Randomized Phase 2 Trial of Two Different Doses of Ixazomib in Patients with Relapsed Multiple Myeloma Not Refractory to Bortezomib

Background: Ixazomib is an experimental, orally bioavailable, proteasome inhibitor that has demonstrated anti-tumor activity in relapsed multiple myeloma (MM). In the dose escalation studies, ixazomib was tolerated up to a dose of 5.5 mg given every week as a single agent, while a dose of 4 mg was utilized in the combination studies with lenalidomide. We undertook this study to examine the efficacy and tolerability of the two doses of ixazomib in combination with dexamethasone in patients with relapsed MM.

Patients and methods: This was a randomized phase 2 study of two doses of ixazomib (4mg; Arm A or 5.5 mg; Arm B) given weekly for three weeks with a week off along with weekly dexamethasone (40 mg) in patients with relapsed MM, who are proteasome inhibitor na•ve (including bortezomib) or have received less than 6 cycles of therapy with bortezomib and had a PR or better with no progression at the time of discontinuation. The primary objective was to determine the confirmed overall response rate (>=PR); secondary objectives included progression free and overall survival. A total of 71 patients were accrued from February 2013 to April 2015; one patient was ineligible.

Results: Baseline characteristics were similar in the two arms; median age across the study was 70 years (46-84); 53% were male. Median number of prior therapies was 4 (range 2-6); 90% of the patients had prior IMiDs, 70% had prior transplant and 29% had prior bortezomib. At a median follow up of 10 months, 17 (49%) and 19 (54%) of patients had disease progression in arms A and B respectively with 12 (34%) patients in each arm still continuing on treatment. All patients in each arm were evaluable for response; the overall response rates were 31% in arm A (95%CI: 17-49) and 51% (95%CI: 34-69) in Arm B. The depth of response, event free survival and overall survival are outlined in Table 1. Among the patients with no prior bortezomib exposure the response rates were 38% for Arm A and 52% for Arm B. The treatment was well tolerated with 2 patients in each arm discontinuing treatment for adverse events; there were no on study deaths. A grade 3 or higher AE that was at least possibly related to treatment was seen in 21% and 54% in Arms A and B respectively; with 15% and 37% hematologic and 6% and 29% non-hematologic AEs. The most common attributable toxicities encountered included fatigue, thrombocytopenia, diarrhea and nausea with more grade 3 toxicities among Arm B. Peripheral neuropathy, possibly related to ixazomib, was seen in 55% (only grade 1 or 2) in arm A and 43% (2 patients with grade 3) in Arm B. Toxicities led to dose reduction of ixazomib in 17% and 43% of patients in Arm A and B respectively; the median number of cycles administered were 5 (1-24) and 5 (1-22) respectively.

Conclusions: Ixazomib in combination with dexamethasone was well tolerated with significant anti-myeloma activity in this group of patients with relapsed MM. Deep responses including stringent CR were observed. The higher dose of ixazomib appears to be associated with a higher response rate but with higher rate of adverse events requiring dose reductions.

Table: Treatment outcome in all patients

	Arm B (4 mg) (N=35)	Arm C (5.5 mg) (N=35)
Response Rate	31% (95%CI: 17-49)	51% (95%CI: 34-69)
No. of Responders	11	18
sCR	0	1
CR	1	0
VGPR	7	8
PR	3	9
MR	5	1
Median Overall Survival1	NA	NA
6 Months	100%	100%
Median Event Free Survival1,2	8.4 mos (95%CI: 4.3-13.2)	8.2 mos (95%CI: 3.8-16.3)
%Event Free at 6 Months	60% (95%CI: 45-81)	60% (95%CI: 45-81)
Median Duration of Response1	16.7 mos (95%CI: 9.3-22.0)	16.3 mos (95%CI: 7.0-20.1)
Median Time to Response	1.1 mos (range: 0.8-3.6)	1.0 mos (range: 0.8-7.5)
CI: confidence interval; mo: month; NA: not attained 1 Kaplan Meier 2Event-free survival time is defined as the time from registration to the first of disease progression, death due to any cause, or subsequent treatment for multiple myeloma.