Soluble BCMA as a Key Mediator of Resistance in Anti-BCMA T-cell Therapies for Multiple Myeloma

Significance 

B-cell maturation antigen (BCMA) is a prominent target in MM therapy due to its expression on malignant plasma cells. Anti-BCMA therapies, particularly T-cell engagers and chimeric antigen receptor (CAR) T-cells, have demonstrated significant efficacy. However, resistance, both primary and acquired, remains a considerable challenge. Recent paper published in Blood Journal and led by Professor Francesco Maura from University of Miami and Professor Nizar Bahlis from the University of Calgary, the study investigated the regulatory mechanisms of BCMA expression, including the shedding of sBCMA, and its potential impact on therapeutic efficacy. The authors present evidence that sBCMA serves as a competitive inhibitor for membrane-bound BCMA, reducing the efficacy of BCMA-targeting therapies by acting as a decoy receptor. By binding to TCEs, sBCMA hinders their ability to effectively engage and eliminate BCMA-positive cancer cells. In patients with elevated sBCMA levels, particularly above 400 ng/mL, therapeutic outcomes are significantly compromised. Notably, 87.5% of patients with sBCMA >400 ng/mL were refractory to anti-BCMA therapies.

 Through whole-genome sequencing and flow cytometry, the study identifies structural mutations in the TNFRSF17 gene, which encodes BCMA, as a contributor to resistance. These mutations, particularly in cases with high levels of sBCMA, exacerbate the challenge of overcoming treatment resistance. Elevated baseline sBCMA, in combination with other factors such as tumor burden and surface antigen density, collectively drive the refractoriness observed in certain patient populations. The authors showed that sBCMA directly interferes with the binding of TCEs to membrane-bound BCMA, significantly reducing TCE efficacy in a dose-dependent manner. Increasing the dose of TCEs, such as teclistamab or elranatamab, or targeting alternative receptors like GPRC5D, demonstrated some ability to overcome the inhibitory effects of sBCMA. Furthermore, higher concentrations of sBCMA, particularly above 1000 ng/mL, led to complete abrogation of TCE binding, regardless of surface BCMA expression. The effector-to-target (E) ratio, which describes the relative abundance of cytotoxic T cells to cancer cells, plays a crucial role in determining the success of TCE-based therapies. In patients with high tumor burden or advanced disease stages, the reduced E ratio correlates with poorer treatment outcomes. Even when TCE doses were increased, the study found that low E ratios could not be fully compensated for, emphasizing the need for strategies to expand the effector T-cell population or reduce the tumor burden prior to therapy. The researchers tested various E ratios in coculture conditions with TCEs to replicate clinical scenarios of high disease burden. They observed that lower E ratios combined with high sBCMA levels significantly attenuated TCE efficacy. While increasing surface BCMA density helped mitigate the effect of sBCMA, it was insufficient to overcome the impact of low E ratios. These findings underscore the importance of considering disease burden in therapeutic planning, with strategies aimed at reducing tumor load or enhancing T-cell function likely to improve clinical outcomes.

One proposed solution to the challenge of sBCMA-mediated resistance is the use of gamma secretase inhibitors (GSIs), which prevent the cleavage of membrane-bound BCMA and reduce the generation of sBCMA. The study tested GSIs such as nirogacestat and demonstrated their ability to increase BCMA surface expression while decreasing sBCMA levels in both in vitro and patient-derived samples. Importantly, the combination of GSIs with anti-BCMA TCEs improved cytotoxicity, particularly in cells with high sBCMA levels. The authors concluded that GSIs could enhance the efficacy of anti-BCMA therapies in patients with elevated sBCMA. This approach appears promising, especially when combined with adequate TCE dosing and efforts to enhance the effector T-cell population. However, GSIs did not show any direct effect on MM cell viability, indicating that their primary benefit lies in modulating BCMA expression and preventing sBCMA-related resistance mechanisms.

The clinical implications of Professors Maura and Bahlis’ study are profound, particularly regarding patient stratification and therapy optimization. Measuring baseline sBCMA levels could become a routine practice for determining the likelihood of treatment success with anti-BCMA therapies. Patients with elevated sBCMA might benefit from modified treatment protocols, such as higher TCE doses, the use of alternative targets like GPRC5D, or combination therapies that include GSIs to reduce sBCMA levels and enhance surface BCMA expression. Furthermore, the findings suggest that patients with high tumor burden and low E ratios may require pre-treatment with therapies that expand T-cell populations or reduce tumor load, such as immunomodulatory drugs or anti-CD38 antibodies. In cases where sBCMA levels are high but tumor burden is manageable, GSIs could offer an additional therapeutic advantage. It supports the integration of sBCMA measurement as a standard diagnostic tool before initiating BCMA-targeted therapies, allowing for better patient stratification and selection. Clinicians may need to adjust dosing strategies, utilize alternative therapeutic targets like GPRC5D, or incorporate gamma secretase inhibitors (GSIs) to reduce sBCMA levels and enhance therapeutic efficacy. The new study also highlighted the importance of addressing the tumor burden and effector-to-target (E) ratio in MM patients. For those with a high tumor burden and low E ratios, the study suggests a need for pre-treatment strategies, such as reducing the tumor load or expanding the T-cell population, before administering BCMA-targeted therapies. These tailored approaches could mitigate primary refractoriness and improve long-term patient outcomes.

Soluble BCMA as a Key Mediator of Resistance in Anti-BCMA T-cell Therapies for Multiple Myeloma - Medicine Innovates
Image credit: Blood. 2024 Sep 25:blood.2024026212. doi: 10.1182/blood.2024026212.

About the author

Dr. Nizar Jacques Bahlis, MD

Associate Professor
Cumming School of Medicine, Department of Oncology
University of Calgary

Dr. Bahlis is an Associate Professor of Medicine at the University of Calgary in the division of Hematology and Bone Marrow Transplantation and a member of the Charbonneau Cancer Research Institute. Dr. Bahlis received his medical degree in 1995 from St Joseph University – French Faculty of Medicine in Beirut. He then completed his internal Medicine residency at the State University of New York in Syracuse followed by a Hematology-Oncology fellowship at the University of Miami, Florida. Dr. Bahlis also completed a postdoctoral fellowship in cancer biology at the University of Miami under the mentorship of Dr. Lawrence Boise. Dr. Bahlis’ clinical and laboratory research focus on the study of plasma cell dyscrasia, with particular interest in multiple myeloma genomics, single cell immune profiling and the development of novel therapeutics. He has received several awards and research funding from numerous agencies including the ASCO young investigator award, the Multiple Myeloma Research Foundation, The Leukemia and Lymphoma Society of Canada, Alberta Cancer Foundation, the National Institute of Health, the Terry Fox Foundations and the Canadian Institute of Health and Research (CIHR). His research work was published in many peer-reviewed journals including New England Journal of Medicine, Blood, JCO, Leukemia, Molecular Cancer Research and Clinical Cancer Research. Dr Bahlis also served on the editorial board for the journal Blood and on the review panels of several national and international funding agencies. He is a member of the American Society of Hematology (ASH) and served on the ASH plasma cell dyscrasia scientific panel and is a current member of the international myeloma society (IMS) education panel.

Summary of Research

Multiple myeloma (MM) is a hematological malignancy that affects bone marrow plasma cells and remains largely incurable. My laboratory is examining the signaling pathways and genomic alterations in multiple myeloma with the goal of discovering new molecular targets that may be translated into therapeutic applications. Aiming to improve the outcomes of patients affected by this disease, we have also established a Myeloma Genome Sequencing Unit with the goal to identify novel druggable genomic alterations and unmask the mechanisms of drug resistance.

We are also studying genomic instability in this disease, in particular the role of the proteasome-ubiquitin pathway in DNA damage repair. The human DNA damage response is reliant upon signaling using the small modifier protein called Ubiquitin (Ub). Since Ub is recycled by the proteasome, proteasome inhibitors (PI) have the effect of depleting free Ub pools such that the DNA damage-induced Ub-mediated signaling fails. We have found that MM displays a particular sensitivity to PI in combination with PARP inhibitors, and we are examining the molecular mechanisms underlying this effect.

Our laboratory has received funding from several national and international agencies including CIHR, Multiple Myeloma Research Foundation (MMRF), the Leukemia Lymphoma Society (LLS), the Cancer Research Society and the Terry Fox Foundation.

About the author

Francesco Maura, MD

Assistant Professor
Department of Medicine
University of Miami

I am an Assistant Professor, co-PI of the Myeloma Computational and Translational Laboratory, and Associate Director of the Myeloma Research Institute at the Sylvester Comprehensive Cancer Center – University of Miami. Between 2015 and 2018 as a postdoctoral fellow at the Cancer, Ageing and Somatic Mutation Programme at Wellcome Sanger Institute, directed by Peter J. Campbell, I gained research skills pertinent to this work, most notably in next-generation sequencing data analysis of whole genome, whole exome, RNA, and targeted sequencing. Furthermore, I conducted several genomic investigations on cancer genome evolution and the chronological reconstruction of early and late driver events in hematological cancers. In the last four years, first at the Memorial Sloan Kettering Cancer Center, and now at Sylvester Comprehensive Cancer Center, my team has modeled and integrated clinical and genomic data to better characterize the pathogenesis and (sub)clonal evolution of hematological malignancies such as multiple myeloma, lymphomas, and therapy-related myeloid neoplasms

Reference 

Lee H, Durante MA, Skerget S, Vishwamitra D, Benaoudia S, Ahn S, Poorebrahim M, Barakat E, Jung D, Leblay N, Ziccheddu B, Diamond BT, Papadimitriou M, Cohen AD, Landgren O, Neri P, Maura F, Bahlis NJ. Impact of soluble BCMA and non-T-cell factors on refractoriness to BCMA-targeting T-cell engagers in multiple myeloma. Blood. 2024 :blood.2024026212. doi: 10.1182/blood.2024026212.

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