Patients with multiple myeloma who have relapsed after or become refractory to lenalidomide in early treatment lines represent a clinically important population in need of effective therapies. The safety and efficacy of pomalidomide, low-dose dexamethasone, and daratumumab was evaluated in lenalidomide-pretreated patients with relapsed or refractory multiple myeloma (RRMM) after one to two prior treatment lines in the phase 2 MM-014 study. Patients received pomalidomide 4 mg daily from days 1–21 and dexamethasone 40 mg weekly (28-day cycles). Daratumumab 16 mg/kg was administered per label. Primary endpoint was overall response rate (ORR); secondary endpoints included progression-free survival (PFS) and safety. Per protocol, all patients (N = 112) had received lenalidomide in their most recent prior regimen (75.0% lenalidomide refractory). ORR was 77.7% (76.2% in lenalidomide-refractory patients); median follow-up was 17.2 months. Median PFS was not reached (1-year PFS rate 75.1%). The most common hematologic grade 3/4 treatment-emergent adverse event was neutropenia (62.5%). Grade 3/4 infections were reported in 31.3% of patients, including 13.4% with grade 3/4 pneumonia. These results demonstrate the safety and efficacy of pomalidomide-based therapy as early as second line in patients with RRMM, even immediately after lenalidomide failure, indicating that switching from the immunomodulatory agent class is not necessary.
Summary
Patients with relapsed/refractory multiple myeloma (RRMM) for whom the benefits of lenalidomide have been exhausted in early treatment lines need effective therapies. In cohort A of the phase 2 MM‐014 trial, we examined the safety and efficacy of pomalidomide plus low‐dose dexamethasone immediately after lenalidomide‐based treatment failure in patients with RRMM and two prior lines of therapy. Pomalidomide 4 mg was given on days 1 to 21 of 28‐day cycles. Dexamethasone 40 mg (20 mg for patients aged >75 years) was given on days 1, 8, 15 and 22 of 28‐day cycles. The primary endpoint was overall response rate (ORR), and secondary endpoints included progression‐free survival (PFS), overall survival (OS) and safety. The intention‐to‐treat population comprised 56 patients; all received prior lenalidomide (87·5% lenalidomide refractory) and 39 (69·6%) received prior bortezomib. ORR was 32·1% (28·2% in the prior‐bortezomib subgroup). Median PFS was 12·2 months (7·9 months in the prior‐bortezomib subgroup). Median OS was 41·7 months (38·6 months in the prior‐bortezomib subgroup). The most common grade 3/4 treatment‐emergent adverse events were anaemia (25·0%), pneumonia (14·3%) and fatigue (14·3%). These findings support earlier sequencing of pomalidomide‐based therapy in lenalidomide‐pretreated patients with RRMM, including those who have become refractory to lenalidomide.
Trial registration: http://www.ClinicalTrials.gov identifier NCT01946477.
Purpose: Addition of daratumumab to pomalidomide and lowdose dexamethasone (LoDEX) is a safe and effective combination for relapsed/refractory multiple myeloma treatment. We sought to better understand immune combinational benefit of pomalidomide and daratumumab with LoDEX. Experimental Design: Immunophenotypic changes were analyzed in peripheral blood from longitudinal sampling of patients treated with this triplet regimen from cohort B of the CC4047-MM-014 phase II trial (NCT01946477). Results: Consistent with the daratumumab mechanism, treatment led to decreased natural killer (NK) and B cells. In contrast, pronounced increases occurred in activated and proliferating NK and T cells, appreciably in CD8 þ T cells, along with reduction in na€ ve and expansion of effector memory compartments. Timing of T-cell changes correlated with pomalidomide dosing schedule. Enhanced activation/differentiation did not result in increased exhausted T-cell phenotypes or increases in regulatory T cells. Similar immune enhancements were also observed in patients previously refractory to lenalidomide. Conclusions: These data support a potential mechanism for enhanced immune-mediated cytotoxicity in which daratumumabmediated NK-cell diminution is partially offset by pomalidomide effects on the remaining NK-cell pool. Furthermore, daratumumab antimyeloma activity and elimination of CD38 þ T cells (regulatory/ activated) provide a rationale for therapeutic combination with direct tumoricidal activity and immunomodulation of pomalidomide-directed T-cell enhancements. These data highlight enhancements in immune subpopulations for the combination of daratumumab with pomalidomide and potentially with next-generation cereblon-targeting agents.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.