The 21st annual International Myeloma Society (IMS) meeting in Rio de Janeiro focused on key advancements and challenges in multiple myeloma treatment. Discussions centered on minimal residual disease (MRD) testing, defining and treating high-risk disease, advancements in CAR-T therapy, and the outcomes of the CEPHEUS trial involving daratumumab.
MRD Testing and its Evolving Role
The FDA's Oncology Drugs Advisory Committee (ODAC) unanimously voted on using MRD negativity as a surrogate endpoint for accelerated approvals in the US, marking a significant shift. Experts at IMS 2024 discussed the implications of this decision, highlighting the need for continued monitoring of the field and addressing challenges in patient recruitment for clinical trials due to improved treatments and progression-free survival rates. The potential for European regulators to follow the FDA's lead was also considered.
Consensus on High-Risk Myeloma
Approximately 20% of multiple myeloma patients face a grim prognosis, not living beyond three years due to high-risk disease. A key session at IMS 2024 addressed the new consensus definition of high-risk myeloma based on genomic features, utilizing the Second Revision of the International Staging System. Patients are classified as high risk if they possess one of four specific genetic alterations. However, it was noted that factors beyond genetics, such as patient age, frailty, medullary disease, and Immunoglobulin D levels, also contribute to predicting poor outcomes.
Advancements in CAR T-Cell Therapy
An investigational allogeneic CAR T-cell therapy, P-BCMA-ALLO1, is showing promise as an off-the-shelf solution for myeloma. This therapy aims to prevent graft-vs-host disease through a combination of stem-cell rich CAR and endogenous T-cell receptor gene editing. Phase 1 findings in 34 patients (median age 66, with 5 prior lines of therapy) revealed no dose-limiting toxicity and the potential for a rapid, one-day window between decision and treatment initiation, addressing challenges like lengthy manufacturing processes and high costs associated with traditional CAR T-cell therapies.
CEPHEUS Trial: Daratumumab's Impact on MRD Negativity
The ongoing CEPHEUS trial examines the anti-CD38 antibody daratumumab in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) compared to VRd alone. Results demonstrated a sustained MRD negativity rate of 60% in the D-VRd group versus 39.4% in the VRd group (sensitivity threshold of 10–5) after a median follow-up of 58.7 months. These findings suggest that daratumumab with VRd improves MRD negativity and progression-free survival in myeloma patients when transplant is deferred. Further analysis of the data, including breakdowns by race, is planned.
