Phase II Trial of Daratumumab, Bortezomib, Lenalidomide and Dexamethasone in High-Risk Smoldering Multiple Myeloma

Background: Daratumumab, bortezomib, lenalidomide and dexamethasone (D-RVD) has shown high rates of minimal residual disease (MRD) negativity in newly-diagnosed multiple myeloma (MM) and is now a standard regimen in transplant-eligible patients. Lenalidomide has shown to delay progression in patients with high-risk smoldering multiple myeloma (HR-SMM) and curative intent trials with carfilzomib-based therapy and stem cell transplantation have been recently reported in HR-SMM leading to deep responses but with concern for treatment-related toxicities. Thus, we proposed to examine the activity and safety of fixed duration D-RVD in patients with HR-SMM, with MRD-adaptive duration of therapy.

Methods: This is a phase II, open-label study evaluating D-RVD in HR-SMM. Eligibility criteria includes HR-SMM per Mayo 2018 “20-2-20” model and other previously established criteria including Mayo 2008 criteria, PETHEMA criteria, 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 1.3mg/m2 SQ on days 1, 8, 15 for cycles 1-6 then biweekly until completion of cycle 24, lenalidomide 25mg on days 1-21 for cycles 1-6 followed by 15mg d1-21 from cycles 7-24 with weekly low dose 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.

In part 2 of the study, patients that are MRD-positive after 2 years of treatment will be randomized 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 in May 2023, 38 patients have been enrolled to part 1 with a median follow up of 18 months. The median age is 62 years old (range 36-77) with 23 females (61%) and 15 males (39%). The median plasmacytosis of enrolled patients was 20%, with median M-protein of 2.17 g/dL and median FLC ratio of 8.1. Twenty-four patients (62%) had at least one high-risk FISH abnormality (fifteen with 1q gain, four with t(4;14), one with t(14;16) and one with del 17p). Eight patients (21%) had more than one high-risk FISH abnormality.

Most common grade 3 toxicities included neutropenia (13%), ALT increased (8%), and diarrhea (8%). Upper respiratory infections occurred in 61% of patients but were mostly low-grade (COVID-19 infection in 11 patients, 1 with grade 3). No patients discontinued therapy due to toxicity.

Of the 35 patients that completed at least 2 cycles of therapy, the ORR is 100% with 43% CR, 34% VGPR and 17% PR with responses deepening over time. Seventy-seven percent of patients achieved VGPR or greater. MRD was evaluable in 22 patients at 6 months with MRD negativity rate of 59% and 14% at thresholds of 10 ^-5 and 10 ^-6, respectively. At 12 months, 20 patients were MRD-evaluable with 65% and 20% achieving MRD negativity at 10 ^-5and 10 ^-6, respectively. Of the 10 MRD-evaluable patients at 24 months, 60% were MRD negative at 10 ^-5 and 40% at 10 ^-6. No patients have progressed on treatment. Stem cell collection was successful in all eligible patients with average stem cell yield of 5.53 x 10 ⁶ CD34+ cells/kg.

Conclusions: D-RVD in HR-SMM demonstrates significant activity, including a 100% ORR and high rates of MRD-negative disease, preventing progression to overt myeloma.