Efficacy and safety of daratumumab combined with all-trans retinoic acid in relapsed/refractory multiple myeloma

Abstract

The efficacy of daratumumab depends partially on CD38 expression on multiple myeloma (MM) cells. We have previously shown that all-trans retinoic acid (ATRA) upregulates CD38 expression and reverts daratumumab-resistance ex vivo. We therefore evaluated the optimal dose, efficacy, and safety of daratumumab combined with ATRA in patients with daratumumab-refractory MM in a phase 1/2 study (NCT02751255). In part A of the study, 63 patients were treated with daratumumab monotherapy. Fifty patients with daratumumab-refractory MM were subsequently enrolled in part B and treated with daratumumab (reintensified schedule) combined with ATRA until disease progression. The recommended phase 2 dose of ATRA in combination with daratumumab was defined as 45 mg/m2. At this dose, the overall response rate (ORR) was 5%, indicating that the primary endpoint (ORR ≥15%) was not met. However, most patients (66%) achieved at least stable disease. After a median follow-up of 43 months, the median progression-free survival (PFS) for all patients was 2.8 months. Patients who previously achieved at least a partial response or minimal response/stable disease with prior daratumumab monotherapy had a significantly longer PFS compared with patients who immediately progressed during daratumumab as single agent (median PFS 3.4 and 2.8 vs 1.3 months). The median overall survival was 19.1 months. The addition of ATRA did not increase the incidence of adverse events. Flow cytometric analysis revealed that ATRA temporarily increased CD38 expression on immune cell subsets. In conclusion, the addition of ATRA and reintensification of daratumumab had limited activity in patients with daratumumab-refractory MM, which may be explained by the transient upregulation of CD38 expression. This trial was registered at www.clinicaltrials.gov as #NCT02751255.

© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Figures

Graphical abstract

Figure 1.

Patient flow diagram. Of 63 patients enrolled in part A (daratumumab monotherapy), 2 patients were still on treatment at data cutoff, 14 patients were enrolled in part B (daratumumab + ATRA) phase 1, 36 patients were enrolled in part B phase 2, and 10 patients were not enrolled in part B because of ineligibility or withdrawal of informed consent. All 63 patients enrolled in part A were evaluated for safety and efficacy, all 14 patients enrolled in part B phase 1 were evaluated for the assessment of the RP2D, and all 44 patients treated at the RP2D in part B were evaluated for safety and efficacy.

Figure 2.

Response, PFS, and OS for patients treated with daratumumab combined with ATRA at the RP2D. (A) Response, (B) PFS-B, and (C) OS-B for all patients treated with daratumumab combined with ATRA at the RP2D of 45 mg/m2. (D) PFS-AB and (E) OS-AB for the whole treatment strategy of daratumumab monotherapy followed by the daratumumab/ATRA combination for all patients treated at the RP2D.

Figure 3.

PFS-B and PFS-AB stratified according to best response to daratumumab monotherapy. (A) PFS-B and (B) PFS-AB stratified according to best response to daratumumab monotherapy during part A of the study (PR or better, SD/MR, or PD). NE, not evaluable.

Figure 4.

CD38 expression levels on immune cell subsets in PB samples obtained during treatment with daratumumab monotherapy followed by daratumumab with ATRA. (A) CD38 expression levels on monocytes, B cells, T cells, NK cells, and activated NK cells (CD16+) in sequential PB samples obtained before start of daratumumab monotherapy (C1D1 of part A; n = 55), and after 1 cycle of daratumumab monotherapy (C2D1 of part A; n = 51). (B) CD38 expression levels on these immune cell subsets in sequential PB samples obtained before start of ATRA treatment (C1D1 of part B; n = 51), before first dose of daratumumab after initiation of ATRA (C1D3 of part B; n = 42), after 1 cycle of daratumumab and ATRA treatment (C2D3 of part B; n = 36), and at disease progression during daratumumab and ATRA treatment (EOT, part B; n = 33). Dots represent individual expression levels; error bars represent median and IQR. Median fluorescence intensity is provided for each timepoint. Differences between indicated groups were calculated using Wilcoxon matched-pairs rank test. *P < .05; **P < .01; ***P < .001; ****P < .0001. EOT, end of treatment; IQR, interquartile range; MFI, median fluorescence intensity; ns, not significant.