Ixazomib, Thalidomide and Dexamethasone (IxaThalDex) in Relapsed/Refractory Multiple Myeloma (RRMM): An Interim Analysis of a Phase II Trial
Authors: Ludwig Heinz , Gunsilius Eberhard , Fridrik Michael , Greil Richard , Petzer Andreas , Kühr Thomas , Knop Stefan , Schreder Martin , Rauch Elisabeth , Poenisch Wolfram , Zojer Niklas 
Published: October 2019

Abstract
Introduction
Ixazomib, a second generation proteasome inhibitor provides the advantage of combining oral administration with pronounced activity and a favorable toxicity profile. Phase II studies employing ixazomib-dexamethasone established a once weekly dosing regimen and showed substantial activity in RRMM yielding response rates of up to 58% when combined with lenalidomide-dexamethasone (Ld). A recent phase III trial proved the superiority of the triple combination ixazomib-Ld compared to Ld in patients with RRMM. Here, we evaluate the activity and tolerability of the all oral combination ixazomib-thalidomide-dexamethasone in patients with RRMM.
Methods
Patients with RRMM with at least 1 prior line of therapy were enrolled. Patients had to have measurable disease, ECOG performance status ≤2, ANC ≥1000/µL, platelet count ≥50000µL, GFR ≥15mL/min. The treatment regimen consisted of ixazomib (4mg, d 1, 8 and 15), thalidomide (100mg daily) and dexamethasone (40mg once weekly). Patients aged ≥75 years received a reduced dose of both thalidomide (50mg daily) and of dexamethasone (20mg, once weekly). A total of 8 cycles was planned, followed by ixazomib maintenance therapy (4mg, days 1, 8, 15 of a 28 cycle and 3mg in patients aged ≥75 years) for one year. Progression-free survival curves were estimated using the Kaplan-Meier method. The EORTC Q30 instrument was used for evaluation of changes in overall health and global QoL during therapy.
Results
Thirty-nine of 77 planned patients have been enrolled so far. Intent-to treat group (ITT), age, median: 67, range 42 to 85; ISS stage I: 13, II 14, III: 10, not known: 2, number of prior treatment lines, median: 2, (range: 1-5). Seven patients have discontinued treatment before completion of 2 cycles (early death: 3, progressive disease: 2, protocol violation: 1, patients request: 1). At present, 8 patients are too early (not yet completed 2 cycles) for evaluation per protocol (PP). Full documentation of at least 2 cycles of therapy is available for 24 patients. In this group, the median number of cycles administered is 4, and the median follow up is 4.5 months. Responses to IxaThalDex were seen in 14 patients (35.8% and 58.3% of ITT and PP group, respectively), 3 achieved ≥ VGPR (8%/ITT, 13%/PP), 10 PR (26%/ITT, 42%/PP) and 2 MR (5%/ITT, 8%/PP), yielding a clinical benefit rate of 38.5%/ITT, 62.5%/PP. FISH data are available in 17 of the 24 PP patients. Responses (≥PR) were seen in 5/6 patients with t (4;14) and/or t (14;16) and/or del17p and in 5/8 with standard risk cytogenetics. Median PFS at the time of reporting is 5.7 and 6.4 months in the ITT and PP group, respectively. An improvement in overall health and of general QoL was noted in 6 and 7 of the 14 responders, respectively.
Toxicity data are presented for the PP group. Neutropenia was the most common hematologic toxicity noted in 20 (83.3%) patients; all of them had grade 1/2, and none higher grade neutropenia. Leukopenia was seen in 15 (62.5%) patients, (14 grade 1/2 and one grade 3). Sixteen (66.7%) had grade 1/2 anemia. Grade 1/2 thrombocytopenia was noted in 8 (33.3%) patients. The most frequent non hematological toxicity was infection seen in 7 (29%) patients. Six were grade 3; pneumonia was seen in 4, sepsis in 1 and other infections in 2 patients. Polyneuropathy at baseline was seen in 7 patients (grade 1 in 2, and grade 2 without pain in 6 patients). During the study the incidence of new PNP was relatively rare (3 new and one worsening PNP) with presently 9 (37.5%) patients with grade 1-2 and only 1 (4.2%) with grade 3. Other notable toxicities were acute renal failure (grade 3) in 2 (8.3%), fatigue in 8 (4 grade 1, 4 grade 2), constipation and diarrhea (all grade 1) each in 4, and edema and vision impairment (all grade 1), each in 3 patients.
Conclusion
The entirely oral IxaThalDex regimen resulted in an ORR of 58.3 in the PP and of 35.8% in the ITT population (with 8 patients being too early for PP evaluation and not having reached 2 cycles as yet). The clinical benefit rate was 62.5% and 38.5% for the PP and ITT group, respectively. Median PFS was 6.4 months in the PP group. General health and QoL improved in 42.8% and 50% of the responders. The ixazomib-thalidomide-dexamethasone regimen was well tolerated and with relatively few side effects being noted. As exposure to therapy is still short at this point of time it is anticipated that efficacy data will further improve with longer therapy and follow up. Updated results will be presented at the meeting.

Disclosures
Ludwig: Takeda: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Janssen: Speakers Bureau. Gunsilius:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Greil:Celgene: Research Funding; Takeda: Honoraria, Research Funding; Novartis: Research Funding; BMS: Honoraria; Celgene: Honoraria; Roche: Honoraria, Speakers Bureau. Petzer:Roche: Honoraria. Knop:Takeda: Consultancy. Poenisch:Mundipharma: Research Funding.