Efficacy and Safety of Daratumumab Combined with All-Trans Retinoic Acid in Relapsed/Refractory Multiple Myeloma; Results of the Phase 1/2 Dara/ATRA Study
Authors: Frerichs Kristine A. , Minnema Monique C. , Levin Mark-David , Broyl Annemiek , Bos Gerard , Kersten Marie José , Mutis Tuna , Verkleij Christie P.M. , Bosman Patricia W.C. , Klein Saskia K. , Zweegman Sonja , Sonneveld Pieter , Van De Donk Niels W. C. J. 
Published: November 2019

Introduction: Daratumumab (DARA) has potent single agent activity in relapsed/refractory multiple myeloma (RRMM). The effectivity of DARA is partially dependent on the expression of its target, CD38, on tumor cells. Upregulation of CD38 on MM cells by all-trans retinoic acid (ATRA) improved the ex vivo efficacy of DARA, even in DARA-resistant MM cells. We therefore evaluated the efficacy and safety of DARA combined with ATRA in RRMM patients in the DARA/ATRA study (NCT02751255).
Methods: In part A of this prospective, multicenter phase 1/2 trial, DARA was administered according to the approved schedule (16 mg/kg; cycles 1-2: weekly; cycles 3-6: biweekly; cycles ≥7: monthly). In part B, ATRA was given twice daily during 3 days prior to each DARA infusion. DARA dosing was resumed according to the aforementioned schedule.
Inclusion criteria were ≥2 prior lines of treatment, WHO performance score 0-2, adequate bone marrow reserve, kidney and hepatic function. Patients were enrolled in part B, after treatment in part A, if they developed disease progression (PD), or if they had insufficient response defined as < minimal response (MR) after cycle 2, or < partial response (PR) after cycle 3, and if they still fulfilled the other inclusion criteria. All patients gave written informed consent.
In phase 1 of part B, we determined the maximum tolerated dose (MTD) of ATRA (dose levels: 15, 30 and 45mg/m2) and the recommended dose level (RDL) for phase 2.
We here report overall response rate (ORR), progression free survival (PFS(A)), overall survival (OS) and adverse events (AEs) for all patients in part A. For patients treated at the RDL in part B, we report ORR, PFS(A), PFS for part A + B combined (PFS(A+B)) and AEs.
Results: Between July 2016 and October 2017, 63 patients were enrolled in part A, baseline characteristics are described in Table 1. At data cut-off (July 1st, 2019), 6 patients were still on treatment in part A. The median duration of follow-up of surviving patients at data cut-off was 26 months (range 18.2 - 39.4 months). The ORR in part A was 41% (22% PR, 14% very good PR [VGPR] and 5% (stringent) complete remission; Figure 1). The median PFS(A) and OS from start of DARA for all enrolled patients were 7.0 months (95% CI 5.3-8.8) and 28.2 months (95% CI 20.4-36.0), respectively. Eight patients did not meet eligibility criteria for part B, and 1 patient refused further treatment in part B.
In part B phase 1, 14 patients were treated with ATRA at the 3 dose levels. The MTD was not reached and the RDL for phase 2 was defined as 45mg/m2. At data cut-off, 34 patients were enrolled in part B phase 2, of whom 2 patients were still on treatment. Thirty-two patients stopped treatment due to PD (n=28) or withdrawal of consent (n=4).
Next, we focused on all 42 patients who were treated at the RDL in part B (8 patients in phase 1, and 34 patients in phase 2). The ORR in part B was 5% (VGPR n=2). However, 57% achieved MR or stable disease (SD; Figure 1). During part A, median PFS(A) in these patients was 6.7 months (95% CI 2.7-10.6). When stratified by ≥PR vs SD/MR vs PD/not evaluable (NE), median PFS(A) was 9.9 months (95% CI 3.1-16.7) vs 3.2 months (95% CI 2.5-3.9) vs 1.2 months (95% CI 0.8-1.5), respectively. Addition of ATRA and re-intensification of DARA in DARA-refractory patients resulted in a median PFS(A+B) of 7.9 months (95% CI 5.6-10.1 months). When stratified by ≥PR vs SD/MR vs PD/NE in part A, median PFS(A+B) was 17.7 months (95% CI 9.6-25.7) vs 5.4 months (95% CI 3.8-7.0) vs 2.5 months (95% CI 2.1-2.9), respectively. The presence of extramedullary plasmacytomas (P=0.004 and P=0.012) and WHO ≥ 1 (P=0.002 and P=0.005) were associated with lower PFS(A) and PFS(A+B).
Importantly, combination of ATRA with DARA did not increase the rate of AEs (Table 2). The incidence of any grade infusion related reactions (IRR) was 34.9%. There were no complications with red blood cell transfusions.
Conclusion: Here, we report for the first time on the efficacy of DARA re-intensification, combined with ATRA in DARA-refractory patients. Overall, this approach resulted in a modest prolongation of PFS. Patients with primary DARA-refractory disease did not benefit from the addition of ATRA. However, in patients with ≥PR on DARA monotherapy prior to progression, addition of ATRA and re-intensification of DARA was of marked clinical benefit with an additional 7.8 months of disease control. The combination of DARA and ATRA was well tolerated and safe.

Disclosures
Minnema: Celgene Corporation: Honoraria, Research Funding; Amgen: Honoraria; Gilead: Honoraria; Servier: Honoraria; Jansen Cilag: Honoraria. Levin:Takeda: 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 ; Janssen: 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; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant. Broyl:Celgene, amgen, Janssen,Takeda: Honoraria. Bos:Celgene: Research Funding; Kiadis Pharma: Other: Shareholder (of Cytosen, acquired by Kiadis). Kersten:Miltenyi: Honoraria; Mundipharma: Honoraria, Research Funding; Kite Pharma: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Gilead: Honoraria; Amgen: Honoraria, Research Funding; Takeda Oncology: Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Novartis: Honoraria. Mutis:Janssen Research and Development: Research Funding; Celgene: Research Funding; Onkimmune: Research Funding; Genmab: 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. Sonneveld:SkylineDx: Research Funding; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding. Van De Donk:Bristol-Myers Squibb: 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; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: 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; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: 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.

OffLabel Disclosure:
ATRA for treatment of MM