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J.F. San-Miguel et al.
Table 3. Response rates after induction and at end of study (response-evaluable population).
Table 4. Time-to-event outcomes with IMP induction and single-agent ixazomib maintenance.
n (%)
Total
N=53* 35 (66) 7 (13) 3 (6) 16 (30) 23 (43) 41 (82) N=53* 35 (66) 15 (28) 10 (19) 9 (17) 24 (48) 43 (86) 24 (48)
RP2D 4.0 mg Arm B
N=23 15 (65) 3 (13) 1 (4) 7 (30) 10 (43) 17 (77) n=23 15 (65) 5 (22) 4 (17) 6 (26) 11 (48) 18 (82) 11 (48)
Outcome
(in months unless otherwise stated)
Median time to first response (range)* Median time to first ≥VGPR (range)* Median time to first CR (range)*
Median DOR (95% CI)*†
Median DOR in patients achieving ≥VGPR (95% CI)*
Median PFS (95% CI)†‡
Median PFS in patients who entered maintenance phase (95% CI)‡
Median time to progression (95% CI)†‡ Median OS (95% CI)†‡
Estimated 3-year OS rate, %†‡
Total (N=61)
1.7 (1-7) 3.7 (1-13) 11.6 (1-23) 22.6 (15.9, 32.4) 25.4 (15.0, 29.5)
22.1 (18.0, 30.0) 27.5 (18.7, 37.8)
23.5 (18.0, 30.0)
54.4 (39.7, NR)
73
RP2D 4.0 mg Arm B (n=26)
1.9 (1-7) 3.7 (1-13) 9.5 (5-22) 25.2 (4.6, NR) 29.5 (2.8, NR)
18.4 (8.3, 38.7) 38.7 (15.6, NR)
22.1 (8.8, NR)
NR (35.0, NR)
68
Response after induction
ORR (≥PR)
CR (confirmed)
sCR (confirmed) VGPR
ORR
CR (confirmed)
sCR (confirmed) VGPR
CR+VGPR (confirmed) ≥50% reduction in M-protein 100% reduction in M-protein
CR+VGPR (confirmed)
≥50% reduction in M-protein Response at end of study
CR: complete response; ORR: overall response rate; PR: partial response; R2PD: recommended phase II dose; sCR: stringent complete response; VGPR: very good partial response. Response-evaluable population was defined as patients receiving ≥5/8 (Arm A), ≥2/3 (Arm B), ≥4/5 (Arm C), or ≥3/4 (Arm D) doses of ixazomib during cycle 1 with measurable disease at baseline and 1 post-baseline response assessment. *Eight patients were not evaluable for response due to: no measurable disease (two patients); no post-baseline assessment (one patient); and incomplete dosing in cycle 1 (5 patients).
induction-only patients vs. 86% for maintenance patients), lymphopenia (28% vs. 44%), anemia (60% vs. 36%), constipation (52% vs. 33%), and rash (16% vs. 33%).
Any-grade PN (classified by the high-level term peripheral neuropathies not elsewhere classified) considered to be study drug-related was reported in 24 patients (39%) (Table 6). PN was primarily low grade, with 12 patients (20%; 5 [19%] at the RP2D) and 19 patients (15%; 5 [19%] at the RP2D) reporting grade 1 and grade 2 PN, respectively. Three patients (5%) had grade 3 PN events. No patient had grade 4. Overall, 8 patients (13%) received dose reductions and 7 patients (11%) had study drug held due to PN. Twenty of the 24 patients (83%) who developed PN events during induction or maintenance had improved symptoms by the end of the study, with 17 (71%) having complete resolution of symptoms. Median time to resolution of PN events was 4.6 months (95% confidence interval: 1.6-14.3). Median time to resolution or improvement of PN events was 1.7 months (95% confidence interval: 1.1-6.4).
Discussion
A PI, namely bortezomib, combined with MP has been shown to be an effective frontline treatment approach for NDMM patients unable to undergo HDT/ASCT due to advanced age and/or significant comorbidities, including those for whom immunomodulatory drugs are not an option.16,17,23 Most studies of the VMP regimen have utilized a fixed duration of treatment (often approximately 1 year) rather than extended or continuous therapy.17,19,32,33 Furthermore, in the real-world clinical
CI: confidence interval; CR: complete response; DOR: duration of response; NR: not reached; OS: overall survival; PFS: progression-free survival; RP2D: recommended phase II dose; VGPR: very good partial response. *Response-evaluable population (total, N=53; RP2D 4.0 mg Arm B, n=23); †Median fol- low up: 18.4 (total) and 16.6 (RP2D) months for DOR; 18.0 (total) and 10.2 (RP2D) months for PFS and time to progression; and 43.6 (total) and 48.6 (RP2D) months for OS. ‡Safety population.
practice setting, early discontinuations due to toxicities are common.34 As long-term, continuous therapy is associated with improved outcomes,9-13 a tolerable, more convenient treatment regimen suitable for long-term use is needed, especially in elderly patients.
The data from this study suggest that all-oral IMP induction followed by single-agent ixazomib maintenance is an active and well-tolerated frontline regimen in transplant-ineligible patients with NDMM. The regimen showed encouraging tolerability over a prolonged treatment period, with ≥50% of patients proceeding to maintenance, including at the RP2D, and duration of therapy of up to 4.8 years. The regimen also demonstrated high response rates, with an overall CR+VGPR rate of 48%, including 28% ≥CR. Additionally, lengthy outcomes were reported, with an overall median PFS of 22.1 months, and an overall median OS of 54.4 months.
Differences in outcomes between the overall and RP2D populations should be interpreted with caution due to the relatively small numbers of patients involved and differences in patient characteristics (for example, 5 of the 7 patients with high-risk cytogenetic abnormalities were in the RP2D cohort). Additionally, the median follow up for PFS in the RP2D cohort was shorter than in the overall population, which also included patients who received more dose-intense regimens that may have resulted in improved short-term efficacy (ORR).
While the efficacy data reported here were obtained in a relatively small number of patients within the context of a non-comparative early-phase trial, they appear similar to those seen with VMP or carfilzomib plus MP in phase III studies in transplant-ineligible patients with
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haematologica | 2018; 103(9)