Clinical Director Dana-Farber Cancer Institute Boston, Massachusetts, United States
Introduction: Lenalidomide has shown to delay progression in patients with high-risk smoldering multiple myeloma (HR-SMM). Curative intent trials with carfilzomib-based therapy and stem cell transplantation are under investigation in HR-SMM, leading to deep responses but with concern for treatment-related toxicities (Mateos ASH 2022). Daratumumab, bortezomib, lenalidomide and dexamethasone (D-RVD) has shown high rates of minimal residual disease (MRD) negativity in MM (Voorhees Blood 2020). Thus, we proposed to examine the activity and safety of D-RVD in patients with HR-SMM.
Methods: This is a phase II, open label study evaluating D-RVD in HR-SMM. Eligibility criteria included HR-SMM per Mayo 2018 “20-2-20” model and other previously established criteria including Mayo 2008 criteria, presence of immunoparesis, evolving type of SMM, and high risk FISH. Treatment with D-RVD is 2 years (24 cycles) with daratumumab subcutaneous (SQ) per standard dose and schedule, bortezomib SQ on days 1, 8, 15 for cycles 1-6 and then biweekly until completion of cycle 24 and lenalidomide on days 1-21 with weekly dexamethasone. All eligible patients undergo stem cell collection after 6 cycles of therapy. The primary objective is rate of MRD-negativity at 2 years. Secondary objectives include PFS, ORR, and safety. The trial has been amended to include part 2, which will randomize patients that are MRD positive after 2 years to observation vs continued therapy with daratumumab and lenalidomide for an additional 24 months. The primary objective of part 2 is rate of MRD conversion from positive to negative.
Results: At the time of data cut off, 30 patients have been enrolled to part 1 with a median follow up of 14 months. The median age is 60 years old (range 36-77). Ninety percent of patients were classified as either high (18, 60%) or intermediate risk (9, 30%) per Mayo 2018 criteria with median plasmacytosis of 20%, median M protein of 2.17 g/dl and median FLC ratio of 8.1. Twelve patients (40%) had high-risk FISH results (10 with 1q gain, 2 with t(4;14), 1 with t(14;16) and 1 with del 17p). Most common grade 3 toxicities included neutropenia (17%), ALT increased (10%), hypertension (7%) and diarrhea (7%). Upper respiratory infections occurred in 66% of patients (COVID 19 infection in 10 patients, only 1 grade 3). No patients discontinued therapy due to toxicity. The overall response rate is 87% with 40% CR, 23% VGPR and 23% PR. Sixty-three percent of patients achieved VGPR or greater. MRD was evaluable in 24 patients with at least 6 months of follow up and MRD negativity rate is 58% (14/24) and 38% (9/24) at thresholds of 10-5 and 10-6, respectively. No patients have progressed on treatment. Stem cell collection was successful in all eligible patients with average stem cell yield of 5.57 x 10-6 CD34+ cells/kg.
Conclusions: D-RVD in HR-SMM demonstrates significant activity, including high rates of MRD-negative disease, and has a similar toxicity profile to MM.
