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

Abstract

The efficacy of daratumumab is partially dependent on CD38 expression on multiple myeloma (MM) cells. We have previously shown that 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 daratumumab-refractory MM patients in a phase 1/2 study (NCT02751255). In part A of the study, 63 patients were treated with daratumumab monotherapy. Fifty daratumumab-refractory patients were subsequently enrolled in part B, and treated with daratumumab (re-intensified 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, the majority of patients (66%) achieved at least stable disease. After a median follow-up of 43 months, the median 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 to those who immediately progressed during daratumumab as single agent (median PFS 3.4 and 2.8 versus 1.3 months). The median OS 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 re-intensification of daratumumab had limited activity in daratumumab-refractory patients, which may be explained by the transient upregulation of CD38 expression.

Activity Screening of Fatty Acid Mimetic Drugs Identified Nuclear Receptor Agonists

“…The proteasome inhibitor, bortezomib, is approved for multiple myeloma treatment [ 27 ]. RAR agonists have been intensively studied in the same indication with promising results [ 28 , 29 , 30 ], suggesting a beneficial dual mode-of-action for bortezomib. Interestingly, sensitization of myeloma cells to proteasome inhibitors by concomitant retinoic acid treatment has recently been reported [ 31 ].…”

Expanding anti-CD38 immunotherapy for lymphoid malignancies

“…These results imply that anti-CD38 immunotherapies, either CAR T cells or antibodies, are effective for cancers with high CD38 expression. The toxicity of ATRA alone [ 37 ] or in combination with arsenic trioxide [ 38 ] or anti-CD38 antibody [ 39 ] is acceptable. Thus, our data broaden the potential clinical use of anti-CD38 immunotherapies to treat CD38 high lymphoid cancer cells and support the combinations with ATRA to treat CD38 low cancers that are sensitive to ATRA.…”

“…Likely, anti-CD38 immunotherapies with ATRA may not be the next best option for rituximab-resistant DLBCL. A recent clinical trial tested the efficacy and safety of daratumumab combined with ATRA in R/R MM patients, yet the addition of ATRA and intensification of daratumumab had limited activity [ 39 ]. Thus, caution must be exercised when evaluating the clinical benefit of anti-CD38 and ATRA to patients with lymphoid neoplasms, particularly for R/R patients.…”

Isatuximab in the Treatment of Multiple Myeloma: A Review and Comparison With Daratumumab

“… 9 However, in the most recent study, Frerichs et al found that the increased efficacy associated with the addition of ATRA was limited and temporary due to the transient nature of the upregulation of CD38 expression. 61 …”