Multiple Myeloma Clinical Trial
Official title:
A Phase II Trial of Daratumumab, Lenalidomide and Dexamethasone (DRd) in Combination With Selinexor for Patients With Newly Diagnosed Multiple Myeloma
This is a single-arm, phase II, open-label trial to investigate the effects of selinexor (S) in combination with daratumumab, lenalidomide, and dexamethasone (DRd) for first-line treatment of multiple myeloma (MM). FDA has approved selinexor plus dexamethasone in multiple myeloma after four prior therapies, and DRd is also already approved by the FDA for multiple myeloma. This study will use all four (S-DRd) together to treat MM as an initial treatment.
Multiple myeloma (MM) is an incurable disease with high death rates as a result of developing resistance to treatments. Even with the advent of novel therapies, myeloma patients ultimately progress from frontline therapy. Common treatments include glucocorticoids, chemotherapy, proteasome inhibitors (PIs), Immunomodulatory imide drugs (IMiDs), stem cell transplants, and radiation therapy. Optimal frontline therapy with deeper remissions translates to improved overall survival and progression free survival. The purpose of this study is to investigate and improve upon reported outcomes in the frontline setting. Selinexor has shown potent anti-myeloma activity in preclinical models of MM and Phase 1, Phase 2 clinical studies as well as in a randomized phase 3 clinical trial called BOSTON. Selinexor was approved by the US FDA in July 2019 in combination with dexamethasone for the treatment of adult patients relapsed/refractory (RR) MM who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 (anti-cluster of differentiation 38) monoclonal antibody. In June 2020, Selinexor was approved as a monotherapy by the FDA for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after at least 2 lines of systemic therapy. Treatment with combination therapies including daratumumab, lenalidomide, and dexamethasone has shown improvement in response rates, time to progression, and survival. Daratumumab is an approved CD38-directed cytolytic antibody used as a monotherapy for patients with heavily pre-treated MM, and in combination with lenalidomide and dexamethasone. The risk of death or disease progression was 44% lower and increased overall response rate (ORR) of 92.9% was observed in patients with newly diagnosed MM that received the triplet combination of daratumumab, lenalidomide, and dexamethasone (DRd) compared to lenalidomide and dexamethasone alone (Rd). Tolerability of the DRd combination in patients was consistent between DRd and Rd treatments. The safety profile of DRd was shown to be consistent with known safety profiles of daratumumab and Rd. Higher rates of infections (upper respiratory tract infection and pneumonia) and neutropenia in DRd treated patients than in Rd treated patients were observed. However, grade 3 or 4 infections were similar between DRd and Rd treatment groups and were managed by standard of care. After exposure to DRd for a median of 34 months, no new safety concerns were observed in the extended follow-up of the POLLUX phase III study. Preclinical data demonstrated that patient-derived MM cells were sensitized to the combination of Selinexor and daratumumab compared to the single agents. Clinical data demonstrate an ORR of 74% in patients with relapsed myeloma treated with Selinexor, daratumumab, and dexamethasone. The rationale for the combination of Selinexor, lenalidomide, daratumumab, and dexamethasone (S-DRd) in the current study is based on the following: preclinical synergistic activities observed with Selinexor and dexamethasone, the preclinical activity of Selinexor combined with both lenalidomide and daratumumab; as well as the clinical experience of the combination of Selinexor and lenalidomide/dexamethasone can be safely combined with 92% ORR in patients with relapsed myeloma; and the combination of Selinexor and daratumumab/dexamethasone can also be safely combined with an ORR of 74%. There is an urgent need to induce more efficient, deeper and durable responses in patients with newly diagnosed MM. ;
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