Deep and durable responses for quadruple therapy in smouldering MM 

The quadruple therapy of daratumumab, carfilzomib, lenalidomide, and dexamethasone was well tolerated in patients with smouldering multiple myeloma (MM), with similar toxicities as those observed in active MM. Furthermore, many patients were still in deep response at 2 years. Long-term follow-up will provide insights on whether some of these patients can be cured through this regimen.

“Smouldering MM is a so-called precursor condition and patients with this condition have a high risk to progress to active MM,” explained Prof. Shaji Kumar (Mayo Clinic, MN, USA). The phase 2 ASCENT trial (NCT03289299) was designed to assess whether an intense, limited duration, quadruple therapy can result in long-term responses or cure patients with smouldering MM and high-risk disease (n=87) [1]. An induction regimen of 6 4-week cycles with daratumumab, carfilzomib, lenalidomide, and dexamethasone was followed by 6 4-week cycles of consolidation therapy and 12 4-week cycles of maintenance therapy with lenalidomide and daratumumab. The primary endpoint was the rate of confirmed stringent complete response (sCR).

The sCR rate was 38% and the CR rate and very good partial response rate were 26% and 30%, respectively. In addition, 84% of the participants achieved marrow MRD-negativity (10^-5). The progression-free survival rate at 3 years was 89.9%.

In 81% of the participants, a treatment-emergent adverse event (AE) of any grade was observed. Also, 18% of the participants experienced a grade 3 haematological toxicity and 51% had non-haematological toxicity. A decreased neutrophil count, hypertension, and pneumonia were the most common grade 3 AEs. Finally, 4 deaths were reported, 2 due to COVID-19, 1 because of an RSV infection, and 1 patient died due to disease progression.

“After 2 years, many patients that were included in this study are still in deep response,” said Prof. Kumar. “Are we able to actually cure some of these patients? The answer to that question has to come from long-term follow-up.”

1. Kumar S, et al. Fixed Duration Therapy with Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone for High RiskSmoldering Multiple Myeloma-Results of the Ascent Trial. Abstract 757, ASH 64^th Annual Meeting, 10–13 December 2022, New Orleans, LA, USA.

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Posted on 20 February 2023