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 February 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 February 2024)
"GPRC5D as a novel target for the treatment of multiple myeloma: a narrative review."
Source
Rodriguez-Otero, P., van de Donk, N.W.C.J., Pillarisetti, K. et al. GPRC5D as a novel target for the treatment of multiple myeloma: a narrative review. Blood Cancer J. 14, 24 (2024). https://doi.org/10.1038/s41408-023-00966-9. February 2, 2024.
Overview
Patients with multiple myeloma typically experience periods of improvement followed by the return of the disease, with each round of treatment becoming less effective. Scientists are looking for new treatments that work differently against this cancer. One promising target is a protein called GPRC5D.
Researchers have been studying GPRC5D and have found that it could be a good target for new treatments for multiple myeloma. They have tested different treatments, including some that use the body's own immune cells to fight the cancer. These treatments, called talquetamab, forimtamig, MCARH109, OriCAR-017, and BMS-986393, have shown some success in early tests.
However, there have been some side effects reported with these treatments, such as skin and mouth problems, and rare issues with the brain. Scientists are still working to understand why these side effects happen and how to manage them better.
Even with these side effects, the new treatments have shown promise. Many patients have responded well to them, with over half of them seeing significant improvement in their condition. These treatments also seem to activate the body's immune system against the cancer cells.
In the future, researchers hope to study these treatments more and see how they can be used alongside other treatments to improve outcomes for people with multiple myeloma.
"Preclinical and clinical evaluation of the Janus Kinase inhibitor ruxolitinib in multiple myeloma"
Source
Del Dosso A., Tadevosyan E., Berenson J. R. Preclinical and clinical evaluation of the Janus Kinase inhibitor ruxolitinib in multiple myeloma. Oncotarget. 2024; 15: 65-75. Retrieved from https://www.oncotarget.com/article/28547/text/. February 5, 2024.
Overview
In recent years, new and better drugs have been developed to treat multiple myeloma. These drugs are often tested together with older ones to see if they work even better. But over time, these combinations can stop working, so we need new treatments to help patients when this happens.
Scientists have discovered a group of proteins called Janus Kinases (JAK) that play a role in how multiple myeloma develops. Studies done in labs have shown that blocking these proteins can slow down the growth of MM cells and help the body's immune system fight against the cancer. When used with other myeloma drugs, blocking JAK proteins makes those treatments work better.
Tests done in real patients have also shown that blocking JAK proteins is safe and helps the treatments work better. More research is needed, but this new approach looks promising for helping people with multiple myeloma in the future.
"Efficacy and immune modulation associated with the addition of IMiDs to Daratumumab backbone in multiple myeloma patients refractory to both drug classes: resetting synergistic activity."
Source
Kostopoulos, I.V., Fotiou, D., Gavriatopoulou, M. et al. Efficacy and immune modulation associated with the addition of IMiDs to Daratumumab backbone in multiple myeloma patients refractory to both drug classes: resetting synergistic activity. Blood Cancer J. 14, 26 (2024). https://doi.org/10.1038/s41408-024-00988-x. February 6, 2024.
Overview
This study discusses "that in selected patients with relapsed or refractory multiple myeloma (RRMM), re-treatment with a combination that retains a Darzalex (daratumumab) backbone, may be associated with clinical benefit. Such regimens may be a bridge therapy, offering a significant disease burden reduction when no other options are available immediately (e.g. prior to CAR-T immunotherapy). Furthermore, our results highlight the dynamics of the immune modulation caused by Darzalex and suggest that the immune microenvironment of the bone marrow (partly reflected in PB) [15] may play an important role on the efficiency of the Dara/IMiD synergistic effect."
"Epigenetic regulation of CD38/CD48 by KDM6A mediates NK cell response in multiple myeloma."
Source
Liu, J., Xing, L., Li, J. et al. Epigenetic regulation of CD38/CD48 by KDM6A mediates NK cell response in multiple myeloma. Nat Commun 15, 1367 (2024). https://doi.org/10.1038/s41467-024-45561-z. February 14, 2024.
Overview
Sometimes myeloma becomes resistant to Darzalex (daratumumab), and it is not understood why. Through laboratory experiments, scientists have found a gene called KDM6A that seems to play a big role in how well Dara works. When this gene is lost, it causes a decrease in another protein called CD38, which is targeted by Dara. This decrease in CD38 might be one reason why the cancer becomes resistant to Dara.
But it's not just CD38; there's another protein called CD48 that's also affected when KDM6A is lost. Scientists have found that if they use a drug to block a process called H3K27me3, which is linked to KDM6A, they can make CD38 and CD48 go back to normal levels. This, in turn, makes Dara work better against the cancer again.
This research suggests that drugs targeting H3K27me3, like the ones already approved by the FDA, could help make Dara treatment more effective for MM patients. It's an exciting step forward in understanding and treating this type of cancer.
"Development and Validation of a Prediction Model of Outcome After B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T-Cell Therapy in Relapsed/Refractory Multiple Myeloma."
Source
Gagelmann, N. et. Al. Development and Validation of a Prediction Model of Outcome After B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T-Cell Therapy in Relapsed/Refractory Multiple Myeloma. Publication: Journal of Clinical Oncology. https://doi.org/10.1200/JCO.23.02232. February 15, 2024.
Overview
This study examines that even though "chimeric antigen receptor T therapy (CAR-T) cells are an established therapy for relapsed/refractory multiple myeloma (RRMM), there are no established models predicting outcomes to identify patients who may benefit the most from CAR-T."
It concludes that "outcomes of patients with RRMM after CAR-T are comparable between Europe and the United States. The MyCARe model may facilitate optimal timing of CAR-T cells in patient-specific subgroups."
"Functional cure and long-term survival in multiple myeloma: how to challenge the previously impossible."
Source
Engelhardt M, Kortüm KM, Goldschmidt H, Merz M. Functional cure and long-term survival in multiple myeloma: how to challenge the previously impossible. Haematologica; https://doi.org/10.3324/haematol.2023.283058 [Early view]. February 15, 2024.
Overview
From the abstract: "Multiple myeloma (MM) is a heterogeneous disease with survival ranging from months to decades. The goal of ‘cure’ remains elusive for most patients, but has been shown to be possible, with durable remission and a transition to a plateau phase (analogous to monoclonal gammopathy of uncertain significance/smoldering Myeloma (MGUS/SMM)). Two representative cases set the stage to illustrate how this might be possible and what still needs to be determined to achieve functional disease control over a prolonged period. Several developments have emerged, such as improved diagnostics including the definitions and use of SLiM-CRAB criteria and MRD with whole genome- /single-cell-sequencing as well as other correlates to better understand disease biology. These advances enable earlier detection, more accurate risk stratification and improved personalized treatment strategies by facilitating analysis of genetic alterations and clonal heterogeneity. Whole genome sequencing may also identify driver mutations and modes of resistance to targets like immunotherapies (IOs) as well as other targeted therapies. Today, induction with a CD38 antibody (CD38mAb), proteasome inhibitor, immunomodulatory drug, and dexamethasone, potentially followed by ASCT and lenalidomide maintenance, can be considered standard of care for transplant-eligible (TE) newly diagnosed (NDMM) patients. Whether prolonged disease control and functional cure can be achieved in non-transplant eligible (NTE) patients is currently emerging as a distinct possibility: data from phase III trials that incorporate a CD38mAb into the treatment of NTE NDMM patients demonstrate impressive MRD negativity rates that appear sustained over several years. While the long-term durability of CAR-Ts, bi-specific antibodies and other IOs are evaluated, several clinical trials are now investigating their role in frontline treatment for TE and NTE patients. These will address whether CAR-Ts will replace ASCT and whether such IOs will represent a truly curative option. We conclude that whilst cure remains elusive, the concept of operational or functional cure provides a new benchmark to strive for and is an emerging area of active and potentially achievable clinical research for MM."
"Short-Chain Fatty Acid Production by Gut Microbiota Predicts Treatment Response in Multiple Myeloma."
Source
Rodríguez-García, A., et.al. Short-Chain Fatty Acid Production by Gut Microbiota Predicts Treatment Response in Multiple Myeloma. Clin Cancer Res (2024) 30 (4): 904–917. https://doi.org/10.1158/1078-0432.CCR-23-0195. February 16, 2024.
Overview
The gut microbiota plays important roles in health and disease. Researchers of ths study "questioned whether the gut microbiota and related metabolites are altered in monoclonal gammopathies and evaluated their potential role in multiple myeloma and its response to treatment."
"Che-1/miR-590-3p/TAZ axis sustains multiple myeloma disease."
Source
Bruno, T., Catena, V., Corleone, G. et al. Che-1/miR-590-3p/TAZ axis sustains multiple myeloma disease. Leukemia (2024). https://doi.org/10.1038/s41375-024-02168-z. February 17, 2024.
Overview
In this study, researchers "identify a novel role of Che-1 in multiple myeloma pathogenesis. Indeed, by performing experiments in cell lines, patient samples, and mice models, we found that Che-1 can negatively control TAZ expression in multiple myeloma by upregulating miR-590-3p."
Their "results clearly demonstrated that during the differentiation of mesenchymal cells into osteoblasts, alongside the induction of TAZ and its target genes, there is also a downregulation of both Che-1 and miR-590-3p."
Furthermore, the study shows "that myeloma cells secrete this miRNA, and high levels of this molecule are found in vivo both in the bone marrow of multiple myeloma mouse models and in patients. Finally, overexpression of either miR-590-3p or Che-1 significantly inhibited TAZ expression in mesenchymal stem cells along with osteoblastic differentiation."
"Multi-dimensional scaling techniques unveiled gain1q&loss13q co-occurrence in Multiple Myeloma patients with specific genomic, transcriptional and adverse clinical features."
Source
Terragna, C., Poletti, A., Solli, V. et al. Multi-dimensional scaling techniques unveiled gain1q&loss13q co-occurrence in Multiple Myeloma patients with specific genomic, transcriptional and adverse clinical features. Nat Commun 15, 1551 (2024). https://doi.org/10.1038/s41467-024-45000-z. February 20, 2024..
Overview
From the abstract: "The complexity of Multiple Myeloma (MM) is driven by several genomic aberrations, interacting with disease-related and/or -unrelated factors and conditioning patients’ clinical outcome. Patient’s prognosis is hardly predictable, as commonly employed MM risk models do not precisely partition high- from low-risk patients, preventing the reliable recognition of early relapsing/refractory patients. By a dimensionality reduction approach, here we dissect the genomic landscape of a large cohort of newly diagnosed MM patients, modelling all the possible interactions between any MM chromosomal alterations. We highlight the presence of a distinguished cluster of patients in the low-dimensionality space, with unfavorable clinical behavior, whose biology was driven by the co-occurrence of chromosomes 1q CN gain and 13 CN loss. Presence or absence of these alterations define MM patients overexpressing either CCND2 or CCND1, fostering the implementation of biology-based patients’ classification models to describe the different MM clinical behaviors."
"Prognostic factors in 448 newly diagnosed multiple myeloma receiving bortezomib-based induction: impact of ASCT, transplant refusal and high-risk multiple myeloma."
Source
Tang, H.K.K., Fung, C.Y., Hwang, Y.Y. et al. Prognostic factors in 448 newly diagnosed multiple myeloma receiving bortezomib-based induction: impact of ASCT, transplant refusal and high-risk MM. Bone Marrow Transplant (2024). https://doi.org/10.1038/s41409-024-02227-0. February 21, 2024.
Overview
From the abstract: "In Hong Kong, newly diagnosed multiple myeloma (NDMM) receives bortezomib-based triplet induction. Upfront autologous stem cell transplant (ASCT) is offered to transplant eligible (TE) patients (NDMM ≤ 65 years of age), unless medically unfit (TE-unfit) or refused (TE-refused). Data was retrieved for 448 patients to assess outcomes."
"The Phase 2 Cartitude-2 Trial: Updated Efficacy and Safety of Ciltacabtagene Autoleucel in Patients with Multiple Myeloma and 1–3 Prior Lines of Therapy (Cohort A) and with Early Relapse after First Line Treatment (Cohort B) ."
Source
Hillengass, J. et. al at the 2024 Tandem Meetings: Transplantation & Cellular Therapy Meetings of the American Society for Transplantation and Cellular Therapy and Center for International Blood and Marrow Transplant Research (Abstract 42). February 22, 2024.
Overview
From the abstract: "CARTITUDE-2 (NCT04133636), a phase 2, multicohort study evaluating safety and efficacy of the anti–B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cell therapy ciltacabtagene autoleucel (cilta-cel) in patients (pts) with multiple myeloma (MM)."
Researchers"present updated efficacy and safety data from CARTITUDE-2 cohorts A and B with a median follow-up (MFU) of around 29 months."
"Quantitative risk factor analysis of prior disease condition and socioeconomic status with the multiple myeloma development: nationwide cohort study."
Source
Choi, S., Kim, E., Jung, J. et al. Quantitative risk factor analysis of prior disease condition and socioeconomic status with the multiple myeloma development: nationwide cohort study. Sci Rep 14, 4885 (2024). https://doi.org/10.1038/s41598-024-52720-1. February 28, 2024.
Overview
From the abstract: "Early diagnosis and following management are important determinants of the prognosis of multiple myeloma (MM). However, screening for MM is not routinely performed because it is rare disease."
In this study, researchers "evaluated the association of prior disease condition and socioeconomic status (SES) with MM diagnosis and developed a simple predictive model that can identify patients at high risk of developing MM who may need screening using nationwide database from South Korea."
"Adjusting for subsequent therapies in the TOURMALINE-MM1 study shows clinically meaningful improvement in overall survival with addition of ixazomib to lenalidomide and dexamethasone."
Source
Ramasamy K, Bahlis NJ, Kumar SK, Kumar A, Cranmer H, Wang B, Dabora J, Labotka R, Richardson PG, Moreau P. Adjusting for subsequent therapies in the TOURMALINE-MM1 study shows clinically meaningful improvement in overall survival with addition of ixazomib to lenalidomide and dexamethasone. Haematologica; https://doi.org/10.3324/haematol.2023.283713 [Early view]. February 29, 2024. .
Overview
From the abstract: "TOURMALINE-MM1, the only blinded randomized study in patients with relapsed and/or refractory multiple myeloma (RRMM; ≥1 prior therapy) in the last 10 years, investigated ixazomib+lenalidomide+dexamethasone (IRd) versus lenalidomide+dexamethasone (Rd). Final overall survival (OS) data were based on a median follow-up of 85 months."