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.