BCMA-Directed Therapies Show Efficacy in Relapsed/Refractory Multiple Myeloma

Multiple myeloma remains an incurable haematological malignancy, with successive relapses leading to increasingly refractory disease. Patients with RRMM, especially those triple-class refractory (to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 monoclonal antibody), have limited treatment options and a median overall survival often measured in months.¹ The identification of B-cell maturation antigen (BCMA) as a highly expressed target on myeloma cells, with limited expression on normal tissues, has opened a new therapeutic frontier.²

Globally, multiple myeloma accounts for approximately 1% of all cancers and 10% of all hematologic malignancies. The incidence of multiple myeloma increases with age, with most diagnoses occurring in individuals over 65 years. Despite advances in frontline therapies, including proteasome inhibitors, immunomodulatory drugs, and autologous stem cell transplantation, nearly all patients eventually relapse. The prognosis for patients with RRMM worsens with each subsequent line of therapy, highlighting the critical need for novel, effective treatment strategies. BCMA-directed therapies leverage different mechanisms to eliminate myeloma cells. Chimeric antigen receptor (CAR) T-cell therapies involve engineering a patient's own T-cells to express a CAR that specifically binds to BCMA, leading to targeted cytotoxicity. Bispecific antibodies, conversely, are designed to bind simultaneously to BCMA on myeloma cells and to CD3 on T-cells, thereby redirecting endogenous T-cells to kill myeloma cells.³ Both approaches have demonstrated efficacy in early-phase trials, leading to their accelerated development and regulatory approvals.

Clinical Evidence for BCMA-Directed Therapies

Multiple trials presented at EHA 2026 reinforced the clinical utility of BCMA-directed agents in RRMM. Studies of BCMA-directed CAR T-cell therapies, such as idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), consistently reported high overall response rates (ORR) and complete response (CR) rates in heavily pretreated patient populations. For instance, a pooled analysis of trials involving ide-cel in patients with at least three prior lines of therapy showed an ORR of approximately 73%, with a CR rate of 33%. The median progression-free survival (PFS) was reported as 8.8 months.⁴ Cilta-cel, in a similar patient cohort, demonstrated an even higher ORR of 97.9% and a stringent CR rate of 82.9%, with a median PFS not yet reached at the time of analysis, suggesting more durable responses.⁵ These CAR T-cell therapies typically involve a complex manufacturing process, where a patient's T-cells are collected via apheresis, genetically modified ex vivo, expanded, and then reinfused. This process can take several weeks, during which patients may require bridging therapy.

Bispecific antibodies targeting BCMA have also shown promising results. Teclistamab, a BCMAxCD3 bispecific antibody, achieved an ORR of 63% in patients who had received a median of five prior lines of therapy. The median duration of response (DOR) was 18.4 months.⁶ Another BCMAxCD3 bispecific antibody, elranatamab, demonstrated an ORR of 61% in a similar patient population, with a median DOR of 17.2 months.⁷ These agents offer an 'off-the-shelf' alternative to CAR T-cells, potentially reducing manufacturing delays and logistical complexities. Bispecific antibodies are typically administered intravenously or subcutaneously, often with a step-up dosing schedule to mitigate the risk of cytokine release syndrome.

Common adverse events associated with both CAR T-cell therapies and bispecific antibodies include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). While generally manageable, these toxicities require careful monitoring and management, often in specialized centres. The incidence and severity of CRS and ICANS vary between agents, with some bispecific antibodies showing a lower rate of severe neurotoxicity compared to CAR T-cells.⁸ Infections and cytopenias also remain significant concerns, particularly in patients with prolonged immune suppression. Long-term follow-up data are still accumulating for many of these newer agents, and the potential for late-onset toxicities, including secondary malignancies, requires ongoing surveillance.

The expanding portfolio of BCMA-directed therapies provides clinicians with more options for RRMM. The choice between CAR T-cells and bispecific antibodies may depend on patient characteristics, prior therapies, disease burden, and access to specialized treatment centres. Ongoing research is exploring combination strategies and earlier lines of therapy for these agents, aiming to further improve outcomes and potentially extend their utility beyond the relapsed/refractory setting. Head-to-head comparisons and real-world evidence will be crucial in refining treatment algorithms. Limitations of current data include the relatively short follow-up periods for some trials and the highly selected patient populations, which may not fully represent the broader RRMM population. Further research is needed to determine the optimal sequencing of these therapies and their efficacy in patients with high-risk cytogenetics or extramedullary disease.