Efficacy and Safety of Nivolumab Combined with Daratumumab with or without Low-Dose Cyclophosphamide in Relapsed/Refractory Multiple Myeloma; Interim Analysis of the Phase 2 Nivo-Dara Study

Introduction: Daratumumab (DARA) monotherapy is effective and well tolerated in heavily pretreated relapsed/refractory multiple myeloma (RRMM) patients. However, approximately 70% of patients do not respond and eventually all patients will develop progressive disease. DARA treatment results in depletion of CD38+ immune suppressor cells and thereby increased T cell frequencies. A partner drug with immune stimulating activity through a different mechanism of action could further improve the efficacy of DARA. As a single agent, the Programmed Death (PD)-1 checkpoint inhibitor nivolumab induced only stable disease in 67% of RRMM. Immune modulation through targeting CD38 combined with blocking the PD-1/PD-L1 axis may lead to improved T and NK cell activity and therefore better anti-MM efficacy. Preclinical studies showed that cyclophosphamide has synergistic activity with both DARA and PD-1 inhibitors. In this study, we investigate the efficacy and safety of DARA combined with nivolumab, with or without low-dose cyclophosphamide, in RRMM. This trial is registered at ClinicalTrials.gov as NCT03184194. Methods: In part A of this prospective multicenter phase 2 trial, we treated 6 patients with nivolumab-daratumumab (ND), and subsequently 6 patients with nivolumab-daratumumab-cyclophosphamide (NDc) as safety run-in. Next, 28 patients were randomized between both treatment arms at a 1:1 ratio. Twenty additional patients will be treated with either ND or NDc in part B, based on safety and efficacy data as derived in part A. Patients were treated with 28-day cycles until progressive disease. Daratumumab 16 mg/kg i.v. was administered weekly in cycles 1-2, biweekly in cycles 3-6 and every 4 weeks from cycle 7. Nivolumab was administered biweekly (240mg i.v) in cycles 1-6 (in cycle 1 on day 2 and 16) and every 4 weeks (480mg i.v ) thereafter. In the NDc arm, low-dose oral cyclophosphamide (50mg once daily) was given continuously. Inclusion criteria were age ≥18 years, WHO performance score of 0-2, ≥2 prior therapies, lenalidomide-refractory disease, and prior treatment with a proteasome-inhibitor-containing regimen for ≥2 consecutive cycles. Main exclusion criteria were platelet count In this first planned interim analysis we report on efficacy (overall response rate (ORR)) and safety of part A of the study. Results: Between February 2018 and January 2019, 40 patients were enrolled in part A of this study. The demographics are described in Table 1. At data cut-off (July 1st 2019), 13 patients were still on treatment. Median follow-up of surviving patients is 8.6 months (range 5.0-16.1). The ORR was 50% in both treatment groups (Figure 1); the disease control rate (≥ stable disease) was 85% for ND and 80% for NDc. Ten patients (25%) died due to progressive disease, which was equally distributed over treatment arms. Two patients died during NDc treatment: one (2.5%) due to a cardiac arrest and one (2.5%) due to an Aspergillus fumigatus infection. Non-hematologic toxicity was manageable: daratumumab-associated infusion related reactions (IRRs) occurred in 8 (20%) patients, all during the first administration and all grade ≤3. No IRRs related to nivolumab were reported. Two immune-mediated adverse events occurred: both concerned grade 2 hypothyroidism. The infection rate was higher in patients treated with NDc (24 infections in 12 patients; CTC grade ≥3 in 25% of infections), compared to ND treatment (13 infections in 9 patients; CTC grade ≥3 in 8%). A higher need for supportive care in the form of granulocyte-colony stimulating factor, erythrocyte- and/or platelet transfusion was found in the NDc arm (n=10; 50%), compared to ND treatment (n=6; 30%). Conclusion: Here we show for the first time that, although follow-up is still short, the combination of daratumumab and nivolumab may be a new therapeutic regimen with an acceptable safety profile in RRMM. Addition of low-dose cyclophosphamide did not improve ORR, but increased the frequency of infections and hematologic toxicity, when compared to ND alone. Therefore, the nivolumab-daratumumab regimen was selected for further evaluation in part B. Download : Download high-res image (153KB) Download : Download full-size image Disclosures Minnema: Gilead: Honoraria; Amgen: Honoraria; Jansen Cilag: Honoraria; Servier: Honoraria; Celgene Corporation: Honoraria, Research Funding. Bos: Celgene: Research Funding; Kiadis Pharma: Other: Shareholder (of Cytosen, acquired by Kiadis). Mutis: Genmab: Research Funding; Janssen Research and Development: Research Funding; Celgene: Research Funding; Onkimmune: Research Funding. Broyl: Celgene, amgen, Janssen,Takeda: Honoraria. Sonneveld: Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; SkylineDx: Research Funding; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding. Zweegman: Celgene: 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 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Levin: Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant ; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant . Van De Donk: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: 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; Celgene: 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, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Nivolumab: off-label treatment for Multiple Myeloma