Highlights in Multiple Myeloma

In this video,  Dr Marie Vercruyssen, hematologist at the Institut Jules Bordet in Brussels shares the key takeaways from 4 presentations related to multiple myeloma (MM) presented at ASH 2025.

The most practice-changing data came from the phase III MajesTEC-3 trial, presented in the late-breaking abstract session, evaluating daratumumab combined with the BCMA-directed bispecific antibody teclistamab vs. standard daratumumab-based triplets in relapsed or refractory MM.¹ Nearly 600 patients treated between first relapse and third line were randomized, including a substantial proportion with high-risk disease and extramedullary involvement. With a median follow-up of approximately three years, the interim analysis demonstrated an unprecedented progression-free survival advantage for the teclistamab–daratumumab doublet, with an 83% reduction in the risk of progression compared with standard of care. The absolute PFS rate at 3 years was 83.4% in the experimental arm as compared to 29.7% in controls, and a clear plateau in the PFS curve suggested durable disease control approaching a functional cure in a subset of patients. Responses were deep and frequent, with more than 80% complete responses and MRD negativity in ~60% of evaluable patients. Toxicity was manageable, with low-grade cytokine release syndrome confined to the teclistamab arm. Although early infection rates were higher, particularly within the first six months, these decreased substantially with improved prophylactic strategies.¹ Overall, MajesTEC-3 establishes an off-the-shelf bispecific-based doublet as a serious competitor to CAR-T therapy in early relapse.

The second study addressed unmet needs in smoldering multiple myeloma (SMM) by exploring circulating tumor plasma cells as a non-invasive biomarker for risk stratification.² Dr Martin-Sanchez and colleagues demonstrated that a CTC cutoff of 0.02% accurately reproduced the established 20-2-20 risk model, which traditionally relies on bone marrow plasma cell quantification. Importantly, serial monitoring of CTCs every six months revealed dynamic risk migration, with approximately one quarter of patients changing risk category over time. Among those transitioning to high risk, nearly half progressed rapidly to symptomatic disease.² These findings suggest that CTCs may not only replace bone marrow sampling for baseline risk assessment but also enable earlier detection of impending progression, allowing clinicians to better balance avoidance of overtreatment with timely intervention.

The third highlighted study was the extended follow-up of the phase II RedirecTT-1 trial, evaluating dual bispecific antibody therapy with teclistamab (anti-BCMA) and talquetamab (anti-GPRC5D) in patients with true extramedullary MM.³ This population represents one of the most aggressive and treatment-resistant forms of the disease. In 90 heavily pretreated patients with a median of four prior lines, dual targeting produced sustained efficacy, with an overall response rate of 79% and complete responses exceeding 50% at a median follow-up of approximately 17 months. The duration of response remained encouraging, with over 60% of patients having an ongoing response at one year. Notably, the combination did not appear to exacerbate infection risk, reflecting the non-overlapping toxicity profiles of BCMA and GPRC5D targeting.³ These results position dual bispecific therapy as a potential breakthrough for extramedullary disease once regulatory access is achieved.

Finally, Dr Vercruyssen underscored the transformative potential of the inMMyCAR trial, the first-in-human demonstration of in vivo CAR-T cell generation in MM.⁴ This approach bypasses ex vivo manufacturing by using a non-replicating lentiviral vector to transduce T cells directly within the patient, delivering a fully human BCMA CAR. In the first four patients treated in this phase I dose-escalation study, rapid and robust CAR-T expansion was observed, with transduction rates reaching up to 85%. All patients achieved MRD negativity at 10⁻⁵ within one month. Toxicity was limited to low-grade CRS, with no neurotoxicity reported. Although follow-up remains short, these early data suggest a future in which CAR-T therapy could become an immediately available, off-the-shelf option, fundamentally reshaping treatment logistics in MM.