A Phase 2 trial of the combination of Ixazomib, Thalidomide and Dexamethasone (ITD) in relapsed and/or refractory multiple myeloma

Abstract

Background: <br/>Despite improved survival outcomes in multiple myeloma (MM) relapse is inevitable and further therapeutic options are required for patients with relapsed and/or refractory disease (RRMM). Recently, the all oral triplet of Ixazomib/lenalidomide/dexamethasone (IRd) has been demonstrated to be an effective, well tolerated and convenient approach for RRMM. The challenge in many jurisdictions, however, is the potential financial burden associated with such a novel-novel combination approach. A more affordable all oral alternative is the combination of ixazomib/thalidomide/dexamethasone (ITd).<br/><br/>Aims: <br/>The AMaRC 16–02 trial was designed to evaluate the efficacy, safety and deliverability of ITd in RRMM.<br/><br/>Methods: <br/>AMaRC 16–02 was a multi-centre, single-arm, open-label, phase-2 study of ITd in RRMM patients with 1–3 prior lines of therapy. Treatment consisted of Ixazomib 4 mg on D1, 8 and 15 of each 28-day cycle; Thalidomide 100 mg daily D1–28; and Dexamethasone 40 mg on D1, 8, 15 and 22 of each 28-day cycle. Supportive care was as per institutional practice and treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent. The primary endpoint of the study was the overall response rate (ORR) as defined by IMWG criteria.<br/><br/>Results: <br/>The target of forty patients was recruited from 2 Australian sites. The data cut-off date was November 16, 2018 at which time 38 patients had either completed 4 cycles of treatment or terminated treatment early due to progression or intolerance. Median age was 66 years (range, 41–85) with 68% males. Median number of prior lines of therapy was 1 (range, 1–3). 42% had high-risk disease - del17p and/or +1q21 and/or t(14;16) and/or t(4;14). Patients received a median of 9 cycles of ITd (range, 1–24). Eleven patients (29%) received 45% is currently 94%. Median time to best response was 83 days for responders and 105 days when non-responders were censored at their dates of last contact. The clinical benefit rate (CBR) was 71.1% (95%CI: 55.0–82.9%). The posterior probability that the true CBR is >45% is currently >99%. The median PFS is 15.6m (95%CI: 8.3–21.1m). The median OS has not been reached.<br/><br/>Thirteen patients (34.2%) tolerated ITd dosing as per protocol. Thalidomide dose reduced in 26.3% and ceased in 26.3%. Dexamethasone was dose reduced in 28.9%. No patients remaining on study have dose reduced or ceased ixazomib. Eighteen patients currently remain on study therapy. Reasons for treatment cessation included - progressive disease 34.2%, adverse event (AE) 5.3%, withdrawal of consent 5.3%, lack of response 2.6%, new diagnosis of AML 2.6% and lost to follow-up 2.6%. Thirty patients experienced a total of 129 (all-grade) AEs regardless of relatedness to study treatment with new or worsening peripheral neuropathy (36.8%) and constipation (34.2%) the most common (all <Gde 3). Grade 3 AEs were reported for nausea (2.6%), infection (5.3%), thrombocytopenia (5.3%) and neutropenia (2.6%). With 1 Grade 4 AE (Cor Pulmonale secondary to severe COPD).<br/><br/>Summary/Conclusion: <br/>The combination of ITd represents an efficacious and tolerable all-oral therapeutic option for RRMM.