Efficacy and Updated Safety Analysis of a Safety Run-in Cohort from Griffin, a Phase 2 Randomized Study of Daratumumab (Dara), Bortezomib (V), Lenalidomide (R), and Dexamethasone (D; Dara‐Vrd) Vs. Vrd in Patients (Pts) with Newly Diagnosed (ND) Multiple Myeloma (MM) Eligible for High‐Dose Therapy (HDT) and Autologous Stem Cell Transplantation (ASCT)
Authors: Voorhees Peter M. , Rodriguez Cesar , Reeves Brandi , Nathwani Nitya , Costa Luciano J , Lutska Yana , Hoehn Daniela , Pei Huiling , Ukropec Jon , Qi Ming , Lin Thomas , Richardson Paul 
Published: October 2019

Abstract
Background: Dara, a human IgGκ monoclonal antibody that targets CD38, is approved as monotherapy and in combination with Vd, Rd, and pomalidomide-d for the treatment of relapsed MM and in combination with V, melphalan, and prednisone (VMP) for treatment of ASCT-ineligible ND MM. Addition of dara to these regimens improved the depth of response including complete response (CR), stringent CR (sCR), and minimal residual disease (MRD) negativity rates. VRd followed by HDT, ASCT, and consolidation VRd has yielded high response rates in ND MM. Therefore, a safety run-in was first conducted to determine the tolerability of dara-VRd before proceeding with a larger randomized phase 2 study of dara-VRd vs. VRd in ASCT-eligible ND MM pts.
Methods: This is an ongoing multicenter, randomized, open‐label, active‐controlled US study. Key eligibility criteria include: aged 18‐70 years; eligibility for HDT/ASCT; documented MM per IMWG criteria; ECOG performance score 0‐2; and no prior systemic therapy for MM. A safety run-in phase was performed in 16 pts to assess potential dose limiting toxicities (DLTs) during Cycle (C)1 of dara-VRd. Pts received 4 induction cycles of dara-VRd every 21 days followed by stem cell (SC) mobilization, HDT, ASCT; 2 consolidation cycles of dara-VRd; and maintenance therapy with dara-R for 24 months. During induction and consolidation (C1‐6), pts received R 25 mg orally on Days 1‐14; V 1.3 mg/m2 subcutaneously on Days 1, 4, 8, and 11; and d 40 mg weekly. Dara 16 mg/kg IV was given on Days 1, 8, and 15 of C1‐4 and on Day 1 of C5‐6. During maintenance (C7-32), pts received R 10 mg daily (15 mg beginning at C10 if tolerated) on Days 1‐21 every 28 days and dara 16 mg/kg IV every 56 days; this was amended to every 28 days. Maintenance R may be continued beyond C32 per local standard of care.
Results: Sixteen pts were enrolled in the safety run-in, and all had completed ≥9 cycles of dara-VRd, including ≥3 cycles of maintenance, as of 18-Jul-2018. Median age was 62.5 years, and 50% were male. Four (25%) pts were ISS stage II or III; the rest were stage I. Most (63%) pts had ECOG=1. Pts have received a median of 11 (9-12) cycles, including 3-6 maintenance cycles, to date. By the end of consolidation (C6), all pts (100%) reached VGPR or better and 63% achieved CR or sCR per investigator assessments (using IMWG criteria). MRD negativity (10-5 using Clonoseq2) was seen in 8 patients. Responses continued to deepen during maintenance. All 16 pts experienced ≥1 treatment-emergent adverse event (AE), with 10 (63%) pts having ≥1 serious AE (SAE), including 3 (19%) pts with ≥1 SAE related to dara. Fourteen (88%) pts had grade 3-4 AEs, with 11 (69%) related to dara. Most commonly reported (≥10%) grade 3-4 AEs included neutropenia, pneumonia, thrombocytopenia, lymphopenia, febrile neutropenia, leukopenia, and hypophosphatemia. Twelve (75%) pts experienced infections, including pneumonia (4), E Coli bacteremia, sinusitis, and gastroenteritis (1 each). No deaths due to SAEs were reported, and no pt discontinued treatment due to an AE. Dara infusion reactions were reported in 5 (31%) pts. All 16 pts underwent successful mobilization with subsequent transplant. With a median follow-up time of 15.6 months, 15 of 16 (94%) pts remain progression free on study treatment.
Conclusion: The overall safety profile of dara-VRd was consistent with those previously reported for dara and VRd, with manageable toxicity and no new safety findings with longer therapy. Dara-VRd was active with an investigator-assessed VGPR+ rate of 100% and an sCR+CR rate of 63% after consolidation therapy. MRD negativity was seen in a subset of patients, and further analysis is underway and will be presented. SC mobilization proved successful in all pts. In aggregate, these data suggest that dara-VRd may be a very effective regimen in ASCT-eligible ND MM and that dara induction does not negatively impact SC mobilization. Enrollment to the 200-pt main phase of the randomized study is now complete, and primary endpoint (sCR after consolidation) will be available next year.
www.clinicaltrials.gov identifier: NCT02874742

Disclosures
Voorhees: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Speakers Bureau; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: served on an IRC; TeneoBio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Other: served on an IRC; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: served on an IRC. Rodriguez:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Costa:Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Research Funding; Sanofi: Honoraria; BMS: Research Funding; Abbvie: Research Funding; Karyopharm: Research Funding. Lutska:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Hoehn:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Pei:Janssen Research & Development, LLC: Employment. Ukropec:Janssen Scientific Affairs, LLC: Employment. Qi:Janssen Research & Development, LLC: Employment. Lin:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Richardson:BMS: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.