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
Authors: Verkleij Christie P.M. , Minnema Monique C. , de Weerdt Okke , Bosman Patricia W.C. , Frerichs Kristine A. , Croockewit Alexandra J. , Klein Saskia K. , Bos Gerard , Mutis Tuna , Plattel Wouter J. , van der Spek Ellen , Broyl Annemiek , Sonneveld Pieter , Zweegman Sonja , Levin Mark-David , Van De Donk Niels W. C. J. 
Published: November 2019

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 <75x109/L, absolute neutrophil count <1.0x109/L, FEV1 <50%, significant hepatic or renal dysfunction (CrCl <30 mL/min), or active autoimmune disease or inflammatory disorder. All patients gave written informed consent. The study was conducted in accordance with the principles of the Declaration of Helsinki.
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.

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