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.

Nadeem:Sanofi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; JNJ: Research Funding; GPCR Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mo:AbbVie, Bristol Myers Squibb, GSK, Janssen, Karyopharm, Sanofi, and Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie, Janssen, Karyopharm, and Sanofi: Consultancy. O'Donnell:Sanofi: Consultancy, Honoraria; BMS: Consultancy; Legend Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Exact Sciences: Honoraria; Natera: Membership on an entity's Board of Directors or advisory committees; Grail: Consultancy; Pfizer: Consultancy. Sperling:Novartis: Consultancy. Hartley-Brown:Karyopharm: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Multiple Myeloma Research Foundation: Consultancy, Honoraria, Research Funding; Cancer Care: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Research Funding. Midha:Pfizer: Consultancy; Janssen: Consultancy. Munshi:Oncopep: Current holder of stock options in a privately-held company; AbbVie, Adaptive Bio, Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Legend Bio, Novartis, Oncopep, Pfizer, Recordati, Sebia, Takeda: Consultancy. Anderson:Pfizer: Consultancy; Amgen: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy; Genentech: Consultancy; Window: Membership on an entity's Board of Directors or advisory committees; Dynamic Cell Therapies: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Starton Therapeutics: Membership on an entity's Board of Directors or advisory committees. Richardson:Celgene/Bristol Myers Squibb, GSK, Karyopharm Therapeutics, Oncopeptides, Regeneron, Sanofi: Consultancy; Oncopeptides: Research Funding. Ghobrial:Novartis: Consultancy; Regeneron: Consultancy, Other: Speaker fees; Disc Medicine: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy; Menarini Silicon Biosystems: Consultancy, Other: Speaker fees; Huron Consulting: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy, Other: Speaker fees; Janssen: Consultancy, Other: Speaker fees; Vor Biopharma: Other: Speaker fees; 10X Genomics: Consultancy; Amgen: Consultancy, Other: Speaker fees; PreDICTA Bioscience: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Other: Co-founder; Adaptive: Consultancy; CurioScience: Consultancy, Other: Speaker fees; AbbVie: Consultancy; Standard Biotools: Other: Speaker fees; Window Therapeutics: Consultancy; GlaxoSmithKline: Consultancy; Binding Site, part of Thermo Fisher Scientific: Consultancy; Bristol Myers Squibb: Consultancy, Other: Speaker fees; Aptitude Health: Consultancy; Takeda: Consultancy, Other: Speaker fees; Sognef: Consultancy.