EM, Prince HM, Oriol A, Crowther H, Tsukada N, Bories P, Madan S, Nathwani N, Sunami K, Semiond D, Yu D, Cordero P, Macé S, Suzan F, Moreau P. A multicenter, phase Ib study of subcutaneous administration of isatuximab in combination with pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma. Haematologica 2024;109(12):4078-4082; https://doi.org/10.3324/haematol.2023.284730. December 2024.
Overview
This study tested a new subcutaneous (SC) version of the drug isatuximab (Isa) for patients with relapsed/refractory multiple myeloma (RRMM). Isatuximab is usually given intravenously (IV), but the SC version offers a more convenient way to administer the drug. The study aimed to compare the safety, effectiveness, and patient experience of SC Isa with the traditional IV Isa, both combined with pomalidomide and dexamethasone (Isa-Pd).
In this phase 1b clinical trial, patients were divided into groups to receive either SC Isa using an infusion pump (IP) or an on-body delivery system (OBDS), or IV Isa. The researchers measured the drug’s safety, how well it worked, and how it was processed in the body.
The study showed that the SC Isa, at a dose of 1,400 mg, was as effective as IV Isa in treating RRMM. Both delivery methods were well tolerated, with very few infusion reactions, and SC Isa had fewer side effects than previous IV treatments. There were no serious new safety concerns. A small number of patients experienced side effects like infections or neutropenia (low white blood cell count), but these were manageable.
Patients using the SC delivery system through the OBDS had very good local tolerance, with very few injection site reactions. The SC version of Isa showed similar effectiveness to IV, with high response rates and good progression-free survival. In addition, patients reported being satisfied with the SC delivery method.
In conclusion, SC Isa is a promising, more convenient treatment option for patients with RRMM, offering the same benefits as IV administration while improving comfort and ease for patients. Further research is needed to confirm these findings in larger trials.
"Minimal residual disease assessment in transplant-eligible patients with multiple myeloma: real-world applications of multiparametric flow cytometry-DURAClone (CAREMM-2104)"
Source
Ahn A, Park S-S, Kim Y, Lee JY, Lee J-M, Jung J, Kim M, Min C-K. Minimal residual disease assessment in transplant-eligible patients with multiple myeloma: real-world applications of multiparametric flow cytometry-DURAClone (CAREMM-2104). Haematologica 2024;109(12):4100-4105; https://doi.org/10.3324/haematol.2024.285278. December 2024.
Overview
This study aimed to develop a faster and more cost-effective method for detecting minimal residual disease (MRD) in multiple myeloma (MM) using a technique called DURAClone-based multiparametric flow cytometry (MFC). MRD detection is important for monitoring the progress of MM and helping decide the best treatments.
The study included 166 patients who had received autologous stem cell transplantation (ASCT) after treatment with novel drugs. Researchers tested bone marrow samples from these patients to detect MRD using the DURAClone method, which showed high sensitivity and quick results. After 3 months, 31% of patients were MRD-positive (MRD+), meaning they still had signs of disease, while 69% were MRD-negative (MRD-).
The results showed that MRD status at 3 months after ASCT was important for predicting patient outcomes. MRD+ patients had a lower chance of reaching complete remission (CR) and a higher risk of disease progression. Patients who remained MRD- for a year had better survival rates than those who later became MRD+. Further treatment for MRD+ patients, such as maintenance therapy, also improved their survival chances.
This study shows that using the DURAClone method for MRD detection can be a practical and reliable tool in real-world settings, with results similar to other methods like EuroFlow. However, more research is needed to fully confirm its benefits and how it can help guide treatment decisions for MM patients.
"Interferon gamma-mediated prevention of tumor progression in a mouse model of multiple myeloma"
Source
Kellermayer, Z., Tahri, S., de Jong, M.M.E., Papazian, N., Fokkema, C., Stoetman, E.C.G., Hoogenboezem, R., van Beek, G., Sanders, M.A., Boon, L., Den Hollander, C., Broijl, A., Sonneveld, P. and Cupedo, T. (2024), Interferon gamma-mediated prevention of tumor progression in a mouse model of multiple myeloma. HemaSphere, 8: e70047. https://doi.org/10.1002/hem3.70047 December 2, 2024.
Overview
This study looked at how the immune system in the bone marrow interacts with malignant plasma cells in multiple myeloma. Researchers used a mouse model to study early immune responses to myeloma cells. They compared two types of disease progression: stable disease, where the tumor remains small, and progressive disease, where the tumor grows.
The study showed that in stable disease, certain immune cells, like natural killer (NK) cells, ILC1 cells, and CD8+ T cells, were activated and expanded to control the tumor. However, this immune response was lost as the disease progressed. By analyzing the immune cells, the researchers found that interferon responses (a type of immune reaction) played a key role in controlling the disease in its early stages. When interferon-γ was blocked in the mice, the disease worsened, showing how important this immune response is for keeping myeloma in check.
Overall, this research provides a better understanding of how the immune system affects myeloma progression and highlights the role of bone marrow immunity in controlling the disease.
"Intercalation of the anticancer drug lenalidomide into montmorillonite for bioavailability improvement: a computational study"
Source
Meruvia-Rojas, Y.V., Molina-Montes, E., Hernández-Laguna, A. et al. Intercalation of the anticancer drug lenalidomide into montmorillonite for bioavailability improvement: a computational study. J Mol Model 31, 5 (2025). https://doi.org/10.1007/s00894-024-06210-w December 4, 2024.
Overview
This study looks at how to improve the effectiveness of lenalidomide (LEN), a drug used to treat myeloma, by making it more easily absorbed by the body. LEN is not very soluble in water, which makes it less effective. The researchers explored using a natural substance called montmorillonite (MNT) to improve how LEN is absorbed.
The study used computer modeling to examine how LEN interacts with MNT at a very detailed, atomic level. The results showed that LEN could be successfully placed between the layers of MNT, and that this process would make the drug easier to release in the body. The researchers also used infrared spectroscopy (IR) and X-ray techniques to predict how this process could be tested in the lab.
They found that the best method for combining LEN with MNT involved using a non-water solvent to insert the drug into MNT. Once inside, LEN can be easily released into an aqueous solution, making it more available for the body to use. This method could lead to better treatment outcomes for myeloma patients, as the drug would be more effective.
This study suggests that combining LEN with MNT can make the drug more bioavailable, potentially improving its effectiveness in treating cancer.
"The development and application of chimeric antigen receptor natural killer (CAR-NK) cells for cancer therapy: current state, challenges and emerging therapeutic advances"
Source
Yao, P., Liu, YG., Huang, G. et al. The development and application of chimeric antigen receptor natural killer (CAR-NK) cells for cancer therapy: current state, challenges and emerging therapeutic advances. Exp Hematol Oncol 13, 118 (2024). https://doi.org/10.1186/s40164-024-00583-7 December 4, 2024.
Overview
Immunotherapy has become a key treatment for cancer, and one promising approach is CAR-T cell therapy, where T cells are modified to target cancer cells. However, severe side effects with CAR-T therapy have led researchers to look for other options. One alternative is using natural killer (NK) cells, which can attack cancer cells without needing the same level of targeting that CAR-T cells do. Now, scientists are combining the benefits of CAR-T therapy with the flexibility of NK cells, creating a new treatment called CAR-NK cell therapy.
Early trials of CAR-NK cells have shown good results, with fewer harmful side effects compared to CAR-T cells. This review explores how CAR-NK therapy works, the current methods used to develop it, and the challenges researchers are facing. The review also discusses the potential of CAR-NK cells to treat not just cancer but also other immune-related diseases.
Although CAR-NK cell therapy shows promise, there are challenges to overcome, like improving how the cells grow and stay active in the body. Researchers are working on making the therapy more effective and easier to produce in large quantities. With continued development, CAR-NK cells could become a powerful and versatile treatment for cancer and other conditions in the future.
"CAR-iNKT cell therapy: mechanisms, advantages, and challenges"
Source
Zixuan Wang, Guangji Zhang, CAR-iNKT cell therapy: mechanisms, advantages, and challenges, Current Research in Translational Medicine, 2024, 103488, ISSN 2452-3186 https://doi.org/10.1016/j.retram.2024.103488.December 4, 2024.
Overview
Chimeric antigen receptor (CAR) T-cell therapy has become a breakthrough treatment for certain blood cancers like leukemia, lymphomas, and multiple myeloma, showing great success and leading to the approval of CAR-T products. However, CAR-T therapy has limitations when it comes to treating solid tumors due to challenges like the tumor's ability to suppress immune cells, varied antigen expression, and side effects. To address these issues, scientists are exploring other immune cells, including invariant natural killer T (iNKT) cells, which have special properties that make them effective against tumors.
iNKT cells are a type of T cell that can recognize lipid-based antigens and have the ability to fight tumors and improve the tumor environment. They are less likely to become exhausted and can enter solid tumors more effectively than regular T cells. Researchers are now combining CAR technology with iNKT cells to enhance their ability to target tumors, especially solid ones. This review looks at the potential of CAR-iNKT cells in cancer treatment, highlighting their advantages over traditional CAR-T cells and their promise for treating solid tumors.
"Chromosome 1 Alterations in Multiple Myeloma: Considerations for Precision Therapy"
Source
McAuley, N., Cymer, I., McAvera, R., Hopkins, A.M. and Glavey, S.V. (2024), Chromosome 1 Alterations in Multiple Myeloma: Considerations for Precision Therapy. Eur J Haematol. https://doi.org/10.1111/ejh.14352 December 4, 2024.
Overview
With multiple myeloma (MM), abnormal plasma cells grow uncontrollably and produce harmful proteins. High-risk MM, caused by specific genetic changes, is harder to treat and leads to worse survival rates. Currently, venetoclax is the only targeted therapy approved for MM, but it's only effective for a specific genetic group (t(11;14)). Other genetic changes, like chromosome 1 abnormalities, are common in MM and are linked to treatment resistance and poor outcomes. This review discusses new potential treatments that focus on genes in chromosome 1, aiming to target key proteins involved in cell survival and drug resistance. Researchers are exploring gene therapies, small molecule drugs, and monoclonal antibodies to target these problematic genes and improve treatment for high-risk MM patients.
"Targeting Caveolin-1 in Multiple Myeloma Cells Enhances Chemotherapy and Natural Killer Cell-Mediated Immunotherapy"
Source
D. Zhan, Z. Du, S. Zhang, J. Huang, J. Zhang, H. Zhang, Z. Liu, E. Menu, J. Wang, Targeting Caveolin-1 in Multiple Myeloma Cells Enhances Chemotherapy and Natural Killer Cell-Mediated Immunotherapy. Adv. Sci. 2024, 2408373. https://doi.org/10.1002/advs.202408373 December 4, 2024.
Overview
Caveolin-1 (CAV1) is a protein found in the cell membranes of multiple myeloma (MM) cells, and it plays a key role in the progression of the disease and resistance to treatment. This study shows that reducing CAV1 in MM cells makes them less able to stick to other cells, which weakens their resistance to the drug bortezomib. CAV1 inhibition also boosts the activity of natural killer (NK) cells, which are immune cells that can kill cancer cells. Additionally, blocking CAV1 changes how the MM cells use energy and nutrients, making them more sensitive to treatments that deplete glutamine, a key nutrient. The study suggests that drugs already approved by the FDA, like 6-mercaptopurine, daidzin, and statins, can help make bortezomib more effective against MM by targeting CAV1. These findings show that CAV1 could be an important target for improving MM treatment.
"Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma"
Source
Meletios A. Dimopoulos, M.D., Peter M. Voorhees, M.D., S. Vincent Rajkumar, M.D. et al, Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma, New England Journal of Medicine, DOI: 10.1056/NEJMoa2409029 December 9, 2024.
Overview
A study tested the effectiveness of daratumumab, a CD38-targeting antibody, in patients with high-risk smoldering multiple myeloma (SMM), a condition that can develop into active multiple myeloma. In the trial, 390 patients were randomly assigned to either receive daratumumab injections or undergo active monitoring (no treatment).
After a median follow-up of 65 months, results showed that daratumumab reduced the risk of progression to active multiple myeloma or death by 51% compared to monitoring. At five years, 63% of patients in the daratumumab group had not progressed, compared to 41% in the monitoring group. Survival rates at five years were higher with daratumumab (93%) compared to monitoring (87%).
The most common severe side effect was high blood pressure, seen in about 6% of daratumumab patients and 5% of those monitored. Only 6% of daratumumab patients stopped treatment due to side effects, and no new safety issues emerged.
Daratumumab significantly delayed disease progression and improved survival in high-risk SMM patients, with manageable side effects.
"Targeted interferon therapy with modakafusp alfa for relapsed or refractory multiple myeloma"
Source
Dan T Vogl, Shebli Atrash, Sarah A Holstein, Omar Nadeem, Don M Benson, Maria Chaudhry, Noa Biran, Kaveri Suryanarayan, Cheryl Li, Yuyin Liu, Sabrina Christine Collins, Xavier Parot, Jonathan L Kaufman; Targeted interferon therapy with modakafusp alfa for relapsed or refractory multiple myeloma. Blood 2024; blood.2024026124. doi: https://doi.org/10.1182/blood.2024026124 December 4, 2024.
Overview
This study tested modakafusp alfa, a new treatment for relapsed or refractory multiple myeloma (MM). The drug combines interferon-alpha, which fights cancer, with an antibody targeting CD38, a protein on MM cells. Researchers aimed to find a safe dose and evaluate how well it works.
The trial included 106 patients who had undergone an average of 6.5 prior treatments, and most were resistant to CD38-targeting drugs. Modakafusp alfa was given in various doses and schedules, with the most effective being 1.5 mg/kg every 4 weeks. At this dose, 43% of patients responded to treatment, with responses lasting an average of 15 months. Patients’ disease progression was delayed for about 6 months on average.
Severe side effects occurred in 93% of patients, mostly low white blood cell counts (67%) and low platelets (47%). Infections were reported in 27% of patients, with serious cases in 17%. The treatment activated the immune system and increased CD38 protein levels on MM cells, enhancing immune responses.
Modakafusp alfa showed promise in treating MM by targeting cancer cells and boosting the immune system, though it caused significant blood-related side effects.
"Bispecific antibodies targeting BCMA or GPRC5D are highly effective in relapsed myeloma after CAR T-cell therapy"
Source
Merz, M., Dima, D., Hashmi, H. et al. Bispecific antibodies targeting BCMA or GPRC5D are highly effective in relapsed myeloma after CAR T-cell therapy. Blood Cancer J. 14, 214 (2024). https://doi.org/10.1038/s41408-024-01197-2 December 5, 2024.
Overview
CAR T-cell therapy has been a breakthrough for relapsed/refractory multiple myeloma (RRMM), but most patients experience relapse within a median of five months. This study analyzed outcomes for 139 patients who relapsed after BCMA-directed CAR T-cell therapy (ide-cel or cilta-cel) and explored the effectiveness of various salvage treatments. Over half of the patients presented with extramedullary disease (EMD), a condition associated with significantly worse outcomes.
Patients treated with bispecific antibodies, such as talquetamab and teclistamab, showed the best results. Talquetamab had a 79% response rate and a 39% complete remission rate, while teclistamab achieved a 64% response rate with 32% complete remissions. In contrast, conventional treatments like IMiDs, PIs, and CD38 antibodies yielded much lower response rates (30%) with no complete remissions. The weakest outcomes were observed in patients receiving other therapies, with only a 26% response rate. Notably, bispecific antibodies not only improved survival but also overcame poor prognostic factors like early relapse and EMD.
These findings suggest that bispecific antibodies should become the standard of care for RRMM patients who relapse after CAR T-cell therapy. By delivering higher response rates and better survival outcomes, they offer new hope for patients facing this challenging stage of the disease.
"Single versus tandem autologous stem cell transplantation in newly diagnosed multiple myeloma"
Source
Grieb, N., Oeser, A., Ferle, M. et al. Single versus tandem autologous stem cell transplantation in newly diagnosed multiple myeloma. Bone Marrow Transplant (2024). https://doi.org/10.1038/s41409-024-02490-1 December 5, 2024.
Overview
This study looked at 12,763 patients with newly diagnosed multiple myeloma who received autologous stem cell transplantation (ASCT) between 1998 and 2021. Researchers compared those who had a single ASCT (8,736 patients) or tandem ASCT (2,027 patients). They found that the average age of patients getting their first ASCT increased over time, and the use of tandem ASCT (two transplants) decreased. This change in treatment happened alongside higher rates of complete response (CR) after initial treatment. The study showed improved survival rates over time for all age groups, especially for older patients, but not for those under 40. Tandem ASCT worked best for patients who didn’t achieve CR after the first transplant. However, patients with advanced-stage disease (ISS III) and kidney problems had worse outcomes with tandem ASCT. In conclusion, while ASCT is still an important treatment for multiple myeloma, doctors should carefully select patients for tandem ASCT, avoiding it in older patients, those with ISS III or kidney problems, and those who already respond well to a single ASCT.
"Advances in CAR-T cell therapy for hematologic and solid malignancies: latest updates from 2024 ESMO Congress"
Source
Huang, H., Yu, L., Weng, H. et al. Advances in CAR-T cell therapy for hematologic and solid malignancies: latest updates from 2024 ESMO Congress. J Hematol Oncol 17, 120 (2024). https://doi.org/10.1186/s13045-024-01639-1 December 5, 2024.
Overview
Chimeric antigen receptor (CAR)-T cell therapy is a promising form of immunotherapy that has shown success in treating blood cancers and encouraging results in solid tumors. However, there are challenges that reduce its effectiveness, such as difficulties with cell expansion, side effects, lack of ideal targets, weakened immune responses, and trouble infiltrating tumors due to the complex tumor environment. At the 2024 European Society for Medical Oncology (ESMO) Congress, new CAR-T therapies for both blood and solid cancers were discussed. These therapies focus on overcoming these challenges by using strategies like cytokine modulation, finding new targets, developing treatments from donor cells, combining with mRNA vaccines, and improving delivery and activation methods.
"Real-world characteristics and outcomes of patients with high-risk and non-high-risk smoldering multiple myeloma using the Flatiron Health database"
Source
Rajkumar, S.V., Mateos, MV., Schaeffer, M. et al. Real-world characteristics and outcomes of patients with high-risk and non-high-risk smoldering multiple myeloma using the Flatiron Health database. Blood Cancer J. 14, 215 (2024). https://doi.org/10.1038/s41408-024-01170-z December 5, 2024.
Overview
This study looked at the risk of disease progression in patients with high-risk smoldering multiple myeloma (SMM) using real-world data from the Flatiron Health database. The researchers used three different risk models (Mayo 2018, IMWG 2020, and AQUILA trial) to evaluate how quickly patients progressed to active multiple myeloma (MM) or died. They found that high-risk SMM patients were 3 to 4 times more likely to progress to active MM, 2 to 3.5 times more likely to experience progression or death, and 1.7 to 3.2 times more likely to progress or die while on first-line therapy compared to non-high-risk patients. These results remained the same even when patients with early treatment or bone disease were excluded. The study shows that high-risk SMM patients have worse outcomes, regardless of the risk model used, and suggests that early treatment may be needed.
"Reengaging life post-BCMA for myeloma"
Source
Hang Quach; Reengaging life post-BCMA for myeloma. Blood 2024; 144 (23): 2365–2367. doi: https://doi.org/10.1182/blood.2024026229 December 5, 2024.
Overview
In this study, Touzeau and colleagues (see the next entry) explored how well patients with multiple myeloma, who had previously been treated with BCMA-targeted therapies (BCMA-TTs), responded to a new treatment called teclistamab, an anti-BCMA T-cell engager (TCE). The study found that 52.5% of these patients responded to teclistamab, with 30% achieving a complete response or better. Although the results were a bit lower than those seen in patients who hadn’t been treated with BCMA-TTs, teclistamab still showed promise for these patients who had already received multiple therapies. The study also highlighted the need for more research into how to sequence these treatments and predict which patients will respond best to BCMA retargeting.
For patients who had previously received BCMA-targeted therapies, the timing of treatment appeared to influence their response to teclistamab. Patients who had a shorter time since their last treatment with BCMA-targeted therapies had a better chance of responding. The study also discussed how prior therapies like CAR-T or antibody-drug conjugates (ADC) affected subsequent responses, noting that the order of treatments and the immune system's status may play a role.
The findings suggest that re-targeting BCMA with a different therapy can still work for many patients, even after they have failed other BCMA treatments. The study also pointed out that exploring combinations or new treatment strategies could improve outcomes for patients who relapse after BCMA-targeted therapy. Researchers are continuing to investigate how to optimize treatment sequences and find the best ways to boost immune responses in these patients.
"Efficacy and safety of teclistamab in patients with relapsed/refractory multiple myeloma after BCMA-targeting therapies"
Source
Cyrille Touzeau, Amrita Y. Krishnan, Philippe Moreau, Aurore Perrot, Saad Z. Usmani, Salomon Manier, Michele Cavo, Carmen Martinez Chamorro, Ajay K. Nooka, Thomas G. Martin, Lionel Karlin, Xavier Leleu, Nizar J. Bahlis, Britta Besemer, Lixia Pei, Sarah Stein, Shun Xin Wang Lin, Danielle Trancucci, Raluca I. Verona, Suzette Girgis, Xin Miao, Clarissa M. Uhlar, Katherine Chastain, Alfred L. Garfall; Efficacy and safety of teclistamab in patients with relapsed/refractory multiple myeloma after BCMA-targeting therapies. Blood 2024; 144 (23): 2375–2388. doi: https://doi.org/10.1182/blood.2023023616 December 5, 2024.
Overview
Teclistamab is a treatment for relapsed or refractory multiple myeloma (R/RMM) that targets a protein called BCMA. It is used in patients who have already been treated with other BCMA-targeted therapies. In the MajesTEC-1 study, 40 patients who had received BCMA treatments like antibody-drug conjugates (ADC) or CAR-T therapy were given subcutaneous teclistamab to see how well it worked. The study found that 52.5% of patients responded to teclistamab, with 30% achieving a complete response or better. The median duration of response was 14.8 months, and the median progression-free survival was 4.5 months. The most common side effects were low white blood cell count (neutropenia), infections, cytokine release syndrome, and anemia, with infections being the most serious. The study also showed that prior BCMA treatments did not affect BCMA expression or immune function before starting teclistamab. Overall, the results suggest that teclistamab is a promising option for heavily treated patients with R/RMM.
"Moving forward in good KarMMa in myeloma"
Source
Giada Bianchi; Moving forward in good KarMMa in myeloma. Blood 2024; 144 (23): 2367–2369. doi: https://doi.org/10.1182/blood.2024026428 December 5, 2024.
Overview
In a recent study, Ailawadhi and colleagues (see the next entry) analyzed the final results of the KarMMa-3 trial, which evaluated the effectiveness of idecabtagene vicleucel (ide-cel), a CAR-T therapy, in patients with triple-class exposed relapsed/refractory multiple myeloma (MM). After nearly 3 years of follow-up, the study confirmed that ide-cel worked better than standard treatments, with a median progression-free survival (PFS) of 13 months compared to just 4.4 months for standard treatments. Patients who received ide-cel had a higher overall response rate and more patients achieved minimal residual disease–negative complete responses. However, overall survival was similar between the two groups, partly because many patients in the standard treatment group switched to ide-cel after their disease progressed.
Some challenges were noted, such as higher mortality before receiving ide-cel, especially in patients with high-risk disease. Also, the study found that patients receiving more treatment lines before ide-cel were more likely to drop out before the infusion. Despite these issues, there were no new treatment-related side effects, and quality of life improved for patients receiving ide-cel compared to standard treatments.
The study highlights the promise of CAR-T therapies but also raises questions about how to improve patient selection, manage bridging therapies, and optimize the use of ide-cel alongside other treatments. The researchers call for further studies to better understand the long-term effectiveness and safety of CAR-T therapies in MM.
"Ide-cel vs standard regimens in triple-class–exposed relapsed and refractory multiple myeloma: updated KarMMa-3 analyses"
Source
Sikander Ailawadhi, Bertrand Arnulf, Krina Patel, Michele Cavo, Ajay K. Nooka, Salomon Manier, Natalie Callander, Luciano J. Costa, Ravi Vij, Nizar J. Bahlis, Philippe Moreau, Scott Solomon, Ingerid Weum Abrahamsen, Rachid Baz, Annemiek Broijl, Christine Chen, Sundar Jagannath, Noopur Raje, Christof Scheid, Michel Delforge, Reuben Benjamin, Thomas Pabst, Shinsuke Iida, Jesús Berdeja, Sergio Giralt, Anna Truppel-Hartmann, Yanping Chen, Xiaobo Zhong, Fan Wu, Julia Piasecki, Laurie Eliason, Devender Dhanda, Jasper Felten, Andrea Caia, Mark Cook, Mihaela Popa McKiver, Paula Rodríguez-Otero; Ide-cel vs standard regimens in triple-class–exposed relapsed and refractory multiple myeloma: updated KarMMa-3 analyses. Blood 2024; 144 (23): 2389–2401. doi: https://doi.org/10.1182/blood.2024024582 December 5, 2024.
Overview
In the phase 3 KarMMa-3 trial, patients with triple-class exposed (TCE) relapsed and refractory multiple myeloma (R/RMM) were treated with idecabtagene vicleucel (ide-cel) or standard treatments (SRs). The results showed that ide-cel significantly improved progression-free survival (PFS), with a median of 13.8 months compared to just 4.4 months for SRs. This benefit was seen regardless of how many prior treatments the patients had, with the greatest improvement after two previous lines of therapy. The overall response rate (ORR) was also higher with ide-cel (71%) compared to SRs (42%), and more patients achieved complete responses with ide-cel (44% vs 5%).
While overall survival (OS) was similar between the two groups, some patients in the SR group switched to ide-cel after their disease progressed, making it harder to interpret the OS results. However, two analyses adjusted for this crossover still showed a survival benefit for ide-cel. The study emphasized the importance of bridging therapy to manage the disease while waiting for ide-cel to be manufactured. No new safety concerns were found, and patients receiving ide-cel reported better quality of life. Overall, ide-cel continued to show a favorable benefit-risk profile for patients with TCE R/RMM.
"It’s in your (peripheral) blood"
Source
Roberto Mina, Mattia D’Agostino; It’s in your (peripheral) blood. Blood 2024; 144 (23): 2371–2372. doi: https://doi.org/10.1182/blood.2024026783 December 5, 2024.
Overview
Puig and colleagues (see the next entry) compare two methods for assessing measurable residual disease (MRD) in patients with newly diagnosed multiple myeloma (MM): immuneprecipitation mass-spectrometry (QIP-MS) for serum and next-generation flow cytometry (NGF) for bone marrow. The study analyzed paired blood and bone marrow samples from patients in two clinical trials. QIP-MS, a sensitive method to detect monoclonal proteins in the blood, was found to be more sensitive than standard methods, detecting disease in patients who appeared negative using traditional techniques. While NGF remains the gold standard for MRD assessment due to its strong correlation with survival, QIP-MS could serve as a helpful tool, especially because it is non-invasive and could be used for ongoing disease monitoring.
The study also highlights the limitations of bone marrow MRD, including its invasiveness and potential false-negative results when disease is unevenly spread. QIP-MS showed good agreement with NGF but performed less well in early-stage assessments or in patients with extramedullary disease. Still, QIP-MS could complement NGF, providing early warnings of disease recurrence, especially in patients showing no bone marrow disease but with monoclonal protein in their blood. Future studies are needed to explore the use of QIP-MS alongside NGF and imaging to improve disease monitoring and treatment decisions.
"Measurable residual disease by mass spectrometry and next-generation flow to assess treatment response in myeloma"
Source
Noemí Puig, Cristina Agulló, Teresa Contreras, María-Teresa Cedena, Joaquín Martínez-López, Albert Oriol, María-Jesús Blanchard, Rafael Ríos, María-Belén Íñigo, Anna Sureda, Sunil Lakhwani, Javier de la Rubia, Verónica González-Calle, Valentín Cabañas, Luis Palomera, José-María Moraleda, Joan Bargay, Sergio Castro, Laura Rosiñol, Joan Bladé, Jesús F. San-Miguel, Juan-José Lahuerta, Bruno Paiva, María-Victoria Mateos; Measurable residual disease by mass spectrometry and next-generation flow to assess treatment response in myeloma. Blood 2024; 144 (23): 2432–2438. doi: https://doi.org/10.1182/blood.2024024995 December 5, 2024.
Overview
This study compares two methods for assessing measurable residual disease (MRD) in patients with multiple myeloma (MM): quantitative immunoprecipitation mass spectrometry (QIP-MS) in blood serum and next-generation flow cytometry (NGF) in bone marrow. The analysis used data from the GEM2012MENOS65 and GEM2014MAIN trials. Both methods were able to identify patients with different risks of disease progression, with those who remained MRD-negative having longer survival. Reappearance of MRD by QIP-MS indicated a higher risk of clinical progression. The study concluded that QIP-MS, a minimally invasive blood test, provides similar prognostic information as NGF and represents a breakthrough in monitoring MM with high sensitivity.
"Prognostic Impact of Patient-Reported Symptoms in Multiple Myeloma"
Source
Nadine Abdallah, Arwa Bohra, Aytaj Mammadzadeh, Francis K Buadi, Prashant Kapoor, Angela Dispenzieri, Morie A Gertz, Suzanne R Hayman, Mohammed ElHaj, David Dingli, Joselle Cook, Moritz Binder, Yi Lin, Taxiarchis V. Kourelis, Rahma Warsame, Carrie A. Thompson, Terri Menser, S. Vincent Rajkumar, Shaji K Kumar; Prognostic Impact of Patient-Reported Symptoms in Multiple Myeloma. Blood Adv 2024; bloodadvances.2024014232. doi: https://doi.org/10.1182/bloodadvances.2024014232 December 5, 2024.
Overview
This study looked at how patient-reported symptoms like fatigue, pain, and quality of life (QOL) affect survival outcomes in patients with newly diagnosed multiple myeloma (MM). Researchers used a simple 3-item questionnaire called the Hematology Patient-Reported Symptom Screen (HPRSS) to assess these symptoms in patients at Mayo Clinic. The study found that higher levels of fatigue, pain, and lower QOL were linked to shorter progression-free survival (PFS) and overall survival (OS). Specifically, fatigue and poor QOL were independently associated with shorter OS. These results suggest that patient-reported symptoms can help predict the outlook for MM patients, even when considering other factors like age, disease stage, and treatment.
"Magnetic resonance imaging-based nomograms predict high-risk cytogenetic abnormalities in multiple myeloma: a two-center study"
Source
Suwei Liu, Chang Liu, Haojie Pan, Shenglin Li, Peihong Teng, Zhengxiao Li, Jiachen Sun, Tiezhu Ren, Guifeng Liu, Junlin Zhou, Magnetic resonance imaging-based nomograms predict high-risk cytogenetic abnormalities in multiple myeloma: a two-center study, Clinical Radiology, 2024, 106768, ISSN 0009-9260, https://doi.org/10.1016/j.crad.2024.106768. December 5, 2024.
Overview
This study explored how MRI scans can help predict high-risk cytogenetic abnormalities (HRCAs) in patients with multiple myeloma (MM). Researchers looked at 195 MM patients and used MRI images, along with clinical factors, to create models that could predict HRCAs. The study found that certain MRI models, which combined specific image types and patient age, were effective at identifying HRCAs. These models performed well in testing groups, showing good accuracy and predictive power. The results suggest that MRI radiomics could be a useful, non-invasive method for predicting HRCAs, helping doctors make better decisions about treatment and prognosis for MM patients.
"Acid ceramidase controls proteasome inhibitor resistance and is a novel therapeutic target for the treatment of relapsed / refractory multiple myeloma"
Source
Bishop RT, Li T, Sudalagunta P, Nasr M, Nyman KJ, Alugubelli RR, Meads M, Frieling J, Nerlakanti N, Tauro M, Fang B, Grant S, Koomen J, Silva AS, Shain KH, Lynch CC. Acid ceramidase controls proteasome inhibitor resistance and is a novel therapeutic target for the treatment of relapsed / refractory multiple myeloma. Haematologica; https://doi.org/10.3324/haematol.2024.285587 [Early view]. December 5, 2024.
Overview
This study looked at how multiple myeloma (MM) patients become resistant to treatments like proteasome inhibitors (PIs). Researchers found that a protein called ASAH1 plays a key role in this resistance. By blocking ASAH1, they were able to make MM cells more sensitive to PIs and prevent the disease from getting worse in mice. The study showed that ASAH1 affects other proteins involved in cell survival, helping MM cells resist treatment. These results suggest that targeting ASAH1 could be a new way to treat relapsed or refractory MM.
"Real-world characteristics and outcomes of patients with multiple myeloma receiving second-line treatment in England"
Source
Moore S, Cornic L, Crossman-Barnes C-J, Jose S, Khalaf Z, Yong K, et al. Real-world characteristics and outcomes of patients with multiple myeloma receiving second-line treatment in England. eJHaem. 2024; 1–12. https://doi.org/10.1002/jha2.1058 December 5, 2024.
Overview
This study looked at the treatment outcomes for patients with relapsed or refractory multiple myeloma (RRMM) in England, specifically those who had already been treated with lenalidomide and then received a combination of daratumumab, bortezomib, and dexamethasone (DaraVd) as a second-line (2L) treatment. The study found that patients who had been exposed to lenalidomide had a median time to next treatment or death (TTNTD) of around 15 months, while those who were refractory to lenalidomide had a shorter TTNTD of about 10 months. These results show that despite treatment, patients with RRMM still face poor outcomes, emphasizing the need for better therapies, especially for those who are resistant to lenalidomide.
"Venetoclax in the Treatment of Multiple Myeloma: A Retrospective Analysis of 79 Patients"
Source
Zolotov, E., Patel, V., Weiss, Y., Biran, N., Phull, P., Vesole, D.H., Siegel, D.S. and Parmar, H. (2024), Venetoclax in the Treatment of Multiple Myeloma: A Retrospective Analysis of 79 Patients. Eur J Haematol. https://doi.org/10.1111/ejh.14343 December 5, 2024
Overview
This study looked at the effectiveness of venetoclax, a drug that targets BCL-2, in patients with relapsed or refractory multiple myeloma (RRMM). The study included 79 patients, with a median age of 61, who had received a median of 5 prior treatments before using venetoclax. The study found that the median progression-free survival (mPFS) was 3.4 months overall, but patients with the t(11;14) genetic abnormality had a much better mPFS of 7.8 months. Patients who had a very good partial response or better had a mPFS of 7.1 months. Common side effects included fatigue, diarrhea, and respiratory infections. The study suggests that venetoclax works moderately well in patients who have been heavily treated before, especially for those with t(11;14), though its effectiveness was lower compared to other studies. Despite this, venetoclax was generally well tolerated, with manageable side effects. The study calls for further research to better understand how venetoclax can be used in treating RRMM.
"Health-Related Quality of Life During Carfilzomib–Lenalidomide–Dexamethasone Consolidation: Findings From the Multiple Myeloma CONPET Study"
Source
Rosenberg, T., Möller, S., Abildgaard, N., Nørgaard, J.N., Lysén, A., Tsykonova, G., Joao, C., Vangsted, A., Schjesvold, F. and Nielsen, L.K. (2024), Health-Related Quality of Life During Carfilzomib–Lenalidomide–Dexamethasone Consolidation: Findings From the Multiple Myeloma CONPET Study. Eur J Haematol. https://doi.org/10.1111/ejh.14358 December 5, 2024.
Overview
The CONPET study looked at how multiple myeloma patients experienced shortness of breath and breathing difficulties during treatment with carfilzomib, lenalidomide, and dexamethasone (KRd) after autologous stem cell transplantation. The study involved 50 patients, with a median age of 62. Patients were asked to report symptoms using specific surveys. The results showed that 17% of patients reported shortness of breath during treatment, and this increased to 11% after treatment compared to before starting KRd. Overall, patients experienced a noticeable worsening in breathing problems during treatment. This confirms earlier findings that carfilzomib can cause shortness of breath in multiple myeloma patients.
"Genetic Disruption of Blimp-1 Drastically Augments the Antitumor Efficacy of BCMA-Targeting CAR-T Cells"
Source
Anthony M Battram, Joan Mañé Pujol, David F Moreno, Aina Oliver-Caldes, Judit Carpio, Oriol Cardus, Luis Gerardo Rodríguez-Lobato, Álvaro Urbano-Ispizua, Carlos Fernández de Larrea; Genetic Disruption of Blimp-1 Drastically Augments the Antitumor Efficacy of BCMA-Targeting CAR-T Cells. Blood Adv 2024; bloodadvances.2024013209. doi: https://doi.org/10.1182/bloodadvances.2024013209 December 6, 2024.
Overview
Chimeric antigen receptor-T (CAR-T) cells that target B-cell maturation antigen (BCMA) are a promising treatment for multiple myeloma (MM), but they often don't last long enough and patients relapse. This study aimed to improve the durability of CAR-T cells by using CRISPR/Cas9 to remove a gene called Blimp-1. CAR-T cells without Blimp-1 (Blimp-1 knockout or KO) looked more like memory cells, which can last longer and help maintain anti-tumor responses. Although these Blimp-1 KO CAR-T cells had less immediate fighting ability, they were more effective in a mouse model of MM, slowing or stopping disease progression and improving survival. When tested in the lab, Blimp-1 KO CAR-T cells maintained a more active state and showed better tumor-fighting ability. RNA analysis revealed that these cells had a memory-like signature and enhanced mechanisms for fighting the tumor. Overall, removing Blimp-1 improved the effectiveness of CAR-T cells in treating MM.
"Value of Innovative Multiple Myeloma Treatments from Patient and Healthcare Provider Perspectives: Evidence from a Discrete Choice Experiment"
Source
Syeed, S., Tan, C.J., Godara, A. et al. Value of Innovative Multiple Myeloma Treatments from Patient and Healthcare Provider Perspectives: Evidence from a Discrete Choice Experiment. PharmacoEconomics (2024). https://doi.org/10.1007/s40273-024-01459-8 December 6, 2024.
Overview
This study looked at what patients with multiple myeloma (MM) and healthcare providers (HCPs) value most when it comes to new MM treatments. A survey was conducted with 200 patients and 30 HCPs in the USA, focusing on five key factors: how long patients live without the disease progressing (progression-free survival or PFS), the risk of severe side effects, the impact of treatment on daily life, scientific innovation, and monthly out-of-pocket costs. Results showed that both patients and HCPs preferred treatments with longer PFS, fewer severe side effects, and lower costs. Patients particularly valued PFS (the most important factor at 44.7%), followed by how treatments affect daily life (21.6%) and scientific innovation (16%). The study suggests that when evaluating MM treatments, factors beyond PFS, like allowing patients to live without treatment or offering new scientific advances, are also important.
"Quantification of serum daratumumab in multiple myeloma patients by LC-MS/MS, comparison with ELISA, Journal of Pharmaceutical and Biomedical Analysis"
Source
Weiqiang Li, Zhuoran Tian, Xiong Yu, Hongyu Xu, Fang Huang, Jinghua Yu, Xingxing Diao, Quantification of serum daratumumab in multiple myeloma patients by LC-MS/MS, comparison with ELISA, Journal of Pharmaceutical and Biomedical Analysis, 2024, 116627, ISSN 0731-7085, https://doi.org/10.1016/j.jpba.2024.116627. December 8, 2024.
Overview
Daratumumab is a monoclonal antibody used to treat relapsed or refractory multiple myeloma and light-chain amyloidosis. Measuring this drug in the blood can be tricky because other substances in the body can interfere with the results.
Researchers developed a new technique using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to accurately measure daratumumab levels in the blood. The method involves purifying immunoglobulin G (IgG) without altering it chemically.
This approach proved effective in patients receiving intravenous daratumumab, with drug levels measured between 181.8 and 975.3 µg/mL. The results were highly accurate and consistent, with less than 10% variation. Additionally, the method showed strong agreement with the standard enzyme-linked immunosorbent assay (ELISA), confirming its reliability.
This advancement could improve drug monitoring for patients on daratumumab, leading to more precise treatment adjustments.
"Bone Marrow Stromal Cells Protect Myeloma Cells from Ferroptosis through GPX4 deSUMOylation"
Source
Hongmei Jiang, Qian Li, Xudan Yang, Linchuang Jia, Hao Cheng, Jingya Wang, Sheng Wang, Xin Li, Ying Xie, Jingjing Wang, Yixuan Wang, Meilin Hu, Jing Guo, Ziyi Peng, Mengqi Wang, Tiantian Li, Haifeng Zhao, Lijuan Wang, Zhiqiang Liu, Bone Marrow Stromal Cells Protect Myeloma Cells from Ferroptosis through GPX4 deSUMOylation, Cancer Letters,2024, 217388,ISSN 0304-3835, https://doi.org/10.1016/j.canlet.2024.217388. December 7, 2024.
Overview
Bone marrow stromal cells (BMSCs) play a critical role in protecting multiple myeloma (MM) cells from various forms of cell death, including ferroptosis—a process triggered by unstable iron and reactive oxygen species (ROS). This study explored how BMSCs help MM cells resist ferroptosis and identified potential therapeutic targets.
In laboratory models, BMSCs shielded MM cells from ferroptosis by boosting levels of a protein called glutathione peroxidase 4 (GPX4), which neutralizes harmful ROS. This protection involved a signaling pathway (CD40/CD40L) that increased a protein called SENP3 in MM cells. SENP3 stabilized GPX4, preventing cell death.
The research also tested potential treatments in mouse models of MM. Blocking SENP3 made MM cells more sensitive to a GPX4 inhibitor called RSL3. This approach reduced tumor growth, improved bone health, and extended survival in mice with MM.
These findings highlight how BMSCs help MM cells survive and suggest that targeting SENP3 and GPX4 could be a promising strategy for treating drug-resistant MM.
"Patient-reported outcome domains in multiple myeloma randomized controlled trials and association with survival outcomes"
Source
Shah, D., Sparano, F., Luo, C. et al. Patient-reported outcome domains in multiple myeloma randomized controlled trials and association with survival outcomes. Ann Hematol (2024). https://doi.org/10.1007/s00277-024-06129-5 December 7, 2024.
Overview
Patient-reported outcomes (PROs) are key to understanding the impact of multiple myeloma (MM) treatments. However, how these outcomes are measured and reported in clinical trials can vary widely. This study reviewed clinical trials to identify the most commonly used PRO categories, their responsiveness to newer treatments, and their link to survival outcomes.
The researchers analyzed 35 MM clinical trials conducted between 2014 and 2023 that used the EORTC QLQ-C30 questionnaire. PROs were included as secondary or exploratory outcomes in all studies. The most common PRO categories were overall quality of life (QoL), physical functioning, fatigue, and pain. About 66% of the trials showed meaningful improvements in at least one of these areas, with QoL and pain improving most often.
The study also found that PROs were linked to survival outcomes. In 71% of trials, improvements in PROs matched better overall survival (OS), suggesting that PROs can reflect treatment success.
These findings highlight the value of including PROs in MM clinical trials to better assess how treatments impact patients’ lives and guide therapy decisions.
"Is Bone Marrow Trephine Biopsy Necessary in Multiple Myeloma Patients at Diagnosis?"
Source
Ana Gea, Tatiana Fernández, Sara Fernández-Luis, Juan J Domínguez-García, Irene Francés, Ana Tobalina, Rodrigo Cantera, Julia Bannatyne, Irene Gorostidi, María Oviedo, Juan M Cerezo, Raquel García, Andrés Insunza, Carmen Montes-Gaisán, Aránzazu Bermúdez, Santiago Montes-Moreno, Montserrat Briz, Enrique M Ocio, Is Bone Marrow Trephine Biopsy Necessary in Multiple Myeloma Patients at Diagnosis?, Clinical Lymphoma Myeloma and Leukemia, 2024, ISSN 2152-2650, https://doi.org/10.1016/j.clml.2024.12.004. December 7, 2024.
Overview
Diagnosing multiple myeloma (MM) typically requires at least 10% plasma cell (PC) infiltration in the bone marrow, determined through either bone marrow aspiration (BMA) or biopsy (BMB). This study compared the results of both techniques in 189 patients to assess how often they agree and whether discrepancies affect diagnosis and treatment.
The findings showed that in 23% of cases, BMA and BMB results did not match. Among these, poor sample quality was a factor in 10 cases. In the remaining 33 cases, BMB identified MM, while BMA showed less than 10% PC infiltration. Of these, 16 patients had symptomatic MM, and 17 were classified as having smoldering MM.
Without using BMB initially, 11% of MM cases could have been misdiagnosed. Additionally, 12% of symptomatic patients might have needed repeat tests to confirm their diagnosis under current guidelines.
This study highlights the importance of BMB in MM diagnosis, as it often provides a more accurate assessment of bone marrow involvement compared to BMA, particularly in cases with patchy infiltration or poor-quality samples. Combining both methods could improve diagnostic accuracy and patient care.
"Canagliflozin differentially modulates carfilzomib-induced endoplasmic reticulum stress in multiple myeloma and endothelial cells"
Source
Dabour, M.S., George, M.Y., Grant, M.K.O. et al. Canagliflozin differentially modulates carfilzomib-induced endoplasmic reticulum stress in multiple myeloma and endothelial cells. Arch Toxicol (2024). https://doi.org/10.1007/s00204-024-03913-0 December 8, 2024.
Overview
Carfilzomib (CFZ) is an effective treatment for multiple myeloma (MM) but often causes serious heart-related side effects, including heart failure and high blood pressure. These issues may result from damage to blood vessel cells (endothelial cells). This study explored how CFZ affects stress responses in cells and whether canagliflozin, a diabetes medication, could reduce these side effects without weakening CFZ’s cancer-fighting ability.
The researchers found that CFZ triggers stress in both endothelial and MM cells. In endothelial cells, canagliflozin reduced most signs of this stress and also blocked CFZ-induced cell recycling processes (autophagy) that can worsen cell damage. Meanwhile, in MM cells, canagliflozin did not interfere with CFZ’s effects on stress but made the drug more effective at killing cancer cells.
Using a co-culture system to simulate interactions between endothelial and MM cells, canagliflozin protected the blood vessel cells from CFZ’s toxic effects while enhancing the drug’s ability to kill MM cells.
These results suggest that canagliflozin could make CFZ safer for the heart while improving its effectiveness in treating multiple myeloma.
"Pseudokinase TRIB3 stabilizes SSRP1 via USP10-mediated deubiquitination to promote multiple myeloma progression"
Source
Wang, H., Liang, L., Xie, Y. et al. Pseudokinase TRIB3 stabilizes SSRP1 via USP10-mediated deubiquitination to promote multiple myeloma progression. Oncogene (2024). https://doi.org/10.1038/s41388-024-03245-4 December 9, 2024.
Overview
Multiple myeloma (MM) is a common and challenging blood cancer known for its rapid progression and resistance to treatment. This study highlights a protein called TRIB3 as a key driver of MM’s growth and survival.
Researchers found that TRIB3 forms a complex with two other proteins, SSRP1 and USP10, which protects SSRP1 from being broken down. This stabilization boosts MM cell growth. To disrupt this harmful interaction, the team developed a specialized peptide called SP-A. SP-A breaks apart the TRIB3/USP10/SSRP1 complex, lowering SSRP1 levels and slowing MM progression.
Importantly, SP-A worked even better when combined with the common MM drug bortezomib, showing a powerful synergistic effect. These findings suggest that targeting the TRIB3/USP10/SSRP1 complex could lead to new and more effective treatments for multiple myeloma.
"Minimal Residual Disease in Multiple Myeloma"
Source
Nour Moukalled, Florent Malard, Ali Bazarbachi, Mohamad Mohty, Minimal Residual Disease in Multiple Myeloma, La Presse Médicale,2024,104261,ISSN 0755-4982, https://doi.org/10.1016/j.lpm.2024.104261. December 9, 2024. .
Overview
Minimal Residual Disease (MRD) is becoming an important marker for predicting outcomes and guiding treatment in multiple myeloma (MM). Despite advances in therapies like proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, CAR-T cell therapy, and bispecific antibodies, completely eliminating cancerous plasma cells remains difficult.
MRD refers to small amounts of cancer cells that survive after treatment, detectable only through highly sensitive methods like next-generation flow cytometry (NGF) and sequencing (NGS). Achieving MRD negativity, where no residual cancer cells are found, has been linked to longer progression-free survival (PFS) and overall survival (OS), making it a key goal in clinical trials.
MRD testing helps doctors tailor treatments—escalating therapy for high-risk patients or reducing intensity for those who achieve MRD negativity. However, challenges remain, including standardizing testing methods, improving access, and addressing variability in results.
Future research will focus on refining MRD-guided treatment strategies and exploring new detection tools, like liquid biopsies, to better monitor patients and improve outcomes in multiple myeloma.
"Evolving Strategies in the Management of Transplant-Eligible Patients with Newly Diagnosed Multiple Myeloma"
Source
Aurore Perrot, Evolving Strategies in the Management of Transplant-Eligible Patients with Newly Diagnosed Multiple Myeloma, La Presse Médicale, 2024, 104262, ISSN 0755-4982, https://doi.org/10.1016/j.lpm.2024.104262. December 9, 2024.
Overview
Treatment for multiple myeloma has advanced with the use of triplet and quadruplet drug combinations, especially those including anti-CD38 antibodies. Autologous stem cell transplantation (ASCT) remains a key treatment, but its role is being debated due to highly effective newer therapies.
Current guidelines still recommend ASCT for eligible patients, particularly those with high-risk disease. However, concerns exist about its lack of overall survival benefits and the long-term side effects of high-dose melphalan. Some suggest delaying ASCT until the first relapse, but this could make some patients ineligible if their health worsens.
Using additional treatment, called consolidation therapy, after ASCT shows mixed results, with some studies suggesting improved progression-free survival (PFS) while others show no clear benefit. Tandem transplants may help high-risk patients.
Maintenance therapy, especially with lenalidomide, is well-supported, providing significant benefits in PFS and overall survival. Combining lenalidomide with proteasome inhibitors or anti-CD38 antibodies may further improve outcomes, particularly for high-risk patients.
As knowledge of myeloma biology grows, treatment plans are increasingly personalized, focusing on patient risk and treatment response to achieve the best results.
"Imaging in Multiple Myeloma"
Source
Jas Virk, Jens Hillengass, Imaging in Multiple Myeloma, La Presse Médicale, 2024,104263, ISSN 0755-4982, https://doi.org/10.1016/j.lpm.2024.104263. December 9, 2024.
Overview
A key sign of multiple myeloma (MM) is damage to the bones, making imaging an important part of diagnosing, monitoring, and tracking the disease.
Traditionally, X-rays were used to evaluate MM, but newer and more sensitive techniques like CT scans, MRIs, and PET/CT scans have largely replaced them. CT, often combined with PET scans, is now the first choice for detecting bone damage. MRI is the gold standard for assessing bone marrow involvement, especially in early stages of MM. PET/CT scans are particularly useful for evaluating how well treatments are working and detecting disease outside the bone marrow.
Emerging evidence suggests that advanced MRI techniques may be even better than PET/CT for monitoring treatment response, though these methods are not widely available yet. This review highlights the current imaging tools used for MM and explores potential advancements in this field.
"Kidney disease in multiple myeloma"
Source
Frank Bridoux, Nelson Leung, Samih H. Nasr, Arnaud Jaccard, Virginie Royal, Kidney disease in multiple myeloma, La Presse Médicale,2024, 104264, ISSN 0755-4982, https://doi.org/10.1016/j.lpm.2024.104264. December 9, 2024.
Overview
Renal disease is a common problem in people with multiple myeloma (MM), and it can make the condition worse, affecting quality of life and survival. The most common type of kidney damage in MM is light chain cast nephropathy (LCCN), which occurs when abnormal proteins called free light chains (FLC) build up in the kidneys. These deposits can cause severe kidney injury and are linked to high levels of FLC in the blood and low levels of protein in the urine.
To treat LCCN, it's important to identify the kidney problem quickly and start treatment right away. Treatment often includes fluids, addressing factors that worsen kidney damage, and using medications that target MM. The choice of treatment depends on how the drug is removed from the body and the patient’s overall health. Reducing FLC levels in the blood is crucial for kidney recovery, so doctors regularly check FLC levels to track progress.
For newly diagnosed patients, a common treatment includes a combination of bortezomib, high-dose steroids, and an anti-CD38 antibody. In some cases, adding cyclophosphamide or other drugs might help, but more research is needed to confirm the best treatment. For patients with severe kidney injury, additional treatments like plasma exchange or specialized dialysis may improve kidney function.
In some cases, doctors may assess kidney damage through a biopsy to help guide treatment decisions. If a patient reaches end-stage kidney failure, kidney transplant might be an option. Thanks to better treatments, people with MM are living longer, and renal transplantation is now considered for some patients.
"Bispecific antibody and chimeric antigen receptor (CAR) modified T-cell in the treatment of multiple myeloma: where do we stand today?"
Source
Xiang Zhou, K. Martin Kortuem, Leo Rasche, Hermann Einsele, Bispecific antibody and chimeric antigen receptor (CAR) modified T-cell in the treatment of multiple myeloma: where do we stand today?, La Presse Médicale, 2024, 104265, ISSN 0755-4982, https://doi.org/10.1016/j.lpm.2024.104265. December 9, 2024.
Overview
Although treatments like proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies have improved survival in multiple myeloma (MM), it is still considered an incurable disease for most patients. Recently, T-cell-based immunotherapy has become a promising treatment for patients with relapsed or refractory (RR) MM. This includes therapies like chimeric antigen receptor (CAR) T-cells and bispecific T-cell engaging antibodies (bsAb), which have shown strong results in clinical trials with manageable side effects. The most common immune target for these therapies is B-cell maturation antigen (BCMA). Several CAR T-cell and bsAb therapies have been approved for RRMM, changing how MM is treated and offering a potential cure. This review looks at how these therapies work, their immune targets, clinical results, resistance mechanisms, and how they can be used together in treatment.
"Increased serum B-cell maturation antigen levels evaluated with an Elecsys-based serum B-cell maturation antigen assay have a negative prognostic value in patients with newly diagnosed multiple myeloma"
Source
Terpos E, Ntanasis Stathopoulos I, Malandrakis P, Fotiou D, Migkou M, Eleutherakis-Papaiakovou E, et al. Increased serum B-cell maturation antigen levels evaluated with an Elecsys-based serum B-cell maturation antigen assay have a negative prognostic value in patients with newly diagnosed multiple myeloma. eJHaem. 2024; 1–4. https://doi.org/10.1002/jha2.889 December 9, 2024.
Overview
This study looked at serum B-cell maturation antigen (sBCMA) levels in 166 newly diagnosed multiple myeloma (MM) patients using a special test. The results showed that higher sBCMA levels at diagnosis were linked to worse survival outcomes, including shorter progression-free and overall survival. In patients who had samples taken during disease progression, there was a trend for lower sBCMA levels. The study suggests that regularly measuring sBCMA in future research could help determine its role in monitoring MM and improving clinical practices.
"ADAR1-regulated cytoplasmic dsRNA-sensing pathway is a novel mechanism of lenalidomide resistance in multiple myeloma"
Source
Mun Yee Koh, Tae-Hoon Chung, Nicole Xin Ning Tang, Sabrina Hui Min Toh, Jianbiao Zhou, Tze King Tan, Leilei Chen, Wee Joo Chng, Phaik Ju Teoh; ADAR1-regulated cytoplasmic dsRNA-sensing pathway is a novel mechanism of lenalidomide resistance in multiple myeloma. Blood 2024; blood.2024024429. doi: https://doi.org/10.1182/blood.2024024429 December 9, 2024.
Overview
This study explores a new reason why some multiple myeloma (MM) patients become resistant to Revlimid (lenalidomide). Researchers found that a protein called ADAR1 plays a key role in this resistance. Lenalidomide works by activating certain pathways in MM cells, leading to cell death. ADAR1 regulates these pathways. When ADAR1 is removed, the cells become more sensitive to lenalidomide, while increasing ADAR1 reduces the drug's effectiveness. The study suggests that targeting ADAR1 could be a new way to help overcome lenalidomide resistance in MM treatment.
"Tumor burden quantified by Soluble B-Cell Maturation Antigen and Metabolic Tumor Volume determine myeloma CAR-T outcomes"
Source
Ciara L Freeman, Jerald Noble, Meghan Menges, Ricardo Villanueva, Justyn Y Nakashima, Nicholas B Figura, R. Petter Tonseth, Dietrich Werner Idiaquez, Lawrence Skelson, Eric C Smith, Julieta Abraham-Miranda, Salvatore Corallo, Gabriel De Avila, Omar Castaneda Puglianini, Hien D Liu, Melissa Alsina, Taiga Nishihori, Kenneth H Shain, Rachid C Baz, Brandon J Blue, Ariel Grajales-Cruz, John M. Koomen, Reginald M Atkins, Doris K Hansen, Ariosto Siqueira Silva, Jongphil Kim, Yoganand Balagurunathan, Frederick L Locke; Tumor burden quantified by Soluble B-Cell Maturation Antigen and Metabolic Tumor Volume determine myeloma CAR-T outcomes. Blood 2024; blood.2024024965. doi: https://doi.org/10.1182/blood.2024024965
Overview
This study looked at how two factors—serum soluble B-cell maturation antigen (sBCMA) levels and metabolic tumor volume (MTV)—can help predict how well patients with relapsed and refractory multiple myeloma (RRMM) will respond to CAR-T therapy. Researchers analyzed data from 183 patients and found that high sBCMA levels were linked to higher tumor burden and more severe CAR-T related side effects, as well as shorter progression-free survival (PFS). High MTV also predicted shorter PFS and overall survival (OS). Interestingly, patients with low sBCMA and high MTV tended to have poor responses to CAR-T therapy. The study suggests that using both sBCMA and MTV measurements could help doctors tailor treatments more effectively for RRMM patients.
"Efficacy and Safety of Daratumumab in Intermediate/High-risk Smoldering Multiple Myeloma: Final Analysis of CENTAURUS"
Source
Carl Ola Landgren, Ajai Chari, Yael C. Cohen, Andrew Spencer, Peter M Voorhees, Irwindeep Sandhu, Matthew W Jenner, Dean Smith, Michele Cavo, Niels W.C.J. van de Donk, Meral Beksac, Phillippe Moreau, Hartmut Goldschmidt, Diego Vieyra, Linlin Sha, Liang Li, Els Rousseau, Robyn M. Dennis, Robin Carson, Craig C. Hofmeister; Efficacy and Safety of Daratumumab in Intermediate/High-risk Smoldering Multiple Myeloma: Final Analysis of CENTAURUS. Blood 2024; blood.2024025897. doi: https://doi.org/10.1182/blood.2024025897 December 9, 2024.
Overview
The final analysis of the CENTAURUS study looked at how daratumumab, a treatment for multiple myeloma, affects patients with smoldering multiple myeloma (SMM), a condition that can progress to full-blown multiple myeloma. The study involved 123 patients with intermediate or high-risk SMM, who were given daratumumab on different dosing schedules: Long intense, Intermediate, and Short intense. After a median follow-up of about 7 years, the results showed that patients in the Long intense group had the best outcomes, with higher complete response rates and longer progression-free survival (PFS). No new safety concerns were found, and the study supports further research into using daratumumab as an early treatment for SMM.
"Health care Systems as Determinants of Outcomes in Multiple Myeloma: Final Results from the Latin American MYLACRE Study"
Source
Vania Tietsche de Moraes Hungria, Rafael D Gaiolla, Kenny Galvez, Guillermina Remaggi, Natalia Schutz, Rosane Isabel Bittencourt, Angelo Maiolino, Guillermo Enrique Quintero-Vega, Maria Silvana Cugliari, Walter Moises Tobias Braga, Carolina Colaco Villarim, Edvan de Queiroz Crusoé, Alicia Ines Ines Enrico, Gaston Caeiro, Jandey Gloria Bigonha, Fernanda Lemos Moura, Jair Figueroa Emiliani, Claudia Sossa-Melo, Milton Lombana, Huiling Pei, Mariana Fernandez, Jaqueline Saes, Damila Cristina Trufelli; Health care Systems as Determinants of Outcomes in Multiple Myeloma: Final Results from the Latin American MYLACRE Study. Blood Adv 2024; bloodadvances.2024013838. doi: https://doi.org/10.1182/bloodadvances.2024013838
Overview
A study in five Latin American countries (Argentina, Brazil, Colombia, Mexico, and Panama) looked at how multiple myeloma (MM) is treated in public versus private healthcare institutions. Researchers found differences in the care patients received, with private institutions offering better treatment options, such as more access to advanced therapies like immunomodulatory drugs, proteasome inhibitors, and anti-CD38 antibodies. Patients in private institutions also had better health at the start of treatment and were more likely to be eligible for transplants. Although overall survival was slightly longer for private institution patients (53.3 months) compared to public institution patients (44.6 months), the difference wasn't large enough to be statistically significant. The study highlights challenges in MM treatment across Latin America, showing disparities between public and private sectors in diagnosis, therapy, and patient outcomes.
"PNPO-Mediated Oxidation of DVL3 Promotes Multiple Myeloma Malignancy and Osteoclastogenesis by Activating the Wnt/β-Catenin Pathway"
Source
Z. Deng, S. Sun, N. Zhou, Y. Peng, L. Cheng, X. Yu, Y. Yuan, M. Guo, M. Xu, Y. Cheng, F. Zhou, N. Li, Y. Yang, C. Gu, PNPO-Mediated Oxidation of DVL3 Promotes Multiple Myeloma Malignancy and Osteoclastogenesis by Activating the Wnt/β-Catenin Pathway. Adv. Sci. 2024, 2407681. https://doi.org/10.1002/advs.202407681 December 10, 2024.
Overview
This study looked at how the bone marrow environment impacts multiple myeloma (MM) and tested a natural compound called celastrol, known for its anticancer effects. The researchers found that celastrol targets a protein called pyridoxine-5′-phosphate oxidase (PNPO), which is linked to poor outcomes in MM patients. PNPO promotes the growth of MM cells and causes bone damage by triggering a pathway called Wnt/β-catenin. The study also identified Eltrombopag as a potential treatment for MM, as it blocks the harmful effects of PNPO and shows promise in mouse models. These findings suggest that targeting PNPO could lead to new treatments for MM.
"Secondary Malignancies After Autologous Stem Cell Transplantations in Patients With Malignant Lymphoma and Multiple Myeloma"
Source
Metzner, B., Müller, T.H., Casper, J., Kimmich, C., Petershofen, E.K., Thole, R., Voß, A. and Köhne, C.H. (2024), Secondary Malignancies After Autologous Stem Cell Transplantations in Patients With Malignant Lymphoma and Multiple Myeloma. Eur J Haematol. https://doi.org/10.1111/ejh.14355 December 10, 2024.
Overview
This study looked at patients who had undergone autologous stem cell transplantation (ASCT) and monitored them for up to 31 years. The researchers focused on secondary cancers that can occur after ASCT. Among 877 patients, 89 developed 94 secondary cancers, including blood cancers and solid tumors. Some patients were diagnosed with non-melanoma skin cancer, and half of the patients with solid tumors were diagnosed early enough to be treated. The risk of developing a secondary cancer increased with age, the type of original cancer (especially lymphoma), and being male. The study suggests that regular, lifelong cancer screenings are important for improving outcomes in these patients.
"Isatuximab, Lenalidomide, Bortezomib, and Dexamethasone Induction Therapy for Transplant-Eligible Newly Diagnosed Multiple Myeloma: Final Part 1 Analysis of the GMMG-HD7 Trial"
Source
Elias K. Mai et al., Isatuximab, Lenalidomide, Bortezomib, and Dexamethasone Induction Therapy for Transplant-Eligible Newly Diagnosed Multiple Myeloma: Final Part 1 Analysis of the GMMG-HD7 Trial. JCO 0, JCO-24-02266 DOI:10.1200/JCO-24-02266 December 9, 2024.
Overview
The GMMG-HD7 trial evaluated the addition of isatuximab (Isa) to the standard lenalidomide-bortezomib-dexamethasone (RVd) regimen in newly diagnosed multiple myeloma (NDMM) patients eligible for autologous stem cell transplant (ASCT). Involving 662 patients, this phase III, open-label, multicenter study assessed minimal residual disease (MRD) negativity, progression-free survival (PFS), and overall outcomes. Patients were randomized to Isa-RVd or RVd for induction therapy, followed by ASCT and maintenance with either lenalidomide alone or Isa-lenalidomide. The trial reflected real-world practice by excluding post-transplant consolidation therapy.
The addition of Isa significantly improved MRD negativity rates, with 66% of the Isa-RVd group achieving MRD-negative status post-transplant compared to 48% in the RVd group. Isa-RVd also provided a notable PFS benefit, with a hazard ratio of 0.70 (P = 0.0184). This advantage was consistent across most subgroups, though diminished in patients with high-risk features like R-ISS stage III or high-risk cytogenetics. MRD-negative patients demonstrated longer PFS, further emphasizing the clinical value of achieving MRD negativity. Comparatively, the PERSEUS trial, which investigated daratumumab with RVd, reported similar benefits, though differing trial designs limit direct comparisons.
Isa-RVd demonstrated a manageable safety profile, aligning with previous studies, and underscored the growing role of quadruplet regimens in NDMM. The trial's results support Isa-RVd as a potential new standard of care for transplant-eligible NDMM patients, offering deeper and more sustained responses without the need for post-transplant consolidation therapy.
"ADAR1-regulated cytoplasmic dsRNA-sensing pathway is a novel mechanism of lenalidomide resistance in multiple myeloma"
Source
Mun Yee Koh, Tae-Hoon Chung, Nicole Xin Ning Tang, Sabrina Hui Min Toh, Jianbiao Zhou, Tze King Tan, Leilei Chen, Wee Joo Chng, Phaik Ju Teoh; ADAR1-regulated cytoplasmic dsRNA-sensing pathway is a novel mechanism of lenalidomide resistance in multiple myeloma. Blood 2024; blood.2024024429. doi: https://doi.org/10.1182/blood.2024024429 December 9, 2024.
Overview
Immunomodulatory drugs (IMiDs) are an important treatment for multiple myeloma (MM), but many patients develop resistance to them over time. While changes in the cereblon (CRBN) pathway are known to explain resistance in some cases, they only account for 20-30% of cases, leaving most of the mechanisms behind resistance unclear. This study identified a new driver of lenalidomide resistance: the RNA-editing enzyme ADAR1.
The researchers found that lenalidomide activates a pathway in MM cells called MDA5-mediated dsRNA sensing, which leads to interferon-driven cell death. ADAR1 plays a key role in regulating this process. When ADAR1 is lost, lenalidomide becomes more effective because the buildup of double-stranded RNA (dsRNA) triggers stronger immune responses that promote cancer cell death. On the other hand, ADAR1 overexpression reduces lenalidomide’s effectiveness by increasing RNA editing, decreasing dsRNA buildup, and suppressing immune pathways.
This study highlights a novel RNA-based mechanism behind lenalidomide resistance in MM. It also suggests that targeting ADAR1 could be a new therapeutic strategy to overcome resistance and improve outcomes for patients.
"Sulforaphane inhibits multiple myeloma cell-induced osteoclast differentiation and macrophage proliferation by elevating ferroportin1"
Source
Sun, W., Sun, J., Hu, W. et al. Sulforaphane inhibits multiple myeloma cell-induced osteoclast differentiation and macrophage proliferation by elevating ferroportin1. Cancer Chemother Pharmacol 95, 3 (2025). https://doi.org/10.1007/s00280-024-04736-7 December 11, 2024.
Overview
Osteolysis, a common issue in multiple myeloma (MM) patients, occurs when cancer cells promote the formation of bone-resorbing cells called osteoclasts. This study investigated the effects of sulforaphane (SFN), a natural compound found in broccoli, on MM-driven osteoclast formation. Using conditioned medium (CM) from MM cells to mimic the tumor environment, researchers examined how SFN influenced osteoclast differentiation and macrophage activity.
MM cell CM was shown to reduce levels of ferroportin1 (Fpn1), a protein that exports iron from cells, causing iron buildup in macrophages and promoting osteoclast formation and macrophage proliferation. Blocking iron overload with an iron chelator, deferoxamine (DFO), significantly reduced these effects. Further analysis revealed that iron overload activated key pathways, including JNK/AP-1/NFATC1 and PI3K/AKT, driving osteoclast formation and macrophage growth. SFN counteracted these effects by increasing Fpn1 expression, lowering iron levels, and suppressing osteoclast differentiation and macrophage proliferation.
These findings suggest that SFN could be a promising treatment for MM-associated bone damage. By targeting iron regulation and blocking harmful cell pathways, SFN may help prevent or reduce osteolysis in MM patients.
"High-risk cytogenetic abnormalities in multiple myeloma: PETHEMA-GEM experience"
Source
González-Calle, V., Rodriguez-Otero, P., Calasanz, M.J., Guijarro, M., Martínez-López, J., Rosiñol, L., Hernández, M.T., Teruel, A.I., Gironella, M., Oriol, A., de la Rubia, J., González-Rodríguez, A.P., Bargay, J., de Arriba, F., Palomera, L., González-Pérez, M.-S., Sureda, A., Ocio, E., Lahuerta, J.J., Bladé, J., San Miguel, J.F., Mateos, M.V. and Gutiérrez, N.C. (2024), High-risk cytogenetic abnormalities in multiple myeloma: PETHEMA-GEM experience. HemaSphere, 8: e70031. https://doi.org/10.1002/hem3.70031 December 10, 2024.
Overview
This study explored how genetic abnormalities and their combinations affect the prognosis of newly diagnosed multiple myeloma (MM) patients. Data from 1,304 patients across four clinical trials were analyzed, focusing on genetic changes like t(4;14), t(14;16), del(17p), +1q, and del(1p), identified using FISH on plasma cells. Frequencies included +1q (43%), t(4;14) (12%), del(17p) (8%), del(1p) (8%), and t(14;16) (3%). Over a median follow-up of 61 months, the median progression-free survival (PFS) was 44 months, while overall survival (OS) was not reached.
As expected, t(4;14) predicted shorter PFS and OS, while del(17p) was associated with a poor prognosis, particularly when 20% or more cells were affected, and outcomes were especially grim with clonal fractions above 80%. Interestingly, t(14;16) had no survival impact in this study, likely due to limited sample size. Gain(1q) shortened both PFS and OS, whereas del(1p) reduced PFS but not OS. However, when these abnormalities occurred alone (without co-segregation with other changes), their adverse effects were diminished. Co-occurring abnormalities worsened outcomes for t(4;14) but did not amplify the impact of del(17p), which remained a strong independent predictor of poor prognosis.
The findings confirm the importance of high-risk genetic changes like t(4;14), del(17p), and +1q in MM prognosis. They also emphasize the need to account for combinations of abnormalities when assessing patient risk and outcomes.
"NAD+ Metabolism Restriction Boosts High-Dose Melphalan Efficacy in Patients with Multiple Myeloma"
Source
Debora Soncini, Pamela Becherini, Francesco Ladisa, Silvia Ravera, Adithya Chedere, Elisa Gelli, Giulia Giorgetti, Claudia Martinuzzi, Francesco Piacente, Luca Mastracci, Claudia Veneziano, Gianluca Santamaria, Fiammetta Monacelli, Moustafa S Ghanem, Antonia Cagnetta, Fabio Guolo, Matteo Garibotto, Sara Aquino, Mario Passalacqua, Santina Bruzzone, Axel Bellotti, Michel A. Duchosal, Aimable A Nahimana, Emanuele Angelucci, Chandra Nagasuma, Alessio Nencioni, Roberto Massimo Lemoli, Michele Cea; NAD+ METABOLISM RESTRICTION BOOSTS HIGH-DOSE MELPHALAN EFFICACY IN PATIENTS WITH MULTIPLE MYELOMA. Blood Adv 2024; bloodadvances.2024013425. doi: https://doi.org/10.1182/bloodadvances.2024013425 December 11, 2024
Overview
Multiple myeloma (MM) cells often show elevated levels of the enzyme NAMPT, which is crucial for producing NAD+, a molecule essential for cell survival. While NAMPT inhibitors have shown promise in preclinical cancer models, they have been less effective in clinical trials due to alternative pathways for NAD+ production. This study identified the Preiss-Handler pathway, which uses nicotinic acid and its key enzyme NAPRT, as a backup NAD+ production route in MM cells, contributing to resistance against NAD+-depleting therapies.
By knocking out NAPRT in MM cells, researchers found weakened antioxidant defenses, greater sensitivity to oxidative stress, and increased genomic instability. Combining NAMPT inhibition with NAPRT knock-out further enhanced the cells’ vulnerability, making them more sensitive to the chemotherapy drug melphalan. Restoring NAPRT reversed these effects, confirming its critical role in supporting NAD+ production and cell survival in MM.
The findings suggest that targeting both NAMPT and NAPRT simultaneously could deplete NAD+ more effectively, weakening MM cells and improving treatment outcomes. This dual approach offers a promising strategy to test in clinical trials, particularly for transplant-eligible patients with aggressive disease.
"Analysis of smoldering multiple myeloma according to the target of the monoclonal immunoglobulin of patient"
Source
Hermouet, S., Mennesson, N., Allain-Maillet, S., Bigot-Corbel, E., Olafsson, A., Viðarsson, B., Önundarson, P.T., Agnarsson, B.A., Sigurðardóttir, M., Þorsteinsdóttir, I., Ólafsson, Í., Eyþórsson, E., Jónsson, Á., Love, T.J., Rognvaldsson, S., Björnsson, E.S., Thorsteinsdóttir, S. and Kristinsson, S.Y. (2024), Analysis of smoldering multiple myeloma according to the target of the monoclonal immunoglobulin of patients. HemaSphere, 8: e70053. https://doi.org/10.1002/hem3.70053 December 11, 2024.
Overview
This study investigated the potential triggers of smoldering multiple myeloma (SMM), a precursor to multiple myeloma.
Key Findings
Frequent Triggers:
Infections such as
- Epstein-Barr virus (EBV) was the most common trigger, found in 27% of cases.
- Cytomegalovirus (CMV) was another significant trigger, identified in 14% of cases.
- Low-Risk Associations: SMM linked to CMV or GlcSph (a lipid associated with Gaucher disease) appeared to have a lower risk of progression.
- McIg Target Identification: The study successfully identified the target of monoclonal immunoglobulins (mcIgs) in a significant number of SMM patients, primarily those with IgG SMM.
Implications:
Prognostic Marker: Identifying the target of mcIgs may help predict the risk of SMM progression.
Therapeutic Potential:
- Targeting the initial trigger (e.g., antiviral therapy for EBV/CMV) may offer potential therapeutic benefits for some SMM patients.
- Suppressing the antigen (like GlcSph in Gaucher disease) could potentially prevent disease progression.
Further Research:
- Expanding the panel of infectious pathogens tested to include region-specific pathogens.
- Larger studies to further validate these findings and explore the prognostic and therapeutic implications.
- In essence: This study provides valuable insights into the potential triggers of SMM and suggests that identifying the target of mcIgs could have significant implications for risk assessment and treatment strategies.
.
"Selective PET imaging of CXCR4 using the Al18F-labeled antagonist LY2510924"
Source
Spahn, M.A., Loy, T.V., Celen, S. et al. Selective PET imaging of CXCR4 using the Al18F-labeled antagonist LY2510924. Eur J Nucl Med Mol Imaging (2024). https://doi.org/10.1007/s00259-024-07025-w December 11, 2024.
Overview
This study developed a new CXCR4-targeted radiotracer, [18F]AlF-NOTA-SC, derived from LY2510924, to enable imaging of CXCR4 overexpression in malignancies like multiple myeloma and non-Hodgkin lymphoma. The radiotracer was designed with a triglutamate linker and NOTA chelator for fluorine-18 labeling, which offers logistical and physical advantages over existing radiotracers like [68Ga]PentixaFor.
Key Findings:
- In vitro: [18F]AlF-NOTA-SC showed similar affinity for human CXCR4 as [68Ga]PentixaFor.
- Radiochemistry: The radiotracer was synthesized with a yield of 21.0 ± 7.1% and molar activity of 16.4 ± 3.6 GBq/µmol.
- In vivo (mice): Significant CXCR4-specific uptake was observed in xenograft tumors, with higher uptake in CXCR4-expressing tumors compared to control tumors.
- Non-human primate: The radiotracer accumulated in CXCR4-expressing organs like the spleen and bone marrow, indicating suitable biodistribution for clinical imaging.
Conclusion:
[18F]AlF-NOTA-SC demonstrated effective CXCR4-targeting and tumor accumulation in both preclinical models and non-human primates, showing promise as an alternative to [68Ga]PentixaFor for clinical PET imaging.
"Treatment of elderly and frail myeloma patients"
Source
Steven Chun-Min Shih, Alissa Visram, Hira Mian, Treatment of elderly and frail myeloma patients, La Presse Médicale,2024, 104266, ISSN 0755-4982, https://doi.org/10.1016/j.lpm.2024.104266. December 12, 2024.
Overview
This review focuses on the treatment of elderly and frail adults with multiple myeloma (MM), a challenging and incurable cancer that primarily affects older adults. With the aging population, the prevalence of MM is expected to rise, posing specific challenges in treatment due to the heterogeneity of both aging and the disease itself.
Key points of the review:
Progress in Treatment: Over the past two decades, significant advances have been made in MM treatment for older adults, with the introduction of novel therapies such as immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies. These therapies have become integral in initial treatment regimens.
Future Developments: New immunotherapies, such as T-cell engagers and chimeric antigen receptor (CAR) therapies, are expected to improve outcomes further in the coming years.
Frailty Assessment: As more novel treatments become available, assessing patient frailty will be crucial to balance the benefits of aggressive therapies with the risks, ensuring optimal treatment for elderly and frail patients.
The review is divided into two parts:
- Initial Treatment Considerations: It covers investigations, treatment initiation strategies, and the importance of risk stratification, including frailty assessment before starting treatment.
- Treatment Options: It discusses the goals of treatment, therapeutic options for newly diagnosed and relapsed/refractory MM, with a focus on novel immunotherapies and supportive care.
The review concludes by identifying knowledge gaps in the field and suggesting future directions for improving treatment outcomes in older adults with MM.
"Neurotoxicity and Rare Adverse Events in BCMA-Directed CAR T Cell Therapy: A Comprehensive Analysis of Real-World FAERS Data. Transplantation and Cellular Therapy, Official Publication of the American Society for Transplantation and Cellular Therapy"
Source
Ellithi, Moataz et al. Neurotoxicity and Rare Adverse Events in BCMA-Directed CAR T Cell Therapy: A Comprehensive Analysis of Real-World FAERS Data. Transplantation and Cellular Therapy, Official Publication of the American Society for Transplantation and Cellular Therapy, Volume 0, Issue 0 December 11, 2024.
Overview
Highlights:
Neurotoxic Adverse Events: Both cilta-cel and ide-cel CAR-T therapies showed neurotoxic side effects, though with distinct manifestations:
Cilta-cel: Associated with cranial nerve palsies, parkinsonism, and polyneuropathies.
Ide-cel: Linked to confusion, disorientation, seizures, and tremors.
Safety Signals for Cilta-cel: Significant concerns were raised regarding cerebrovascular accidents, intracranial hemorrhage, and infections (Haemophilus and cytomegalovirus).
Safety Signals for Ide-cel: New safety signals included parkinsonism, sarcoidosis, ventricular arrhythmias, and cardiac arrest.
Ongoing Surveillance: The study highlights the need for continuous monitoring of long-term adverse effects in patients undergoing CAR-T therapy.
Abstract Summary:
This study aimed to identify safety signals associated with commercial anti-BCMA CAR T therapies, specifically cilta-cel and ide-cel, using the FDA Adverse Event Reporting System (FAERS). A total of 1,496 reports related to these therapies were analyzed, with a focus on immune-related conditions and neurological disorders.
Key findings:
- Neurotoxicity was a common adverse event, with cilta-cel showing cranial nerve issues and parkinsonism, and ide-cel associated with confusion, seizures, and balance problems.
- Cilta-cel also raised safety concerns for Guillain-Barré syndrome, intracranial hemorrhage, cerebrovascular accidents, and viral infections (Haemophilus, cytomegalovirus).
- Ide-cel showed new signals for parkinsonism, sarcoidosis, ventricular arrhythmias, and cardiac arrest.
The study underscores the importance of post-marketing surveillance to track and manage the potential long-term risks of these CAR-T therapies, ensuring patient safety.
"Red Cell Distribution Width at Diagnosis Reflects Advanced Disease While Dynamic Changes Predict Survival at Relapse in Multiple Myeloma: A Retrospective Study"
Source
Yigit Ayhan E, Pinar I E, Ozkocaman V, et al. (December 13, 2024) Red Cell Distribution Width at Diagnosis Reflects Advanced Disease While Dynamic Changes Predict Survival at Relapse in Multiple Myeloma: A Retrospective Study. Cureus 16(12): e75662. doi:10.7759/cureus.75662 December 13, 2024.
Overview
Red cell distribution width (RDW), a simple and low-cost parameter in blood tests, has emerged as a potential prognostic marker for MM. This study investigates the role of RDW in predicting patient outcomes, particularly in those undergoing autologous stem cell transplantation (ASCT).
RDW, a parameter in complete blood counts, has gained attention as a potential marker for MM prognosis, as it correlates with disease severity and outcomes. This study examines the prognostic value of RDW, particularly in the context of ASCT.
A retrospective study of 218 MM patients diagnosed between 2010 and 2018 was conducted. Data on RDW levels at diagnosis, ASCT, and first relapse were analyzed. Patients were divided into high (>16.5%) and low (≤16.5%) RDW groups. The study analyzed the impact of RDW levels and changes on progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier and log-rank tests
Results
- Higher RDW at diagnosis was linked to more advanced disease stages, especially R-ISS stage 3 (p=0.022).
- No significant survival differences were observed based on baseline RDW, but dynamic changes in RDW were prognostic.
- Patients with consistently low RDW had the best survival outcomes (PFS: 37 months, OS: 88.8 months), while those whose RDW increased from low to high had the poorest (PFS: 9 months, OS: 40.6 months).
- At relapse, low RDW was associated with better outcomes (PFS: 34 vs. 14 months, OS: 81.2 vs. 40.6 months; p<0.001).
- ASCT improved both PFS (p=0.028) and OS (p<0.001). Higher hemoglobin levels (>10 g/dL) also correlated with better PFS (p=0.038).
- Reassessing RDW before ASCT did not show significant changes, indicating that the dynamic nature of RDW, especially around relapse, is more important than its baseline value.
Conclusions
RDW at diagnosis correlates with advanced disease stages but is not an independent predictor of survival. However, changes in RDW from diagnosis to relapse are highly prognostic and can be a useful marker for monitoring disease progression and relapse risk. ASCT remains a crucial treatment, significantly improving survival outcomes. Standardizing RDW thresholds and integrating its dynamic changes into clinical practice could improve risk stratification and personalized treatment strategies. Further prospective, multi-center trials are needed to confirm these findings and solidify RDW's role in MM prognosis.
"Expression profile of Bcl-2 family proteins in newly diagnosed multiple myeloma patients"
Source
De Ramón, C., Rojas, E.A., Misiewicz-Krzeminska, I., Cardona-Benavides, I.J., Cuadrado, M., Isidro, I., Calasanz, M.-J., Fernandez, M., García-Sanz, R., Puig, N., Cedena, M.T., Paiva, B., Rosiñol, L., Martínez-López, J., Bladé, J., Lahuerta, J.J., San Miguel, J.F., Mateos, M.V., Corchete, L.A., Gutiérrez, N.C. and (2024), Expression profile of Bcl-2 family proteins in newly diagnosed multiple myeloma patients. HemaSphere, 8: e70036. https://doi.org/10.1002/hem3.70036 December 13, 2024.
Overview
This study quantifies the protein expression of Bcl-2 family members in 120 newly diagnosed multiple myeloma (MM) patients using a capillary electrophoresis immunoassay. The research explores the relationship between Bcl-2 protein expression and cytogenetic abnormalities, particularly the t(11;14) translocation, and its impact on patient prognosis and response to treatment.
Key Findings
- Heterogeneity in Expression: The expression patterns of Bcl-2 family proteins were highly variable among MM patients, with no clear overexpression of antiapoptotic proteins like Bcl-2, Bcl-xL, or Mcl-1.
- t(11;14) and Protein Expression: While patients with t(11;14) had higher Bcl-2/Bcl-xL and Bcl-2+Bim+Bax/Bcl-xL ratios, these ratios varied considerably within this group and were not exclusive to it. Some patients with other genetic alterations exhibited similarly high ratios, suggesting that t(11;14) is not a reliable biomarker for predicting response to venetoclax.
- Impact on Survival and Response: High levels of the proapoptotic proteins Bad and Puma were associated with significantly longer overall survival (OS). Conversely, high expression of certain antiapoptotic proteins, particularly Bcl-2-based ratios, was linked to poorer responses to conventional therapies and shorter time to progression (TTP) in patients treated with triplet induction therapy and autologous stem cell transplantation (ASCT).
- Venetoclax Sensitivity: Bcl-2 family protein ratios were predictive of venetoclax sensitivity. MM cell lines sensitive to venetoclax exhibited high Bcl-2 protein ratios, regardless of t(11;14) status. This suggests that Bcl-2 family protein ratios may be a better predictive biomarker for venetoclax response than t(11;14).
- Bim and Survival: High levels of Bim (especially its short isoform) were associated with shorter TTP, which could be due to its potent apoptotic effects. This highlights the complexity of Bcl-2 protein interactions and their varied impact on prognosis.
Conclusion
This study provides a comprehensive analysis of Bcl-2 family protein expression in MM patients, revealing that protein ratios—especially involving Bcl-2, Bcl-xL, Puma, and Bad—are important prognostic factors. These findings suggest that Bcl-2 protein ratios could help identify MM patients who might benefit from venetoclax treatment and those likely to have poor survival outcomes with conventional therapies. The study also challenges the idea of using t(11;14) as a sole biomarker for venetoclax efficacy, emphasizing the need for broader protein-based profiling in therapeutic decision-making.
"The function and mechanism of clinical trial agent CPI-613 in multiple myeloma"
Source
Haiqin Wang, Yibin Zhang, Yu Jiang, Ruohong Xiang, Han Gong, Yanfei Gong, Hao Xu, Zekang Ma, Yifang Xie, Yu Zhu, Bin Hu, Xiao He, Jing Liu, Ji Zhang, Xiaojuan Xiao, The function and mechanism of clinical trial agent CPI-613 in multiple myeloma, Biochemical Pharmacology, 2024, 116717, ISSN 0006-2952, https://doi.org/10.1016/j.bcp.2024.116717. December 14, 2024.
Overview
Multiple myeloma (MM) is an incurable hematological cancer characterized by clonal proliferation of plasma cells in the bone marrow. Despite advances in treatment with multi-drug combinations, MM remains prone to drug resistance and recurrence. This study investigates the potential of targeting key metabolic enzymes in MM, specifically oxoglutarate dehydrogenase (OGDH) and pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1), which were identified as clinically relevant through a comprehensive screen of the TCA cycle.
CPI-613, a novel non-redox-active lipoic acid analog that disrupts mitochondrial metabolism by targeting OGDH and PDHA1, was tested for its effects on MM. The study found that CPI-613 inhibited MM cell proliferation and, when combined with bortezomib (BTZ), enhanced the inhibitory effect at lower doses. CPI-613 disrupted several mitochondrial functions, including mitochondrial morphology, oxidative phosphorylation, ATP production, and increased reactive oxygen species (ROS), leading to cell death through the intrinsic apoptotic pathway.
In MM mouse xenograft models, CPI-613 significantly inhibited tumor growth and induced apoptosis. These results suggest that CPI-613 could be a promising new therapeutic option for MM, although further clinical trials are needed to evaluate its efficacy in patients.
"Radiomics and Artificial Intelligence Landscape for [18F]FDG PET/CT in Multiple Myeloma"
Source
Christos Sachpekidis, Hartmut Goldschmidt, Lars Edenbrandt, Antonia Dimitrakopoulou-Strauss, Radiomics and Artificial Intelligence Landscape for [18F]FDG PET/CT in Multiple Myeloma, Seminars in Nuclear Medicine, 2024, ISSN 0001-2998, https://doi.org/10.1053/j.semnuclmed.2024.11.005. December 13, 2024.
Overview
[18F]FDG PET/CT is a highly effective imaging technique for assessing treatment response in multiple myeloma (MM), but interpreting the images can be challenging due to the heterogeneous nature of bone marrow infiltration in MM. This complexity can lead to issues with interobserver reproducibility, limiting the diagnostic and prognostic value of PET/CT. Despite efforts to standardize interpretation methods, no universally accepted approach has been established yet.
To address this issue, advanced diagnostic quantification methods are needed. Radiomics, which involves extracting high-dimensional image features for clinical decision-making, has emerged as a promising solution in oncology. Additionally, machine learning and deep learning, subfields of artificial intelligence (AI), have been increasingly applied to automate image analysis, including PET/CT, CT, and MRI scans, providing new opportunities for standardized evaluations in cancer care.
Recent studies have explored the application of radiomics and AI-based methods in the analysis of [18F]FDG PET/CT scans in MM. Early results are promising, suggesting that these technologies could enhance the accuracy and consistency of PET/CT interpretation, ultimately improving the management and treatment of MM. This review summarizes the key findings from these studies, highlighting their potential to optimize and standardize imaging assessments in MM.
"Radiomics and Artificial Intelligence Landscape for [18F]FDG PET/CT in Multiple Myeloma"
Source
Christos Sachpekidis, Hartmut Goldschmidt, Lars Edenbrandt, Antonia Dimitrakopoulou-Strauss, Radiomics and Artificial Intelligence Landscape for [18F]FDG PET/CT in Multiple Myeloma, Seminars in Nuclear Medicine, 2024, ISSN 0001-2998, https://doi.org/10.1053/j.semnuclmed.2024.11.005. December 13, 2024.
Overview
[18F]FDG PET/CT is a highly effective imaging technique for assessing treatment response in multiple myeloma (MM), but interpreting the images can be challenging due to the heterogeneous nature of bone marrow infiltration in MM. This complexity can lead to issues with interobserver reproducibility, limiting the diagnostic and prognostic value of PET/CT. Despite efforts to standardize interpretation methods, no universally accepted approach has been established yet.
To address this issue, advanced diagnostic quantification methods are needed. Radiomics, which involves extracting high-dimensional image features for clinical decision-making, has emerged as a promising solution in oncology. Additionally, machine learning and deep learning, subfields of artificial intelligence (AI), have been increasingly applied to automate image analysis, including PET/CT, CT, and MRI scans, providing new opportunities for standardized evaluations in cancer care.
Recent studies have explored the application of radiomics and AI-based methods in the analysis of [18F]FDG PET/CT scans in MM. Early results are promising, suggesting that these technologies could enhance the accuracy and consistency of PET/CT interpretation, ultimately improving the management and treatment of MM. This review summarizes the key findings from these studies, highlighting their potential to optimize and standardize imaging assessments in MM.
"Retreatment of multiple myeloma with previously refractory drugs"
Source
Utkarsh Goel, Charalampos Charalampous, Prashant Kapoor, Moritz Binder, Francis K. Buadi, David Dingli, Angela Dispenzieri, Amie Fonder, Morie A. Gertz, Wilson I. Gonsalves, Suzanne R. Hayman, Miriam A. Hobbs, Yi L. Hwa, Taxiarchis Kourelis, Martha Q. Lacy, Nelson Leung, Yi Lin, Rahma M. Warsame, Robert A. Kyle, S. Vincent Rajkumar, Shaji K. Kumar; Retreatment of multiple myeloma with previously refractory drugs. Blood Adv 2024; 8 (24): 6321–6328. doi: https://doi.org/10.1182/bloodadvances.2024014723 December 24, 2024.
Overview
For patients with relapsed or refractory multiple myeloma (RRMM), retreating with a previously used drug may be an option, even if the disease was initially resistant. A recent retrospective study analyzed 315 RRMM patients who were retreated with such drugs. The findings showed a 56.2% overall response rate and a median progression-free survival (PFS) of 11 months.
Patients who had longer initial treatment with the drug (over 28.4 months) saw better outcomes, with a median PFS of 16.9 months compared to 8.1 months for those with shorter initial use. Similarly, a longer time gap between the initial treatment and retreatment (over 46.1 months) led to improved PFS (28.2 vs. 8.9 months).
These results suggest that retreatment can be a viable option, especially for patients who showed sensitivity to the drug during initial use or had a significant time gap before retreatment. This approach provides hope for those running out of options in advanced stages of the disease.
"Multi-Niche Human Bone Marrow On-A-Chip for Studying the Interactions of Adoptive CAR-T Cell Therapies with Multiple Myeloma"
Source
Delta Ghoshal, Ingrid Petersen, Rachel Ringquist, Liana Kramer, Eshant Bhatia, Thomas Hu, Ariane Richard, Reda Park, Jenna Corbin, Savi Agarwal, Abel Thomas, Sebastian Ramirez, Jacob Tharayil, Emma Downey, Frank Ketchum, Abigail Ochal, Neha Sonthi, Sagar Lonial, James N. Kochenderfer, Reginald Tran, Mandy Zhu, Wilbur A. Lam, Ahmet F. Coskun, Krishnendu Roy, Multi-Niche Human Bone Marrow On-A-Chip for Studying the Interactions of Adoptive CAR-T Cell Therapies with Multiple Myeloma, Biomaterials, 2024, 123016,ISSN 0142-9612, https://doi.org/10.1016/j.biomaterials.2024.123016. December 15, 2024.
Overview
This study developed a 3D model of human multiple myeloma (MM) on a bone marrow-on-a-chip (hMM-on-a-chip) platform to investigate MM's response to anti-cancer therapies, particularly therapeutic chimeric antigen receptor (CAR)-T cells. Key findings from the study include:
Model Development
The hMM-on-a-chip was designed to mimic the human bone marrow environment, preserving the bone marrow's endosteal and perivascular niches, which are critical for MM cell survival and proliferation. The model successfully supported both cell line-based and primary MM samples, and allowed for automated analysis using techniques like timelapse imaging, flow cytometry, and immunohistochemical staining.
Proliferation and Niche Importance
MM cells proliferated only when cultured with both the endosteal and perivascular niches, with the perivascular niche playing a dominant role. This was linked to the secretion of matrix metalloproteinases (MMPs) by MM-associated endothelial cells, which might contribute to MM cell spread and proliferation.
Vascular Network and Localization
Using fluorescently tagged lectins, the study observed that MM cells and stromal components localized primarily in the perivascular niche. A 3D analysis of various extracellular matrix (ECM) markers revealed distinct spatial patterns for markers like type I collagen, fibronectin, and osteopontin, which were predominantly endosteal, while others like HA and collagen IV were found in both niches.
CAR-T Cell Efficacy
CAR-T cells from healthy donors were shown to migrate to and kill MM cells in the model, with some cytokine release observed. The study noted that graft-versus-host (GVH) effects were not a concern for MM CAR-T therapies, but off-target responses were carefully monitored to ensure that T cells specifically targeted MM cells. Notably, off-target T cells activated cytokine responses, but did not affect the vascular network or MM growth significantly.
Cytokine Secretion and Cytotoxicity
The release of specific cytokines (TNF-α, IFN-γ, and sFasL) was linked to antigen recognition by CAR-T cells. Off-target T cells (not CAR-expressing) showed increased secretion of cytolytic molecules, suggesting a non-specific immune response against allogeneic BM-MNCs. Real-time imaging and flow cytometry confirmed that CAR-T cells specifically targeted BCMA-expressing MM cells.
Target Cell Killing and T Cell Memory
Primary patient-derived T cells from MM patients were successfully transduced and used to study MM cell killing. Despite challenges in quantifying target cell death due to low plasma cell populations, the study used distance filters to accurately measure T cell-target cell interactions. The presence of terminally differentiated effector memory T cells (TEMs) suggested that more immature T cell subsets might be more durable in vivo, supporting the idea that less differentiated T cells may provide longer-lasting therapeutic benefits.
Conclusion
The hMM-on-a-chip system proved to be a valuable tool for studying MM and CAR-T cell therapies, offering insights into tumor behavior, immune responses, and potential avenues for improving CAR-T cell efficacy. The findings also highlight the importance of T cell memory subsets in the durability of CAR-T therapies.
"Capillary leak phenotype as a major cause of death in patients with POEMS syndrome"
Source
Lee, K., Kourelis, T., Tschautscher, M. et al. Capillary leak phenotype as a major cause of death in patients with POEMS syndrome. Leukemia (2024). https://doi.org/10.1038/s41375-024-02489-z December 16, 2024.
Overview
This study investigates the causes of death (COD) in patients with POEMS syndrome (a rare paraneoplastic disorder characterized by polyneuropathy, organomegaly, endocrinopathies, monoclonal protein, and skin changes). The study involved 49 patients from the Mayo Clinic who died between 2000 and 2022, out of 89 total deaths among POEMS patients.
The findings revealed that 65% of deaths were related to POEMS syndrome or its treatments, while 35% were due to causes unrelated to POEMS. A notable cause of death in 39% of patients was a distinct clinical syndrome termed the capillary leak phenotype (CLP), characterized by persistent ascites, effusions, and anasarca leading to hypotension, renal failure, and cardiopulmonary arrest. CLP had a rapid progression, with a median survival of only 4 months after onset, much shorter than the median survival of 12 years for other causes of death. This phenotype was not well understood, and no single cause (e.g., heart failure, liver disease) explained it completely. Despite multiple treatments, including corticosteroids and chemotherapy, CLP remained refractory and often fatal.
The study also identified secondary malignancies (e.g., myelodysplastic syndrome, acute leukemia) as causes of death in a small number of patients, with complications from POEMS-directed therapy contributing to a smaller proportion of deaths. The findings highlight the need for further research into the pathophysiology and treatment of CLP in POEMS syndrome.
While the study’s small sample size and potential biases (such as overestimating CLP as a COD) limit its conclusions, it emphasizes the importance of recognizing and understanding CLP as a critical aspect of POEMS syndrome. Further studies are needed to explore its underlying mechanisms and optimal treatments.
"A real-world study on the impact of infection load on mortality in multiple myeloma patients in Finland"
Source
Anttalainen, A., Havula, E., Kysenius, K. et al. A real-world study on the impact of infection load on mortality in multiple myeloma patients in Finland. Ann Hematol (2024). https://doi.org/10.1007/s00277-024-06101-3 December 16, 2024.
Overview
This real-world evidence (RWE) study investigates the impact of infections on mortality in multiple myeloma (MM) patients in Finland between 1997 and 2021. The study found that infections are a major cause of morbidity and mortality in MM patients, with the highest infection load observed during the first year after diagnosis. Patients who underwent stem cell transplantation (ASCT) had a significantly higher infection burden during the first two years post-diagnosis compared to those who did not receive ASCT. Additionally, MM patients experienced more infections even before diagnosis, particularly patients under 70 years old, who had infections up to three years prior to diagnosis.
The study revealed a notable shift in the infection spectrum, with increased incidence of streptococcal septicaemia and pneumonia due to Streptococcus pneumoniae before diagnosis, and higher rates of cytomegaloviral disease, herpes zoster, and streptococcal septicemia following diagnosis. Even one recorded infection before diagnosis was associated with significantly reduced median overall survival (mOS) and an increased risk of mortality. The study also highlighted the complex relationship between infection risk, disease stage, and treatment, noting that treatments like ASCT and newer immunotherapies exacerbate immunosuppression and infection risk.
The study emphasizes the need for effective infection prevention strategies, such as vaccinations and antimicrobial prophylaxis, for MM patients. It also acknowledges limitations in the data, including incomplete registry information and potential biases due to changing diagnostic and coding practices. Despite these limitations, the study underscores the critical role of infections in the prognosis of MM patients and the importance of proactive infection management.
Conclusion
Infections, especially those occurring prior to MM diagnosis, significantly impact the survival and mortality of MM patients. Even a single infection before diagnosis can shorten overall survival, highlighting the importance of infection prevention and early management in this patient group.
"The inhibitory receptor PVRIG is dominantly expressed in the bone marrow of patients with multiple myeloma and its blockade enhances T-cell engager's immune activation"
Source
Masha Frenkel, Zoya Alteber, Ning Xu, Mingjie Li, Haiming Chen, Deborah Hayoun, Roy Granit, Gady Cojocaru, James Berenson, Eran Ophir, The inhibitory receptor PVRIG is dominantly expressed in the bone marrow of patients with multiple myeloma and its blockade enhances T-cell engager's immune activation, Experimental Hematology, 2024, 104696, ISSN 0301-472X, https://doi.org/10.1016/j.exphem.2024.104696. December 16, 2024.
Overview
This study investigates the potential of PVRIG blockade as a therapeutic strategy for multiple myeloma (MM), particularly in combination with bispecific T-cell engagers (BiTEs). Despite advances in MM treatment, including proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, and CAR T-cell therapies, MM remains incurable, with immune escape mechanisms, such as T-cell exhaustion, contributing to disease progression.
The DNAM-1 immune axis, which includes the inhibitory receptor PVRIG, plays a key role in regulating both innate and adaptive immunity. PVRIG competes with the co-stimulatory receptor DNAM-1 for binding to its shared ligand, PVRL2. In MM, CD8+ T-cells exhibit an exhausted phenotype, marked by high expression of immune checkpoints like PD-1, TIGIT, and PVRIG. While TIGIT blockade has shown promise in preclinical MM models, the role of PVRIG blockade is less understood.
In this study, the authors analyzed PVRIG expression in bone marrow (BM) samples from MM patients, both newly diagnosed and relapsed. They found that PVRIG is highly expressed in various T-cell populations, including NK and NKT cells. The study also demonstrated that PVRIG blockade, when combined with BiTEs, enhanced T-cell activation in the BM, suggesting a potential synergistic approach to improving anti-tumor immunity in MM patients. This combination approach could represent a novel therapeutic opportunity, potentially overcoming immune evasion mechanisms in MM.
Key Highlights
- PVRIG is highly expressed on T-cell populations in MM patients' BM, including NK and NKT cells.
- PVRIG blockade may improve clinical outcomes in MM patients, particularly when combined with BiTE therapy.
- This combination enhances T-cell activation in the bone marrow, offering a promising approach to address the immune evasion seen in MM.
The findings highlight PVRIG as a potential target for improving the effectiveness of MM immunotherapy, especially in combination with BiTEs, and warrant further investigation into its therapeutic potential.
"Targeted Delivery of c(RGDfk)-Modified Liposomes to Bone Marrow Through In Vivo Hitchhiking Neutrophils for Multiple Myeloma Therapy"
Source
H. Liu, B. Zhang, H. Chen, H. Wang, X. Qin, C. Sun, Z. Pang, Y. Hu, Targeted Delivery of c(RGDfk)-Modified Liposomes to Bone Marrow Through In Vivo Hitchhiking Neutrophils for Multiple Myeloma Therapy. Adv. Sci. 2024, 2409895. https://doi.org/10.1002/advs.202409895 December 16, 2024.
Overview
This study presents a novel bone marrow-targeting strategy for treating multiple myeloma (MM) using c(RGDfk)-functionalized liposomes loaded with chemotherapeutic agents. The approach leverages the aging process of neutrophils, which naturally migrate to the bone marrow, to enhance drug delivery with minimal off-target effects.
Key Findings
- c(RGDfk)-modified liposomes (RLPs) effectively hijack aging neutrophils, facilitating targeted delivery of therapeutic drugs to the bone marrow.
- Two drug-loaded liposomes were used:
- Carfilzomib-loaded liposomes (CRLPs): A proteasome inhibitor that transforms M2 macrophages into the M1 phenotype, boosting immunotherapeutic responses.
- BMS-202-loaded liposomes (BRLPs): A small-molecule PD-L1 inhibitor that disrupts the PD-1/PD-L1 axis, promoting cytotoxic T cell infiltration.
- Co-administration of CRLPs and BRLPs significantly reduced tumor growth and improved survival in MM-bearing mouse models.
- Mechanistic studies revealed decreased immune-suppressive cells (M2 macrophages, Tregs) and increased cytotoxic T cells (CTLs) and NK cells in the bone marrow, which helped modulate the myeloma microenvironment.
Conclusion
This neutrophil hijacking strategy provides a promising approach to targeting bone marrow for myeloma treatment. By modulating the immune microenvironment and delivering a combination of carfilzomib and BMS-202, this method improved therapeutic efficacy and reduced toxicity compared to traditional drug delivery methods. The study opens up new possibilities for bone marrow-specific drug delivery, improving the treatment of multiple myeloma, particularly in relapsed/refractory cases.
"Behandlung von nephrologischen und ossären Komplikationen beim multiplen Myelom (Treatment of nephrological and skeletal complications in multiple myeloma)"
Source
Kus, J., Niewald, M., de Bra, S. et al. Behandlung von nephrologischen und ossären Komplikationen beim multiplen Myelom (Treatment of nephrological and skeletal complications in multiple myeloma). Onkologie (2024). https://doi.org/10.1007/s00761-024-01656-2 December 17, 2024.
Overview
Kidney and bone complications are common in multiple myeloma (MM) and significantly affect patients’ health. Kidney damage in MM is often caused by toxic free light chains forming aggregates in the tubules, leading to acute or chronic kidney failure. Other conditions, like AL amyloidosis or monoclonal immunoglobulin deposition disease (MIDD), can also harm the kidneys. Treatment focuses on preserving kidney function, preventing dialysis, and using supportive measures like fluid replacement and avoiding nephrotoxic substances. High-cutoff hemodialysis can also aid alongside systemic anti-MM therapies.
Bone disease in MM results from an imbalance where increased osteoclast activity (bone breakdown) and suppressed osteoblast activity (bone formation) lead to bone loss, lytic lesions, and fractures. Advanced imaging, including whole-body CT, MRI, or PET/CT, is key for diagnosis. Treatments like bisphosphonates (e.g., zoledronate, pamidronate) and denosumab help reduce bone breakdown. However, precautions are needed to avoid rare side effects, such as kidney damage or jaw osteonecrosis. Pathological fractures may require surgery, while spinal cord compression is treated with decompression and radiation.
"Germline Predisposition in Multiple Myeloma"
Source
Fernanda Martins Rodrigues, Jagoda Jasielec, Melody Perpich, Aelin Kim, Luke Moma, Yize Li, Erik Storrs, Michael C. Wendl, Reyka G. Jayasinghe, Mark Fiala, Andrew Stefka, Benjamin Derman, Andrzej J. Jakubowiak, John F. DiPersio, Ravi Vij, Lucy A. Godley, Li Ding, Germline Predisposition in Multiple Myeloma, iScience, 2024,111620, ISSN 2589-0042, https://doi.org/10.1016/j.isci.2024.111620. December 17, 2024.
Overview
This study investigates rare germline predisposition variants in multiple myeloma (MM) by analyzing 954 unrelated individuals and 82 MM families. Using a candidate gene approach, rare variants were found in 9.1% of sporadic MM cases and 18% of familial MM cases. The implicated genes included both those previously associated with MM risk (e.g., DIS3, EP300, KDM1A, USP45) and genes linked to other cancers (e.g., ATM, BRCA1/2, TP53). Additionally, genes such as BRIP1, EP300, and FANCM were notable in individuals of African ancestry. The study identified 31 variants in 3.25% of sporadic MM cases, with multiple supporting lines of evidence for their pathogenicity, including loss of heterozygosity (LOH) and gene expression analysis. The findings suggest that disruptions in DNA damage repair pathways may contribute to MM susceptibility, offering insights into improved surveillance and potential therapeutic approaches for high-risk groups.
Highlights
- Rare risk variants were found in 9% of sporadic and 18% of familial MM cases.
- DNA analysis identified 31 variants in 3.25% of sporadic cases with supporting evidence for pathogenicity.
- Candidate variants were linked to genes associated with cancer risk and MM.
- Disruptions in DNA damage repair pathways may play a role in MM susceptibility.
"Hexamethylene amiloride induces lysosome-mediated cell death in multiple myeloma through transcription factor E3"
Source
Yang, N., Dong, Z., Xiao, W. et al. Hexamethylene amiloride induces lysosome-mediated cell death in multiple myeloma through transcription factor E3. Cell Death Discov. 10, 505 (2024). https://doi.org/10.1038/s41420-024-02269-9 December 18, 2024.
Overview
Multiple myeloma (MM) is a cancer of plasma cells that remains difficult to cure, despite recent advances in treatment. A new study explores a promising target for MM therapy—the proton exporter NHE1—and its potential inhibitor, hexamethylene amiloride (HA).
MM cells rely on NHE1 to maintain an ideal pH balance for survival. The study found that higher levels of NHE1 are linked to worse outcomes for MM patients. By blocking NHE1 with HA, researchers observed significant tumor-killing effects. HA reduced the growth of MM cells and triggered their death in lab tests and in a mouse model of the disease. Importantly, HA also worked against MM cells that had developed resistance to the drug carfilzomib and boosted the effectiveness of carfilzomib when used together.
These findings suggest that targeting NHE1 with HA could offer a new approach to treating MM, especially in patients with drug-resistant forms of the disease.
"Elranatamab monotherapy in the real-word setting in relapsed-refractory multiple myeloma: results of the French compassionate use program on behalf of the IFM"
Source
Malard, F., Bobin, A., Labopin, M. et al. Elranatamab monotherapy in the real-word setting in relapsed-refractory multiple myeloma: results of the French compassionate use program on behalf of the IFM. Blood Cancer J. 14, 219 (2024). https://doi.org/10.1038/s41408-024-01200-w December 18, 2024.
Overview
A recent real-world study from France shows that elranatamab, a bispecific antibody targeting BCMA on multiple myeloma (MM) cells, is effective and safe for patients with relapsed or refractory MM (RRMM). Among 101 patients treated through a compassionate use program, the overall response rate (ORR) was 51.5%, with 42% achieving a complete or very good partial response. Notably, 22% of patients responded after just one treatment cycle. The study included older and frail patients who would not have qualified for clinical trials, many of whom had already undergone multiple prior therapies, including BCMA-targeting treatments.
The treatment had a manageable safety profile. **Mild cytokine release syndrome (CRS)** occurred in 45% of patients, with no severe cases reported, and mild neurotoxicity (ICANS) occurred in only 3%. Infections were common, but severe infections occurred in 24% of patients Overall, this study confirms that elranatamab is a valuable new option for RRMM, particularly for patients with limited treatment options.
"The significance of free light-chain ratio in light-chain monoclonal gammopathy of undetermined significance: a flow cytometry sub-study of the iStopMM screening study"
Source
Óskarsson, J.Þ., Rögnvaldsson, S., Thorsteinsdottir, S. et al. The significance of free light-chain ratio in light-chain monoclonal gammopathy of undetermined significance: a flow cytometry sub-study of the iStopMM screening study. Blood Cancer J. 14, 221 (2024). https://doi.org/10.1038/s41408-024-01201-9 December 18, 2024.
Overview
Light-chain monoclonal gammopathy of undetermined significance (LC-MGUS) is a condition that can progress to multiple myeloma (MM) or related disorders. Researchers from the iStopMM study used next-generation flow cytometry (NGF) to detect abnormal plasma cells in bone marrow samples from people with LC-MGUS, aiming to better predict who may be at risk of progression to more serious diseases.
The study found that 53.6% of LC-MGUS patients had clonal plasma cells in their bone marrow, and the presence of these cells was strongly linked to high kappa-free light-chain (FLC) ratios. Patients with a kappa FLC ratio above 3.15 had a significantly higher risk of progression to MM, with 5.6% developing MM over a median of 55 months. In contrast, none of the patients with FLC ratios between 1.65 and 3.15 progressed. These findings suggest that using an FLC ratio cutoff of greater than 3.15 could help doctors identify patients with LC-MGUS who are more likely to develop symptomatic plasma cell disorders.
"Cytotoxic Effects of the Combination of Pam3CSK4 with Carfilzomib, Ixazomib, and Venetoclax in Human Multiple Myeloma Cells"
Source
Avci, K., Erdoğan, M.Ö., Yildiz, S.H. et al. Cytotoxic Effects of the Combination of Pam3CSK4 with Carfilzomib, Ixazomib, and Venetoclax in Human Multiple Myeloma Cells. Mol Biol 58, 1268–1279 (2024). https://doi.org/10.1134/S0026893324060037 December 18, 2024.
Overview
Proteasome inhibitors (PIs) are an important part of treating multiple myeloma (MM), a cancer of plasma cells. Researchers are exploring ways to make these treatments more effective by targeting toll-like receptors (TLRs)and combining PIs with other drugs. This study focused on using Pam3CSK4, a TLR1/2 activator, alongside PIs like carfilzomib (CFZ) and ixazomib (IXS) and the anti-apoptotic drug venetoclax (VNT) to enhance cancer cell death.
The researchers found that combining PIs with VNT in the presence of the TLR activator made MM cells more sensitive to treatment. The combination of XS + VNT was particularly effective, as it increased tBid protein, which helps trigger cell death through both major apoptotic pathways. These results suggest that targeting TLRs and combining PIs with anti-apoptotic drugs could improve MM therapy and pave the way for new treatment strategies.
"Molecular insights unlocking therapeutic potential for multiple myeloma and bone disease management"
Source
Bruno, T., Catena, V., Blandino, G. et al. Molecular insights unlocking therapeutic potential for multiple myeloma and bone disease management. J Exp Clin Cancer Res 43, 322 (2024). https://doi.org/10.1186/s13046-024-03248-9 December 18, 2024.
Overview
Multiple myeloma (MM) is a blood cancer that causes plasma cells to multiply uncontrollably in the bone marrow, often leading to osteolytic bone lesions—damaged areas of bone that increase the risk of fractures and worsen patient outcomes. Researchers are exploring the role of specific proteins and pathways involved in MM progression and bone damage. One protein of interest is Che-1/AATF, which helps MM cells survive and grow.
Recent research highlights a connection between Che-1 and the Hippo pathway, a key regulator of tumor growth. The Hippo pathway influences how the bone environment responds to cancer and plays a role in causing bone lesions by disrupting the normal function of bone-building cells. Specifically, the interaction between Che-1 and TAZ, a Hippo pathway protein, offers new insights into how MM cells damage bone. These findings point to potential new targets for therapies aimed at reducing bone lesions in MM patients.
"The impact of high-risk cytogenetic abnormalities in extramedullary multiple myeloma in the era of novel agents: insights from a multicenter study"
Source
Liang, D., Yan, Y., Bai, S. et al. The impact of high-risk cytogenetic abnormalities in extramedullary multiple myeloma in the era of novel agents: insights from a multicenter study. BMC Cancer 24, 1551 (2024). https://doi.org/10.1186/s12885-024-13309-z December 18, 2024.
Overview
This study explored how high-risk genetic changes (HRA) affect survival in multiple myeloma patients with extramedullary disease (EMD). Researchers analyzed 371 patients in China, including those with extramedullary extraosseous (EME) tumors and bone-related extramedullary (EMB) disease.
Patients with one or more HRA had worse overall survival (OS) and progression-free survival (PFS) compared to those without HRA. Specifically, a genetic abnormality known as 1q21 gain/amplification (1q21+) predicted poor outcomes. Standard treatments, like CD38 monoclonal antibodies and single transplants, were less effective in patients with two or more HRAs.
The study found that factors such as high LDH and creatinine levels, EME, and multiple HRAs were linked to worse survival. These findings suggest that the number of HRAs can help predict patient outcomes and guide treatment strategies for those with EMD.
"The impact of high-risk cytogenetic abnormalities in extramedullary multiple myeloma in the era of novel agents: insights from a multicenter study"
Source
Liang, D., Yan, Y., Bai, S. et al. The impact of high-risk cytogenetic abnormalities in extramedullary multiple myeloma in the era of novel agents: insights from a multicenter study. BMC Cancer 24, 1551 (2024). https://doi.org/10.1186/s12885-024-13309-z December 18, 2024.
Overview
This study explored how high-risk genetic changes (HRA) affect survival in multiple myeloma patients with extramedullary disease (EMD). Researchers analyzed 371 patients in China, including those with extramedullary extraosseous (EME) tumors and bone-related extramedullary (EMB) disease.
Patients with one or more HRA had worse overall survival (OS) and progression-free survival (PFS) compared to those without HRA. Specifically, a genetic abnormality known as 1q21 gain/amplification (1q21+) predicted poor outcomes. Standard treatments, like CD38 monoclonal antibodies and single transplants, were less effective in patients with two or more HRAs.
The study found that factors such as high LDH and creatinine levels, EME, and multiple HRAs were linked to worse survival. These findings suggest that the number of HRAs can help predict patient outcomes and guide treatment strategies for those with EMD.
"Bortezomib-releasing silica-collagen xerogels for local treatment of osteolytic bone- and minimal residual disease in multiple myeloma"
Source
Hose, D., Ray, S., Rößler, S. et al. Bortezomib-releasing silica-collagen xerogels for local treatment of osteolytic bone- and minimal residual disease in multiple myeloma. J Hematol Oncol 17, 128 (2024). https://doi.org/10.1186/s13045-024-01636-4 December 18, 2024.
Overview
This study looks at new treatments for bone damage caused by multiple myeloma, a type of cancer where abnormal plasma cells damage the bone. These damaged bones often fracture and are difficult to treat with surgery. The researchers created two materials, sicXer and boXer, which are gels made from silica and collagen. The boXer gel also releases a cancer-fighting drug called bortezomib. These gels were tested to see if they could help heal the bone damage, reduce cancer cell growth, and make the treatment more effective.
The results showed that both gels helped bone healing by reducing harmful bone cell activity and encouraging healthy bone cells to work. They also helped fight cancer by killing myeloma cells in lab tests and in animal models. In the rats and mice, the gels improved bone healing and controlled cancer growth in bone defects.
The study suggests that these gels could be tested in humans as a new treatment that combines bone healing and cancer treatment for multiple myeloma.
This study explored how high-risk genetic changes (HRA) affect survival in multiple myeloma patients with extramedullary disease (EMD). Researchers analyzed 371 patients in China, including those with extramedullary extraosseous (EME) tumors and bone-related extramedullary (EMB) disease.
Patients with one or more HRA had worse overall survival (OS) and progression-free survival (PFS) compared to those without HRA. Specifically, a genetic abnormality known as 1q21 gain/amplification (1q21+) predicted poor outcomes. Standard treatments, like CD38 monoclonal antibodies and single transplants, were less effective in patients with two or more HRAs.
The study found that factors such as high LDH and creatinine levels, EME, and multiple HRAs were linked to worse survival. These findings suggest that the number of HRAs can help predict patient outcomes and guide treatment strategies for those with EMD.
"Retrospective Claims Data Analysis of ASCT Characteristics and Costs for Working-Age Multiple Myeloma Patients in the US, 2017-2019"
Source
Whanhui Chi, Juhyeon Song, Tyler J. Varisco, Retrospective Claims Data Analysis of ASCT Characteristics and Costs for Working-Age Multiple Myeloma Patients in the US, 2017-2019, Leukemia Research Reports,2024,100496, ISSN 2213-0489, https://doi.org/10.1016/j.lrr.2024.100496. December 18, 2024.
Overview
Multiple myeloma (MM) has a 5-year survival rate of 52%. For patients who are eligible for a stem cell transplant (ASCT), high-dose chemotherapy followed by the transplant is often recommended. This study looked at factors affecting the ASCT process and its costs in MM patients aged 18-65. Using data from the Merative™ MarketScan® database from 2017 to 2019, the study analyzed 643 patients who received ASCT. It examined patient characteristics like age, sex, and health status, as well as ASCT-related costs and hospital stays.
The study found that over 80% of patients were over 50 years old, suggesting the need for age-specific treatment strategies. Most had moderate health conditions, with an average comorbidity score of 2-4. Patients stayed in the hospital for an average of 21.7 days, and the total cost of ASCT was around $166,236. The study also found a small link between longer hospital stays and higher costs. These results highlight the importance of personalized care and resource management for ASCT, helping guide future treatment decisions.
"Expert consensus on a multidisciplinary approach for the management of multiple myeloma-related bone disease"
Source
Yutong Wang, Qiming Xu, Yuan Li, Yongbin Su, Ling Wang, Xiaoquan Wang, Jian Ge, Hongmei Jing, Yuxing Guo, Yalin Chen, Xianan Li, Jun-ling Zhuang, Jing Tan, Xiaobo Wang, Liye Zhong, Jun Luo, Peng Zhao, Shengjin Fan, Jinhai Ren, Haiping Yang, Heng Mei, Chunyan Sun, Chunrui Li, Xuemei Sun, Xuechun Lu, Guangxun Gao, Zeping Zhou, Yaozhu Pan, Ying Sun, Zhang Hong, Zhiqiang Liu, Yanping Ma, Yi Wang, Wei Sun, Jian Hou, Jianqing Mi, Wenming Chen, Xiaobing Huang, Bingzong Li, Rong Fu, Jumei Shi, Xuehong Ran, Fuling Zhou, Aili He, Min Mao, Zhen Cai, Nan Li, Meng Xu, Xiaojing Yan, Wei Yang, Gang An, Lihua Gong, Lichao Sun, Zhihong Li, Tang Li, Yanjuan He, Junqiang Yin, Yao Liu, Weifeng Liu, Li Bao, Expert consensus on a multidisciplinary approach for the management of multiple myeloma-related bone disease, Cancer Pathogenesis and Therapy, 2024, ISSN 2949-7132, https://doi.org/10.1016/j.cpt.2024.12.002. December 18, 2024.
Overview
Multiple myeloma-related bone diseases (MBDs) are common and serious complications of multiple myeloma, causing pain, fractures, and other bone problems that significantly affect patients’ quality of life. A new set of guidelines emphasizes the need for a team-based approach involving specialists like hematologists, radiologists, and orthopedic doctors to manage these issues effectively. The guidelines focus on early detection and ongoing monitoring using imaging tools like PET-CT and MRI. Treatment includes anti-myeloma medications, bisphosphonates, and denosumab to protect bones and reduce the risk of bone-related complications. For more serious issues, surgery and radiation therapy may be needed. In addition to these treatments, pain management, rehabilitation, good nutrition, and dental care are essential to improving patient outcomes. The goal is to provide a coordinated, evidence-based approach to care that addresses all aspects of MBD and helps patients maintain their quality of life.
"Heme promotes venetoclax resistance in multiple myeloma through MEK-ERK signaling and purine biosynthesis"
Source
Remya Nair, An Vu, Abigail K Freer, Karanpreet S Bhatia, Dongxue Wang, Milan R Savani, Shannon M Matulis, Sagar Lonial, David L Jaye, Lawrence H Boise, Seung-Yong Seo, Timothy William Corson, Ajay K. Nooka, Shruti Bhatt, Samuel K McBrayer, Vikas A Gupta, Xin Hu, Benjamin G Barwick, Amit R Reddi, Mala Shanmugam; Heme promotes venetoclax resistance in multiple myeloma through MEK-ERK signaling and purine biosynthesis. Blood 2024; blood.2024025690. doi: https://doi.org/10.1182/blood.2024025690 December 18, 2024.
Overview
This study looks at how heme, a crucial molecule in energy production, affects the sensitivity of multiple myeloma (MM) to venetoclax (Ven), a drug used to treat MM. The research found that MM cells sensitive to Ven (VS MM) have lower levels of heme production but higher levels of oxidized heme (hemin). When heme or a similar compound is added to these cells, they become resistant to Ven. The study also showed that targeting a specific enzyme involved in heme production can make MM cells more sensitive to Ven. The mechanism behind this resistance involves heme activating certain survival pathways in the cell, leading to increased production of purines, which are necessary for DNA and RNA. The study also suggests that higher levels of heme and purine production are linked to worse patient outcomes. These findings reveal how heme metabolism can impact treatment responses in MM and could guide future therapies targeting both heme production and Ven resistance.
"Cumulative Deficits Frailty Index and Relationship Status Predict Survival in Multiple Myeloma"
Source
Nadine Abdallah, Paul Dizona, Amanika Kumar, Betsy LaPlant, Terri Menser, Gavin Schaeferle, Sarah Aug, Megan Weivoda, Angela Dispenzieri, Francis K Buadi, Rahma Warsame, Joselle Cook, Martha Q Lacy, Suzanne R Hayman, Morie A Gertz, S. Vincent Rajkumar, Shaji K Kumar; Cumulative Deficits Frailty Index and Relationship Status Predict Survival in Multiple Myeloma. Blood Adv 2024; bloodadvances.2024014624. doi: https://doi.org/10.1182/bloodadvances.2024014624 December 18, 2024.
Overview
This study looks at how frailty and social factors impact the health and survival of patients with multiple myeloma (MM). The researchers used a "frailty index" (FI) to measure frailty, based on patient-reported data about daily activities and health conditions. The study included 515 newly diagnosed MM patients from the Mayo Clinic between 2005 and 2018. They found that 39% of patients were frail, and frail patients had worse health outcomes, including higher disease stages, fewer chances for early stem cell transplants, and lower survival rates. Frail patients also reported more fatigue, pain, and lower quality of life. Social factors, like being unmarried or lacking a partner, were linked to worse outcomes, while socioeconomic status did not have an independent effect. The study also showed that frailty can change over time, with about 25% of patients becoming more frail within a year, and fewer than 10% improving. The results suggest that frailty should be monitored throughout treatment, and social support should be considered when making treatment decisions.
"Impact of soluble BCMA and non–T-cell factors on refractoriness to BCMA-targeting T-cell engagers in multiple myeloma"
Source
Holly Lee, Michael Durante, Sheri Skerget, Deeksha Vishwamitra, Sacha Benaoudia, Sungwoo Ahn, Mansour Poorebrahim, Elie Barakat, David Jung, Noémie Leblay, Bachisio Ziccheddu, Benjamin 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; 144 (25): 2637–2651. doi: https://doi.org/10.1182/blood.2024026212 December 19, 2024.
Overview
Adoptive T-cell therapy is a promising treatment for multiple myeloma (MM), but its success depends on understanding key factors that predict how patients will respond. One important target for treatment is a protein called B-cell maturation antigen (BCMA). MM cells can shed a form of BCMA into the blood, known as soluble BCMA (sBCMA), which may affect treatment outcomes. This study shows that high levels of sBCMA can predict resistance to anti-BCMA therapies. Along with sBCMA, factors like tumor size and the amount of BCMA on the surface of the cancer cells also play a role in how well the treatment works.
The study further confirmed that patients with high baseline sBCMA levels (greater than 400 ng/mL) were less likely to respond to the anti-BCMA treatment, teclistamab. However, increasing the dose of the treatment or using therapies targeting different proteins, like GPRC5D, can help overcome the challenges posed by high sBCMA levels. These findings suggest that doctors should consider sBCMA levels, disease size, and treatment intensity when planning anti-BCMA therapy to improve outcomes.
"BCMA bispecifics: breaking the chains of resistance"
Source
Johannes M. Waldschmidt, Leo Rasche; BCMA bispecifics: breaking the chains of resistance. Blood 2024; 144 (25): 2566–2568. doi: https://doi.org/10.1182/blood.2024026932 December 19, 2024.
Overview
In this commentary, researchers examine why some multiple myeloma patients don't respond to BCMA×CD3 bispecific antibodies, a promising treatment. While these antibodies work well for many, up to 40% of patients develop primary resistance. The study focuses on soluble BCMA (sBCMA), a protein that can interfere with the therapy's effectiveness. High sBCMA levels were found to reduce the treatment's ability to bind to cancer cells, leading to poor responses. However, a new bispecific antibody, alnuctamab, showed better performance against high sBCMA levels, though its development was halted. The study also highlights the importance of the effector-to-target (E:T) ratio, where a higher ratio of immune cells to tumor cells improves treatment outcomes, even with high sBCMA. Other approaches, such as combining bispecifics with a drug that lowers sBCMA, are being tested to improve results. Overall, this research provides new insights into overcoming resistance to bispecific antibody therapies and suggests strategies to make these treatments more effective for all patients.
"Approaching Hypercalcemia in Monoclonal Gammopathy of Undetermined Significance: Insights from the iStopMM study"
Source
Ástrún Helga Jónsdóttir, Helga Ágústa Sigurjónsdóttir, Sigrun Thorsteinsdottir, Thorir Einarsson Long, Ingigerður Sólveig Sverrisdóttir, Elias Eythorsson, Jon Thorir Oskarsson, Runólfur Pálsson, Olafur Skuli Indridason, Bryjnar Vidarsson, Pall T Onundarson, Isleifur Olafsson, Ingunn Þorsteinsdóttir, Bjarni A Agnarsson, Margret Sigurdardottir, Asbjorn Jonsson, Malin L. Hultcrantz, Brian G.M. Durie, Stephen Harding, Carl Ola Landgren, Thorvardur Jon Love, Sigurdur Yngvi Kristinsson, Sæmundur Rögnvaldsson; Approaching Hypercalcemia in Monoclonal Gammopathy of Undetermined Significance: Insights from the iStopMM study. Blood 2024; blood.2024025624. doi: https://doi.org/10.1182/blood.2024025624 December 19, 2024.
Overview
Hypercalcemia in monoclonal gammopathy of undetermined significance (MGUS) presents a clinical challenge since it may indicate progression to multiple myeloma (MM) but could also be due to a multitude of unrelated disorders. To inform the approach to this clinical challenge, we conducted a nested cohort study within the iStopMM screening study. Of the 75,422 Icelanders aged 40 years and above who underwent screening for MGUS, we included 2,546 with MGUS who were in active follow-up, including regular serum calcium measurements. In total, 191 individuals (7.5%) had hypercalcemia detected at least once, of whom 93 had persistent hypercalcemia (48.7%). MM was found in 3 participants with persistent hypercalcemia (3.2%); all had concurrent bone disease and other end-organ damage. The most common causes of hypercalcemia were primary hyperparathyroidism (56.0%) and malignancies other than MM (16.0%). In this first comprehensive study on hypercalcemia in MGUS, we observed that hypercalcemia rarely indicated MGUS progression and never in the absence of other symptoms of MM. More than half of hypercalcemia cases were transient and the underlying causes were similar to those in the general population. We conclude that hypercalcemia in MGUS should be approached in the same way as in those without MGUS.
"Global disparities in drug-related adverse events of patients with multiple myeloma: a pharmacovigilance study"
Source
Jaberi-Douraki, M., Xu, X., Dima, D. et al. Global disparities in drug-related adverse events of patients with multiple myeloma: a pharmacovigilance study. Blood Cancer J. 14, 223 (2024). https://doi.org/10.1038/s41408-024-01206-4 December 20, 2024.
Overview
Multiple myeloma (MM) affects racial and ethnic groups differently, with disparities in diagnosis, treatment, and outcomes influenced by factors such as genetics, socioeconomic status, and access to care. This study analyzed global treatment-related side effects (adverse events, or AEs) in MM patients using the openFDA database, focusing on six regions: North America (NA), Europe (EU), Asia (AS), Africa (AF), Oceania (OC), and Latin America & the Caribbean (LA).
Key findings revealed that men reported more AEs than women across all regions. Heart-related side effects were more common in Asia and Europe, while secondary cancers were frequently reported in Europe. Kidney issues were seen in Oceania, Africa (in men), and Asia (in women), and blood clots were more prevalent in North America, especially in men. Survival rates have improved in North America, Europe, and Asia, with a decline in MM-related deaths. However, hospitalization rates varied, with more fluctuations observed in Africa, Oceania, and Latin America.
This analysis highlights global differences in treatment outcomes for MM patients and underscores the need to address healthcare disparities to improve care for all patients.
"Association of p16(INK4a), a biomarker of cellular senescence, with receipt of therapy and frailty status among adults with plasma cell disorders"
Source
Christopher E. Jensen, Allison M. Deal, Shweta Srikanth, Kirsten A. Nyrop, Natalia Mitin, Matthew R. LeBlanc, Hyman B. Muss, Samuel M. Rubinstein, Sascha A. Tuchman, Eben I. Lichtman, Association of p16(INK4a), a biomarker of cellular senescence, with receipt of therapy and frailty status among adults with plasma cell disorders, Journal of Geriatric Oncology, 2024, 102174, ISSN 1879-4068, https://doi.org/10.1016/j.jgo.2024.102174. December 20, 2024.
Overview
Multiple myeloma (MM) is more common in older adults, who often have other health issues that complicate treatment decisions. Researchers are exploring biomarkers of aging to better understand how age impacts patients with MM. One potential biomarker is p16INK4a (p16), a gene linked to cellular aging and reduced tissue repair. Higher p16 levels may indicate increased frailty and could contribute to problems like inflammation and cognitive decline. Previous studies found that p16 levels rise with age and after autologous stem cell transplantation (ASCT), but little is known about how non-ASCT treatments affect this biomarker.
In this study, researchers analyzed data from 97 patients with plasma cell disorders to see if non-ASCT treatments impacted p16 levels. They found that patients who received more intensive and longer treatments had higher p16 levels, suggesting that certain therapies may accelerate cellular aging. The strongest link between p16 and aging was seen in patients who had undergone ASCT, supporting earlier findings. However, this was an observational study, meaning more research is needed to confirm these results. Understanding how p16 levels change during treatment could help doctors better assess frailty and personalize care for older adults with MM.
"Effect of adipose tissue on the development of multiple myeloma"
Source
Stanisławowski, M. Effect of adipose tissue on the development of multiple myeloma. Mol Biol Rep 52, 74 (2025). https://doi.org/10.1007/s11033-024-10174-8 December 21, 2024.
Overview
Multiple myeloma (MM) causes abnormal plasma cells to grow uncontrollably and damage bone tissue. Research shows that bone marrow adipose tissue (BMAT) — fat stored in the bone marrow — plays a role in how MM develops, spreads, and becomes resistant to treatment. BMAT makes up about 10% of body fat and affects myeloma cells through various paracrine, hormonal, and metabolic pathways.
Obesity can increase BMAT, which disrupts bone metabolism and reduces bone density, potentially contributing to the progression from monoclonal gammopathy of undetermined significance (MGUS) — a precursor condition — to full-blown MM. Factors like impaired fatty acid metabolism, adipokines that promote myeloma growth, and cancer-promoting microRNAs may drive this progression. A review of existing research highlights the connection between excess fat tissue and a higher risk of developing MM, offering insights into how obesity might impact the disease.
"Novel insights into the circ_0003489/let-7b-5p/GLUT1 axis and its possible role in multiple myeloma"
Source
Xiaoyan Wang, Qinqin Yang, Yuedi Wu, Novel insights into the circ_0003489/let-7b-5p/GLUT1 axis and its possible role in multiple myeloma, Transplant Immunology, 2024,102165, ISSN 0966-3274, https://doi.org/10.1016/j.trim.2024.102165. December 21, 2024.
Overview
Recent research highlights the role of circular RNA hsa_circ_0003489 (circ_0003489) in promoting multiple myeloma (MM) progression and resistance to the drug bortezomib (BTZ), a common treatment for MM. High levels of circ_0003489 were found in the bone marrow of MM patients. Lab studies showed that reducing circ_0003489 slowed cancer cell growth, reduced BTZ resistance, and increased cancer cell death.
The study found that circ_0003489 interacts with let-7b-5p microRNA, a molecule that helps regulate gene expression. By blocking circ_0003489, let-7b-5p levels increased, which reduced the activity of GLUT1, a glucose transporter that fuels cancer cell metabolism. Lower GLUT1 levels slowed MM cell growth and made the cells more sensitive to BTZ. However, when GLUT1 levels were restored, cancer cells regained their drug resistance.
These findings suggest that targeting circ_0003489 RNA could be a promising strategy to overcome bortezomib resistance in MM patients, potentially improving treatment outcomes.
"Comparison of thrombopoietin receptor agonists plus recombinant human thrombopoietin vs. recombinant human thrombopoietin alone for hematopoietic reconstruction in multiple myeloma patients undergoing autologous hematopoietic stem cell transplantation"
Source
Fangxia Wang, Xuezhu Xu, Ruoyu Yang, Yachun Jia, Gongzhizi Gao, Tianyu Huang, Aili He, Comparison of thrombopoietin receptor agonists plus recombinant human thrombopoietin vs. recombinant human thrombopoietin alone for hematopoietic reconstruction in multiple myeloma patients undergoing autologous hematopoietic stem cell transplantation, Transplantation and Cellular Therapy, 2024, ISSN 2666-6367, https://doi.org/10.1016/j.jtct.2024.12.015. December 21, 2024.
Overview
A new study suggests that combining hetrombopag, a thrombopoietin receptor agonist (TPO-RA), with recombinant human thrombopoietin (rhTPO) may help multiple myeloma (MM) patients recover platelets faster after autologous stem cell transplant (ASCT). Platelets are essential for blood clotting, and low levels after ASCT can increase the risk of bleeding.
The study compared two groups of newly diagnosed MM patients: one received rhTPO with hetrombopag, and the other received rhTPO alone. Patients in the combination group recovered platelets in a median of 9 days, faster than the control group. They also required fewer platelet transfusions. Both groups had similar survival rates, and no major side effects or blood clots were reported.
While more research is needed, the findings suggest that using hetrombopag with rhTPO could be a safe way to improve blood cell recovery after stem cell transplants without adding extra costs or risks.
"Impact of liquid–liquid phase separation- and immune-related gene signatures on multiple myeloma prognosis: focus on DDX21 and EZH"
Source
Wang, F., & Shen, C. (2024). Impact of liquid–liquid phase separation- and immune-related gene signatures on multiple myeloma prognosis: focus on DDX21 and EZH2. Hematology, 30(1). https://doi.org/10.1080/16078454.2024.2445403 December 23, 2024.
Overview
A recent study has identified two key genes, EZH2 and DDX21, that could help predict prognosis in multiple myeloma (MM) and guide future personalized treatments. These genes are linked to a process called liquid–liquid phase separation (LLPS), which may influence MM progression and drug resistance.
Using public genetic data, researchers analyzed 103 LLPS-related genes and grouped MM patients into three subtypes based on survival outcomes and immune characteristics. Patients with Subtype 2 had a worse prognosis and higher risk scores. In lab tests, silencing the DDX21 gene in MM cells significantly reduced cell growth, migration, and invasion, suggesting it plays a role in tumor progression.
The study highlights EZH2 and DDX21 as potential biomarkers for predicting MM patient survival. These findings could pave the way for personalized treatments that target these genes to improve outcomes for high-risk patients.
"Integration of clinical outcomes and molecular features in extramedullary disease in multiple myeloma"
Source
Nakamoto-Matsubara, R., Nardi, V., Horick, N. et al. Integration of clinical outcomes and molecular features in extramedullary disease in multiple myeloma. Blood Cancer J. 14, 224 (2024). https://doi.org/10.1038/s41408-024-01190-9 December 23, 2024.
Overview
One of the biggest challenges in the treatment of multiple myeloma (MM) is when the disease spreads outside the bone marrow to other organs, a condition known as extramedullary disease (EMD). Researchers studied the molecular profiles of 528 MM patients to understand the factors behind EMD and how it impacts patient outcomes. They found that mutations in the RAS and BRAF genes are critical for the development of EMD, while high-risk genetic changes like 1q duplication and 17p deletion were commonly associated with poor outcomes due to EMD.
Additionally, the TP53 mutation, known to signal poor prognosis, still had a negative impact on patients with EMD. Interestingly, the types of TP53 mutations were different in patients with and without EMD, with gain-of-function mutations more common in those with EMD. These findings suggest that EMD in MM is driven by specific genetic abnormalities, providing important insights into potential therapeutic targets for future treatments aimed at improving patient outcomes.
"5-Hydroxymethylcytosine Profiles of cfDNA in Urine as Diagnostic, Differential Diagnosis and Prognostic Markers for Multiple Myeloma"
Source
Xie, W., Li, X., Chen, H., Chu, J., Zhang, L., Tang, B., Huang, W., Li, L., Lin, J. and Dong, Y. (2024), 5-Hydroxymethylcytosine Profiles of cfDNA in Urine as Diagnostic, Differential Diagnosis and Prognostic Markers for Multiple Myeloma. Cancer Med, 13: e70477. https://doi.org/10.1002/cam4.70477 December 23, 2024.
Overview
A non-invasive urine-based test for diagnosing and monitoring multiple myeloma (MM) has not been developed yet, but researchers are working on a promising approach using urine cell-free DNA (cfDNA). In this study, the team identified specific genetic markers in the urine of MM patients that could help diagnose and differentiate MM from other conditions like amyloidosis. They found 11 key markers that could accurately diagnose MM with high sensitivity and specificity, and the same markers could distinguish MM from other diseases.
Additionally, the researchers developed a model that could predict the prognosis of MM patients based on their survival data, identifying four key markers that could independently predict outcomes. These findings highlight the potential of urine cfDNA markers in providing a completely non-invasive method for diagnosing and monitoring MM, offering a new approach to managing the disease.
"Monoclonal gammopathy of undetermined significance and the risk of thrombotic events: Results from iStopMM, a prospective population-based screening study"
Source
Rögnvaldsson S, Gasparini A, Thorsteinsdottir S, Sverrisdottir I, Eythorsson E, Long TE, et al. Monoclonal gammopathy of undetermined significance and the risk of thrombotic events: Results from iStopMM, a prospective population-based screening study. Br J Haematol. 2024; 00: 1–8. https://doi.org/10.1111/bjh.19957 December 25, 2024.
Overview
Monoclonal gammopathy of undetermined significance (MGUS) is a condition that can lead to multiple myeloma and related diseases. While MGUS is typically asymptomatic, it has been linked to an increased risk of thrombosis (blood clots). A study conducted in Iceland screened over 75,000 individuals aged 40 and older for MGUS, finding that people with MGUS had a higher risk of venous thrombosis (clots in veins) compared to those without the condition.
After about 3.7 years of follow-up, 124 venous and 252 arterial thrombotic events occurred in the MGUS group. While venous thrombosis was more common in the MGUS group, no increased risk for arterial thrombosis (clots in arteries) was found. Interestingly, the concentration of M protein, which is often elevated in MGUS, did not seem to affect the risk of either type of thrombosis. The results suggest that MGUS may lead to venous thrombosis and that some individuals with MGUS may have a form of the condition linked to increased clotting risk, even if they don’t show other symptoms.
"Monoclonal gammopathy of undetermined significance and the risk of thrombotic events: Results from iStopMM, a prospective population-based screening study"
Source
Rögnvaldsson S, Gasparini A, Thorsteinsdottir S, Sverrisdottir I, Eythorsson E, Long TE, et al. Monoclonal gammopathy of undetermined significance and the risk of thrombotic events: Results from iStopMM, a prospective population-based screening study. Br J Haematol. 2024; 00: 1–8. https://doi.org/10.1111/bjh.19957 December 25, 2024.
Overview
Monoclonal gammopathy of undetermined significance (MGUS) is a condition that can lead to multiple myeloma and related diseases. While MGUS is typically asymptomatic, it has been linked to an increased risk of thrombosis (blood clots). A study conducted in Iceland screened over 75,000 individuals aged 40 and older for MGUS, finding that people with MGUS had a higher risk of venous thrombosis (clots in veins) compared to those without the condition.
After about 3.7 years of follow-up, 124 venous and 252 arterial thrombotic events occurred in the MGUS group. While venous thrombosis was more common in the MGUS group, no increased risk for arterial thrombosis (clots in arteries) was found. Interestingly, the concentration of M protein, which is often elevated in MGUS, did not seem to affect the risk of either type of thrombosis. The results suggest that MGUS may lead to venous thrombosis and that some individuals with MGUS may have a form of the condition linked to increased clotting risk, even if they don’t show other symptoms.
"Population differences in the associations between chromosomal abnormalities and overall survival of multiple myeloma"
Source
Bei Wang, Benjamin A. Derman, Madina Sukhanova, Daniel Appelbaum, John Cursio, Wei Zhang, Andrzej Jakubowiak, Brian C.-H. Chiu; Population differences in the associations between chromosomal abnormalities and overall survival of multiple myeloma. Blood Neoplasia 2024; 100065. doi: https://doi.org/10.1016/j.bneo.2024.100065 December 26, 2024.
Overview
Cytogenetic abnormalities play an important role in predicting the prognosis of multiple myeloma (MM), but their effects may differ between different populations. A study examined data from 181 patients diagnosed with MM, including 55 African Americans (AAs) and 126 European Americans (EAs), to explore how these genetic changes impact overall survival (OS). The researchers focused on high-risk cytogenetic abnormalities (HRCAs), such as t(4;14), t(14;16), t(14;20), del 17p, and gain/amplification of 1q, which are known to be linked with poor outcomes in MM.
The results showed that high-risk MM with HRCAs was linked to worse OS in EAs but not in AAs. For both groups, del 13q was associated with poorer survival. Specific abnormalities also had different effects on survival between the groups. For instance, gain/amplification of 1q worsened OS in EAs, while t(4;14) was tied to poorer survival in AAs. These findings suggest that the impact of certain cytogenetic abnormalities on survival may vary by population, highlighting the importance of considering population differences when assessing prognosis in MM.
"Targeting Enterobacter cloacae attenuates osteolysis by reducing ammonium in multiple myeloma"
Source
Qin Yang, Yinghong Zhu, Xingxing Jian, Yi Qiu, Yan Zhu, Lia Zhao, Yanjuan He, Gang An, Lugui Qiu, Jiaojiao Guo, Nihan He, Huerxidan Abudumijiti, Cong Hu, Xun Chen, Siqing Huang, Xiangling Feng, Xin Li, Jing Liu, Yajing Xu, Wen Zhou; Targeting Enterobacter cloacae attenuates osteolysis by reducing ammonium in multiple myeloma. Blood 2024; blood.2024025694. doi: https://doi.org/10.1182/blood.2024025694 December 30, 2024.
Overview
While previous studies have shown that the gut microbiome impacts multiple myeloma (MM) progression and drug resistance, its role in MM-related bone disease was not well understood. In this study, researchers found that a specific bacteria, E. cloacae, is more common in the gut of MM patients with bone damage. They used a mouse model to show that E. cloacae promotes bone loss by increasing levels of ammonium in the body.
Higher ammonium levels encourage the formation of osteoclasts, the cells responsible for breaking down bone. This process happens by boosting certain proteins that help osteoclasts form and by affecting proteins in MM cells that promote bone destruction. The researchers found that blocking ammonium production by using a modified E. cloacae and adding probiotics helped reduce bone damage in the mice. This research points to E. cloacae and ammonium as key factors in bone disease in MM, offering a potential new approach for treatment.
"Isatuximab plus pomalidomide and dexamethasone in frail individuals with relapsed/refractory multiple myeloma in Japan"
Source
Tagami, N., Uchiyama, M., Suzuki, K. et al. Isatuximab plus pomalidomide and dexamethasone in frail individuals with relapsed/refractory multiple myeloma in Japan. Int J Hematol (2024). https://doi.org/10.1007/s12185-024-03904-y December 27, 2024.
Overview
This study looked at the safety and effectiveness of combining isatuximab, pomalidomide, and dexamethasone (Isa-Pd) for treating relapsed or refractory multiple myeloma (RRMM) in frail patients in Japan. The data was collected from October 2020 to October 2021, including 40 frail patients and 29 fit or intermediate patients. The results showed that frail patients experienced more side effects, such as bone marrow suppression and infections, compared to those who were fitter. However, the treatment was still effective, with a higher response rate in the fit or intermediate group.
The study found that Isa-Pd is safe and effective for frail individuals with RRMM in real-world conditions, although frail patients may experience more complications than fitter patients. Despite the challenges, the treatment was well-tolerated, with similar rates of treatment discontinuation due to disease progression in both groups.
"DREAMM-11, Part 2: Japanese phase I trial of belantamab mafodotin combination therapies in relapsed/refractory multiple myeloma"
Source
Sunami, K., Iida, S., Tsukada, N. et al. DREAMM-11, Part 2: Japanese phase I trial of belantamab mafodotin combination therapies in relapsed/refractory multiple myeloma. Int J Hematol (2024). https://doi.org/10.1007/s12185-024-03889-8 December 24, 2024.
Overview
The DREAMM-11 study tested the drug belantamab mafodotin in Japanese patients with relapsed or refractory multiple myeloma (RRMM). In Part 1, the drug was given alone and showed good results with manageable side effects. In Part 2, the drug was combined with either bortezomib and dexamethasone (Arm A) or pomalidomide and dexamethasone (Arm B). Both combinations were well-tolerated, with only one case of a non-serious liver injury in Arm B. The treatments had similar side effects to what has been seen in Western patients. In terms of effectiveness, all three patients in Arm A responded positively, while half of those in Arm B showed a response. The results suggest that belantamab mafodotin combined with these drugs could be an effective treatment for Japanese patients with RRMM.