Clinical efficacy of daratumumab, pomalidomide, and dexamethasone in patients with relapsed or refractory myeloma: Utility of re‐treatment with daratumumab among refractory patients

Abstract

BACKGROUND:The efficacy of daratumumab (DARA) both as a monotherapy and in combination with standard-of-care regimens in multiple myeloma (MM) has been established in clinical trials. This article presents a retrospective analysis of the safety and efficacy of DARA in combination with pomalidomide (POM) and dexamethasone (ie, daratumumab, pomalidomide, and dexamethasone [DARA-POM-D]) and, more importantly, the long-term follow-up of a cohort that was naive to DARA and POM as well as a cohort in which the utility of re-treatment was evaluated among patients who were DARA-and/or POM-refractory. METHODS: Thirty-four consecutive patients with relapsed and/or refractory MM treated with DARA-POM-D at the Winship Cancer Institute of Emory University from January 2015 through July 2016 were included in the analysis. The study was approved by Emory University's institutional review board. All received prior proteasome inhibitors and immunomodulatory drugs (IMiDs) and were refractory to their last line of therapy. RESULTS: All patients were lenalidomide-refractory, and 91% were bortezomibrefractory. Two cohorts were identified on the basis of prior exposure to DARA and/or POM. Cohort 1 (12 patients) was DARAand POM-naive, and cohort 2 (22 patients) was DARA-and/or POM-refractory. A subgroup of 12 patients in cohort 2 (cohort 3) was DARA-and POM-refractory. The combination's tolerability was consistent with the results of the published phase 1b study (EQUULES) that evaluated the combination and no new safety signals were observed. The overall response rates (ORRs) were 91.7%, 40.9%, and 33.3% in cohorts 1, 2, and 3, respectively. Deep responses, including 4 stringent complete responses, were observed in cohort 1. In cohort 2, the ORR comprised 8 partial responses (PRs) and 1 very good PR. The median progression-free survival (PFS) was not reached in cohort 1 at a median follow-up of 41 months, and it was 3.2 months in cohort 2. DARA-POM-D not only was effective in DARA-and POM-naive patients but also produced clinical responses in a third of patients re-treated with these drugs. CONCLUSIONS: A better than quadrupled PFS benefit observed in cohort 1 in comparison with the previously reported benefit in the EQUULEUS trial (which led to US Food and Drug Administration approval of the DARA-POM-D combination) highlights the fact that the introduction of monoclonal antibody combination strategies and IMiDs as earlier lines of therapeutic options potentially could deliver better clinical outcomes. One-third of patients refractory to separate lines of DARA and/or POM responded when they were re-treated with a combination, and this resulted in survival benefits equivalent to those of other antimyeloma agents/combinations available for DARA-refractory patients. Cancer 2019;125:2991-3000.

Daratumumab, pomalidomide and dexamethasone combination therapy in daratumumab and/or pomalidomide refractory multiple myeloma

“…Our observations are in line with those reported by Nooka et al (). In their hands, the ORR with DaraPd was 36·8% in patients with Dara or Pom‐refractory disease and 33·3% for those with Dara and Pom‐refractory disease (Nooka et al , ). This would support the hypothesis that the DaraPd combination has the potential to overcome resistance to the individual agents, at least in some cases.…”

Daratumumab in multiple myeloma

“…Other grade 3 or higher hematologic AEs of interest were anemia and thrombocytopenia, which were observed in 32% and 24% of the patients, respectively. Most importantly, this analysis has demonstrated that even in patients who are refractory to both daratumumab and pomalidomide as individual lines of therapy, the combination can be reused to recapture responses, as evidenced by the ORR of nearly 35% in this cohort of daratumumab‐ and pomalidomide‐refractory patients . A phase 3 randomized study of DPd versus Pd (APOLLO; NCT03180736) for patients with relapsed/refractory multiple myeloma is ongoing (Table ).…”

“…Our group at Emory evaluated the efficacy of the DPd regimen in heavily pretreated patients with relapsed/refractory multiple myeloma. This analysis reviewed the utility of retreatment with daratumumab among daratumumab‐refractory patients . A subgroup of 12 patients in cohort 2 (cohort 3) were daratumumab‐ and pomalidomide‐refractory.…”

“…No dose reductions should be made for daratumumab. When daratumumab is used in combination with IMiDs (DRd or DPd), the dose of the myelosuppressive combination agent can be at started at 1 dose level lower . If there are no issues with myelosuppression, the dose of the IMiD can be escalated to the original dose in the following cycle.…”

New developments in the treatment of multiple myeloma &ndash; <br />clinical utility of daratumumab

“…An ORR of 57.5% was noted in 40 double-refractory patients. Retrospective data from Emory University Hospital using this combination have also been presented 40. In 19 daratumumab- and pomalidomide-naïve patients with a median of three prior lines of treatment, they reported an ORR of 89%.…”