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 and clinical benefit in newly-diagnosed multiple myeloma (MM) and is now a standard of care regimen for transplant-eligible patients. Lenalidomide has been shown to delay progression in patients with high-risk smoldering multiple myeloma (HR-SMM) and curative intent trials in this population with carfilzomib-based therapy and stem cell transplantation have shown deep responses but generated concern for treatment-related toxicities and mortality. Thus, we proposed to examine the activity and safety of fixed duration D-RVD in patients with HR-SMM, incorporating an MRD-adapted approach to duration of therapy. Methods: This is a phase II, open-label study evaluating D-RVD in HR-SMM. Eligibility criteria includes HR-SMM per IMWG/Mayo 2018 “20-2-20” model, Mayo 2008 criteria, PETHEMA criteria, evolving type of SMM, and/or high-risk FISH. Treatment with D-RVD is 2 years (24, 28 day 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, and lenalidomide 25mg on days 1-21 for cycles 1-6 followed by 15mg d1-21 from cycles 7-24 with 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 to evaluate the rate of MRD conversion from positive to negative. Results: At the time of data cut off in May 2024, 45 patients have been enrolled to part 1 with a median follow up of 25 months. The median age is 64 years old (range 36-78) with 26 females (58%) and 19 males (42%). The median bone marrow plasmacytosis of enrolled patients was 30%, with median M-protein of 1.99 g/dL and median FLC ratio of 22.11. Thirty patients (67%) were high-risk per 20-2-20 criteria. Twenty- two of the 32 FISH-evaluable patients (69%) had at least one high-risk FISH abnormality (seventeen with 1q gain, four with t(4;14), three with monosomy 13, two with t(14;16) and two with del 17p). Four patients (13%) had more than one high-risk FISH abnormality. Most common grade 3 toxicities included neutropenia (22%), ALT increased (9%), and diarrhea (7%). Upper respiratory infections occurred in 57% of patients but were mostly low-grade, with grade 3 lung infection occurring in only 7% of patients. One participant discontinued therapy secondary to intolerable adverse events. Of the 43 patients that completed at least 2 cycles of therapy, the ORR is 98% with 63% CR, 21% VGPR and 14% PR, including responses deepening over time. Eighty-four percent of patients achieved VGPR or greater. MRD was evaluable in 36 patients at 6 months with an MRD negativity rate of 53% and 17% at thresholds of 10-5 and 10-6, respectively. At 12 months, 31 patients were MRD-evaluable with 55% and 23% achieving MRD negativity at 10-5 and 10-6, respectively. Of the 20 MRD-evaluable patients at 24 months, 65% were MRD negative at 10-5 and 45% at 10-6. One patient has progressed biochemically and there are no SLIM-CRAB progressions to date. Median PFS has not been reached and the 2-year biochemically assessed PFS-rate is 92%. Stem cell collection was successful in all eligible patients with an average stem cell yield of 4.89 x 106 CD34+ cells/kg, collected over median of 1 day. Conclusions: D-RVD in HR-SMM demonstrates significant activity, including a 98% ORR and high rates of MRD-negative disease, preventing progression to overt MM, with improvements in outcome seen over time.