The treatment landscape for relapsed and refractory multiple myeloma (RRMM) is undergoing a dramatic transformation with the emergence of novel BCMA-targeted therapies and innovative treatment approaches that are providing new hope for heavily pretreated patients.
BCMA-Directed Therapies Lead the Revolution
B-cell maturation antigen (BCMA) has emerged as a critical therapeutic target, being highly expressed on multiple myeloma cells while minimally expressed elsewhere. The first wave of commercially approved BCMA-directed therapies includes two chimeric antigen receptor (CAR) T-cell products: idecabtagene vicleucel (ide-cel) approved in March 2021 and ciltacabtagene autoleucel (cilta-cel) approved in February 2022.
Both CAR T-cell products have demonstrated unprecedented outcomes compared with non-BCMA-directed therapies for heavily pretreated patients, with low rates of grade 3/4 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). However, 6% of patients receiving cilta-cel experienced treatment-related parkinsonism. An indirect comparison between the two products suggests that cilta-cel has higher efficacy.
The first bispecific T-cell engager targeting BCMA, teclistamab, received accelerated approval in late 2022. In a phase 2 study, teclistamab demonstrated favorable outcomes with an overall response rate of 63% and median duration of response of 18.4 months, with minimal rates of grade 3/4 CRS or ICANS.
Emerging Bispecific Antibodies Show Promise
Elranatamab, a bispecific antibody targeting both BCMA on myeloma cells and CD3 on T cells, has shown remarkable efficacy in clinical trials. In the MagnetisMM-3 trial involving 123 patients with RRMM refractory to proteasome inhibitors, immunomodulatory drugs, and anti-CD38 antibodies, elranatamab achieved an overall response rate of 61.0% with a manageable safety profile. The FDA recently granted breakthrough therapy designation to elranatamab based on these results.
Talquetamab represents a first-in-class bispecific T-cell engager targeting GPRC5D and CD3. In the MonumenTAL-1 study, talquetamab demonstrated robust efficacy in heavily pretreated patients with a median of 5 prior lines of therapy. Among 143 patients treated with subcutaneous talquetamab at 0.4 mg/kg weekly, the overall response rate was 74.1% with a median duration of response of 9.3 months and median progression-free survival of 7.5 months.
Novel Mechanisms of Action Expand Options
Mezigdomide (CC-92480), a potent oral cereblon E3 ligase modulatory drug (CELMoD), works by tagging cancer-promoting proteins for destruction. In the CC-92480-MM-001 trial, the combination of mezigdomide and dexamethasone demonstrated promising efficacy with an overall response rate of 40.6% in heavily pretreated patients. Among 30 patients with prior anti-BCMA therapy, the response rate was 50.0%.
Purinostat mesylate, a selective inhibitor of class I and IIb histone deacetylases, showed antitumor activity in a first-in-human phase 1 study. Among 11 heavily pretreated evaluable patients with RRMM, the disease control rate was 72.7%, with the majority of adverse events being grade 1 or 2.
Innovative CAR T-Cell Approaches
Bispecific CS1-BCMA CAR T cells represent an innovative approach to overcome resistance mechanisms. In a phase 1 trial involving 16 evaluable patients with RRMM, these cells demonstrated clinical activity even in heavily pretreated patients with a median of 5.4 prior lines of therapy. The overall response rate was 81% for all patients and 100% for patients with myeloma cells in bone marrow, with 12-month overall survival, progression-free survival, and duration of response rates of 83.9%, 55.2%, and 68.8%, respectively.
Treatment Selection Challenges
The increasing complexity of treatment selection reflects the growing number of available therapies and the reality that patients are increasingly exposed to multiple drug classes. Triple-class refractory patients (exposed or refractory to immunomodulators, proteasome inhibitors, and anti-CD38 antibodies) experience a median progression-free survival and overall survival of 2.8 months and 10.3 months, respectively, while penta-class refractory patients fare even worse with 2.5 months and 6.9 months, respectively.
For early-line relapse patients, the main principles include utilizing at least one therapeutic class not used in induction, avoiding agents to which patients are refractory, and accounting for previous treatment toxicities. Recent randomized phase 3 trials have demonstrated the benefit of triplet combinations over doublets, with regimens like daratumumab/lenalidomide/dexamethasone showing superior overall survival outcomes.
Future Directions and Clinical Impact
The optimal selection and sequencing of BCMA-directed therapies remain to be determined, although bispecific T-cell engagers have shown efficacy in patients relapsing after BCMA-directed CAR T products. Patients requiring urgent responses should be preferentially considered for teclistamab given the time delay associated with CAR T-cell manufacturing.
As Paul G. Richardson, MD, from Dana-Farber Cancer Institute, noted: "CELMoDs as a particular class of new agent provide such an example of an important therapeutic option for our patients with multiple myeloma. Moreover, they can be readily added to existing platforms, such as proteasome inhibitors and monoclonal antibodies."
The evolving treatment landscape suggests that therapies directed toward BCMA and other novel targets will increasingly be deployed at earlier time points and in combination with current standard-of-care agents, indicating that survival for patients with RRMM will continue to improve with time.
