Mamtha Balla, Transplant Oncology-ID fellow at MD Anderson Cancer Center and Hematology Oncology Fellow at The University of Toledo, shared post on X:
“Golden era for Multiple Myeloma (2024–2026). Triplets quadruplets and immunotherapy reaching frontline settings. Myeloma MELTS bones!
1. Frontline Quadruplets: The New Gold Standard. The biggest shift is the move away from VRd (triplet) to Anti-CD38 Quadruplets for nearly all newly diagnosed patients.
- PERSEUS Trial (Transplant-Eligible): Confirmed that Dara-VRd (Daratumumab + VRd) is the new standard of care. At 4 years, 84.3% of patients were progression-free compared to 67.7% with VRd alone. (N Engl J Med 2024)
- IMROZ Trial (Transplant-Ineligible): Showed that Isatuximab-VRd significantly reduced the risk of progression or death by 40% in older/unfit patients. This led to its FDA approval in late 2024/2025. (Nature Medicine 2024)
- CEPHEUS Trial: Demonstrated that Dara-VRd is also a potent option for those deferring or ineligible for transplant, showing superior MRD negativity rates (~55% vs 41%). (ASH 2024)
2. Immunotherapy Evolution: Earlier and Stronger Immunotherapies that were once “last-resort” are moving into 1st and 2nd lines.
- MajesTEC-3 (Bispecifics): Data from ASH 2025/early 2026 showed that the combination of Teclistamab + Daratumumab in early relapse (1–3 prior lines) achieved a 3-year PFS of 83%—unprecedented for relapsed disease. (NEJM 2025/2026)
- CARTITUDE-4 (CAR-T): Led to the FDA approval of Cilta-cel (Carvykti) for patients after only one prior line of therapy (previously required four lines).
- Linvoseltamab Approval (2025): A new BCMA-targeting bispecific antibody was approved for relapsed/refractory MM, adding more “off-the-shelf” options. (FDA 2025)
3. Early Intervention: High-Risk Smoldering MM. We are no longer just “watching and waiting” for high-risk precursor disease.
- FDA Approval for SMM (2025): Daratumumab was approved as the first and only treatment for High-Risk Smoldering Multiple Myeloma to prevent or delay progression to active cancer. (JCO 2025/FDA 2025)
- SLiM Criteria Validation: Continuous evidence has reinforced that using biomarkers (marrow % and light chains) to treat early prevents irreversible organ damage (CRAB).
4. High-Risk Genomics and MRD
- Genomic Staging: The IMS/IMWG Consensus Genomic Staging (2025/2026) now better defines high-risk patients using NGS, identifying ~22% of newly diagnosed patients as high-risk who need intensified therapy. (Blood 2026)
- MRD as a Primary Endpoint: Minimal Residual Disease (MRD) negativity at 10^{-5}or 10^{-6} is now the surrogate gold standard for “cure-like” states, guiding when to stop or de-escalate maintenance.
5. New Targets and Next-Gen Drugs
- CELMoDs (Iberdomide/Mezigdomide): These “super-IMiDs” are showing effectiveness even in patients refractory to Lenalidomide/Pomalidomide. Iberdomide is being tested as a more potent, less toxic alternative for maintenance. (IMS 2024)
- GPRC5D Targets: Talquetamab (bispecific) and new CAR-Ts targeting GPRC5D (rather than BCMA) are successfully treating patients who failed previous BCMA therapies. “
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