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IMP phase I/II study in transplant-ineligible NDMM
Introduction
Methods
Study design
This was a phase I/II, open-label, multicenter, dose-escalation study. The primary phase I objectives were to determine safety, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of ixazomib in combination with MP. A secondary objective was to characterize ixazomib pharmacokinetics. The primary phase II objective was to determine the complete response plus very good partial response (CR+VGPR) rate. Secondary objectives included overall response rate (ORR), time to response, duration of response, PFS, time to progression, OS, and safety (for details, see the Online Supplementary Material).
Patients
Patients with previously untreated MM who were ineligible for HDT/ASCT due to age (≥65 years) or comorbidity, and for whom standard MP treatment was indicated, were enrolled. Detailed eligibility criteria are presented in the Online Supplementary Material.
The study complied with regulatory requirements, the Declaration of Helsinki, and Good Clinical Practice standards. Independent review boards/ethics committees approved the study. Patients gave written informed consent.
Treatment
In phase I, patients were enrolled into one of four arms, as assigned by investigators under direction of the sponsor (Figure 1). In Arm A, patients received up to 9 42-day cycles of twice-weekly ixazomib (days 1, 4, 8, 11, 22, 25, 29, 32). In Arm B, patients received up to 13 28-day cycles of weekly ixazomib (days 1, 8, 15). In Arms C and D, patients received up to 9 42-day cycles of weekly ixazomib (days 1, 8, 15, 22, 29 for Arm C and days 1, 8, 22, 29 for Arm D). Patients also received melphalan 6 mg/m2 (Arm B) or 9 mg/m2 (Arms A, C, D) on days 1-4 and prednisone 60 mg/m2 (days 1-4) in each cycle.
Ixazomib dose-escalation proceeded via a standard 3+3 design based on cycle 1 dose-limiting toxicities (DLTs; as defined in the Online Supplementary Material). The MTD required no more than 1 out of 6 DLT-evaluable patients to have a first-cycle DLT. Planned dose levels for ixazomib are shown in Online Supplementary Table S1. In phase II, an expansion cohort was enrolled at the RP2D, which was established by considering all available phase I toxicity (grade 3/4 AEs, serious AEs [SAEs], all-grade PN, and treatment discontinuation) and ORR over multi- plecycles.
After induction, patients with stable disease or better could receive single-agent ixazomib maintenance (at the dose tolerated for induction) on days 1, 8, 15 for up to 12 28-day cycles, or until disease progression or unacceptable toxicity (Figure 1).
Assessments
Responses were assessed by investigators on day 1 of each cycle, at the end of induction, every 2 cycles during maintenance, and every 16 weeks during follow up until progression or start of subsequent antineoplastic therapy, according to International Myeloma Working Group criteria.31 AEs were monitored throughout and graded using the National Cancer Institute- Common Terminology Criteria for AEs, version 4.03. Details of the pharmacokinetic, minimal residual disease (MRD), and safety assessments are provided in the Online Supplementary Material.
Analyses
Analysis populations are defined in the Online Supplementary Material. Time-to-event endpoints were analyzed using survival
Although multiple myeloma (MM) remains, for most patients, an incurable hematologic malignancy, recent advances in treatment and diagnosis have led to substan- tial improvements in both progression-free survival (PFS) and overall survival (OS).1-4 As with many malignancies, younger, fitter patients usually achieve the best outcomes with initial treatment, while outcomes for elderly patients and those with comorbidities, who are unable to tolerate high-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT), have traditionally lagged behind.3-8 For these elderly and frail patients, active, novel, frontline combination regimens are needed to achieve the best long-term outcomes. However, tolerability can be an issue for some patients,5,6 particularly in the case of long-term, continuous therapy, which is associated with improved outcomes.9-13
Following demonstration of favorable efficacy and tolerability in phase III trials,14-17 the combination of the proteasome inhibitor (PI) bortezomib plus melphalan and prednisone (VMP) is now, in many geographies, a standard-of-care regimen for the first-line treatment of elderly patients with newly diagnosed MM (NDMM) who are not eligible to receive HDT/ASCT because of age-related frailty and/or comorbidity.3,4 VMP represents an active, feasible frontline treatment option, including for patients with high-risk cytogenetic abnormalities (due to the activity of PI-based regimens in this population) and patients with renal impairment (as no starting dose adjust- ment is required), and offers a suitable option for patients in whom immunomodulatory drug-containing therapy is contraindicated.18-22
However, despite being a standard of care, the parenteral administration of bortezomib may create a burden for elderly patients, limiting its feasibility for long-term use. The combination of another parenterally administered PI, carfilzomib, and melphalan-prednisone (MP) was recently compared with VMP and demonstrated no statistically significant difference in PFS in transplant-ineligible NDMM; however, carfilzomib-MP was associated with a higher number of specific grade ≥3 adverse events (AEs), notably acute renal failure, cardiac failure, dyspnea, and hypertension, and fewer incidences of peripheral neuropathy (PN) than VMP.23
Therefore, there remains a need for a tolerable, efficacious, and convenient PI option for elderly patients with transplant-ineligible NDMM. Ixazomib is an oral PI with a safety profile amenable to extended dosing.24-26 Based on the results of the TOURMALINE-MM1 study, which led to its first approval in 2015, ixazomib has been approved in more than 50 countries worldwide, including the US, EU, and Japan, for use in combination with lenalidomide-dexamethasone (IRd) for the treatment of MM patients who have received at least one prior therapy.26-28 Recent phase I/II studies have demonstrated the activity and tolerability of ixazomib-based induction (IRd) and long-term ixazomib maintenance therapy in NDMM, demonstrating the feasibility of this approach.29,30 This phase I/II trial (clinicaltrials.gov identifier 01335685) was undertaken to evaluate the all-oral ixazomib-MP (IMP) induction regimen, followed by long-term maintenance with single-agent ixazomib, in predominantly elderly, transplant-ineligible patients with NDMM.
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