Almost a decade ago, the FDA approved daratumumab (Darzalex), a groundbreaking monoclonal antibody for multiple myeloma (MM). This marked a significant shift in the MM treatment landscape, ushering in an era of immunotherapies. Experts at the 2024 International Myeloma Society (IMS) Annual Meeting highlighted the evolution of these treatments, including bispecific and monoclonal antibodies, and CAR T-cell therapy, emphasizing their increasing efficacy in earlier treatment lines.
Targeted Therapies: Monoclonal Antibodies
A deeper understanding of the tumor microenvironment and the role of immune cells in MM progression has led to the development of targeted therapies. The discovery of CD38, a protein highly expressed on myeloma cells, paved the way for monoclonal antibodies like daratumumab and isatuximab (Sarclisa). These antibodies target CD38, leading to significant improvements in minimal residual disease (MRD) negativity and progression-free survival (PFS). Trials like IMROZ and PERSEUS supported their approval in combination with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd), forming a potent quadruple therapy.
Clinical Trial Results: Quadruple Therapy Success
The IMROZ, PERSEUS, MAIA, and CEPHEUS trials demonstrated the effectiveness of daratumumab in combination with VRd (D-VRd). These studies showed remarkable MRD negativity rates in newly diagnosed MM patients. The CEPHEUS trial, for instance, revealed a 60% improvement in MRD negativity with D-VRd compared to 39% with VRd alone. The PERSEUS trial further solidified these findings, with 75% of patients in the D-VRd arm achieving MRD negativity versus 47.5% with VRd. Impressively, 84.3% of patients in the D-VRd arm remained progression-free at 48 months.
Multiple myeloma treatment
Addressing Challenges: Bispecific Antibodies
Despite the success of quadruple therapies, challenges persist, especially in patients with high-risk cytogenetics or extramedullary disease. These patients often experience lower response rates and shorter survival times, particularly in relapsed or refractory cases. This has spurred the development of bispecific antibodies, such as teclistamab (Tecvayli) targeting BCMA and talquetamab (Taley) targeting GPRC5D. Teclistamab, a T-cell redirecting bispecific antibody, has shown promising results in relapsed/refractory MM, particularly in the MAJESTIC-1 trial, achieving a 63% overall response rate and a 46% MRD negativity rate in patients achieving a complete response or better. Similarly, talquetamab, also targeting CD3 but redirecting T-cells against GPRC5D, has demonstrated efficacy as a standalone therapy and in combination regimens, as explored in the ongoing MonumenTAL-3 trial.
Managing Adverse Effects
Bispecific antibodies, while effective, can cause adverse effects, including cytokine release syndrome (CRS) and neutropenia, as well as an increased risk of infections. Strategies to mitigate these effects involve spacing out treatment doses after remission or partial response is achieved. This approach has shown promise in reducing the incidence of infections and managing taste changes and skin/nail toxicities associated with talquetamab.
CAR T-Cell Therapy: A Personalized Approach
CAR T-cell therapy represents another significant advancement. By modifying a patient’s T-cells to target specific antigens, this personalized approach offers precise and effective treatment tailored to individual disease characteristics. In patients with triple-class refractory disease who have failed multiple prior therapies, CAR T-cell therapy has demonstrated promising results in clinical trials, with lower CRS rates and reduced toxicity. The KarMMA-2 trial, evaluating idecabtagene vicleucel (ide-cel), a BCMA-directed CAR T-cell therapy, showed a 72% overall response rate in triple-class refractory patients. Another CAR T-cell product, ciltacabtagene autoleucel (cilta-cel), also targeting BCMA, has shown enhanced clinical benefit and deeper responses in heavily pretreated patients.
Challenges and Future Directions
Despite its potential, CAR T-cell therapy faces challenges, including the complex manufacturing process, limited accessibility, and its current positioning in later treatment lines. However, discussions are ongoing regarding the potential benefits of using CAR T-cell therapy, along with other immunotherapies, earlier in the treatment course, especially for high-risk patients. While the prospect of earlier intervention with these powerful therapies is exciting, further research is needed to fully understand the risk-benefit profile in newly diagnosed, untreated MM patients.
Conclusion
Immunotherapies and targeted therapies have revolutionized MM treatment, significantly improving patient outcomes. However, ongoing research is crucial to optimize treatment strategies, address remaining challenges, and ultimately provide the most effective and personalized care for all individuals with MM. Consult with a healthcare professional for personalized treatment recommendations.
