Final Results of a Phase I/II Trial of the Combination of Concurrent Lenalidomide, Thalidomide and Dexamethasone in Patients with Relapsed and/or Refractory Myeloma

The combination of lenalidomide (Len) and dexamethasone (Dex) has demonstrated overall response rates (ORR) of 60% in relapsed and/or refractory multiple myeloma (RRMM). Preclinical studies have demonstrated Len resistance is mediated via the Wnt/β-catenin pathway, which can be reversed by thalidomide (Thal). The concurrent administration of Len, Thal and Dex has not previously been evaluated in RRMM. Our hypothesis proposed that the concurrent administration of Len, Thal and Dex may overcome Len resistance and improve response rates in patients with relapsed and/or refractory myeloma. The aim of this study was to determine the maximum tolerated dose (MTD) of the combination of Len/Thal/Dex and evaluate efficacy of the combination.

The primary objective of the phase 1 portion was to determine the MTD, and the primary objective of the phase 2 was to determine the overall response rate. Patients (pts) with relapsed and/or refractory myeloma with ≥1 line of therapy were eligible, and received dexamethasone in pulse dose fashion in cycles 1–2, and weekly Dex in cycles 3 and beyond. The protocol was amended to enroll an additional 10 patient cohort who were Len refractory and received Dex on days 1, 8, 15 and 22 starting with cycle 1. All patients received anticoagulation with warfarin or low molecular weight heparin. Phase 1 data has been previously presented, and herein we present the final data from the phase 1/2. Adverse events (AEs) were graded by NCI-CTCAE v4, and responses were assessed by the modified International Uniform Response Criteria.

64 patients were enrolled who had a median of 4 prior lines of therapy (range: 1–12), a median age of 65 (range: 36–86), and 40/64 (63%) were males. 60/64 patients had available cytogenetic data; and 52% (31/60) had high risk cytogenetics, including 40% (24/60) with deletion 13; 13% (8/60) with deletion 17p; 5% (3/60) with t(4:14); and 12% (7/60) with t(11:14). These patients were heavily pretreated, with 66% (42/64) having Len refractory disease; 56% (36/64) had prior Thal; and 77% (49/64) had prior autologous transplantation. The maximum tolerated dose used for phase 2 was Len 25 mg/Thal 100 mg/Dex 40 mg. Among the 64 patients, 59/64 patients were evaluable for efficacy, excluding 5 who withdrew consent during cycle 1. Among the 59 evaluable patients, 56% (34/59) had a partial remission (PR) or greater, and 73% (43/59) had at least a minor response (MR). 13% (8/60) achieved a complete remission (CR/near CR (nCR)), 7% (4/60) had a very good partial remission (VGPR), 37% (22/60) had a PR, 15% (9/60) had MR, 15% had stable disease (SD), and 12% (7/60) had progressive disease (PD).Among the 42 patients who were Len refractory, 38 were efficacy evaluable. The ORR (≥MR) was 63% (24/38) and ≥PR was 39% (15/38), and achieved at least a minor response. 2/38 had a CR/nCR, 1/38 a VGPR, 12/38 a PR, 9/38 a, MR, 8/38 had SD, and 6/38 had PD.Grade 1–4 AEs regardless of causality occurring in >20% of patients included anemia (26/56), thrombocytopenia (29/56), neutropenia (21/56), diarrhea (24/56), constipation (32/56), nausea (15/56), dizziness (32/56), memory changes (21/56), blurred vision (24/56), fatigue (41/56), elevated creatinine (16/56), dyspnea (32/56), transaminitis (11/56), pneumonia (14/56), upper respiratory infection (16/56), hyperglycemia (18/56), hypomagnesemia (23/56), hypokalemia (16/56), hyponatermia (14/56), and hypophosphatemia (15/56). Grade ≥3 AEs regardless of causality included anemia (10/56), thrombocytopenia (12/56), neutropenia (15/56), diarrhea (2/56), dizziness (5/56), fatigue (17/56), elevated creatinine (5/56), and pneumonia (10/56).One venous thromboembolic (VTE) event was observed. No treatment emergent G3/4 peripheral neuropathy was seen. 1 patient died on study with cardiac arrest at home.

The recommended dose for this regimen is Len 25 mg/Thal 100 mg/Dex 40 mg. The combination is well tolerated with an expected side effect profile and, importantly, limited incidence of VTE and treatment emergent neuropathy. The ORR of 73% was higher than would be expected of the two-drug regimen of Len/Dex. The preserved activity in Len-refractory disease, with a response rate of 63%, supports the hypothesis that the combination of Len and Thal can overcome lenalidomide resistance, and provides a new treatment option for patients with Len-refractory disease.

Shah:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Off Label Use: This presentation will include information about panobinostat, which is not yet approved for use in patients with multiple myeloma. Orlowski:Celgene: Honoraria, Research Funding. Thomas:celgene: Research Funding.