General MM

Long-term follow-up of ixazomib, lenalidomide, and dexamethasone in combination with ixazomib maintenance, in patients with newly diagnosed multiple myeloma

The standard-of-care therapy for patients with newly diagnosed multiple myeloma (NDMM) is triplet combinations containing a proteasome inhibitor and immunomodulatory agents.1 However, long-term maintenance therapy has been limited by adverse event risks, such as peripheral neuropathy from bortezomib consolidation therapy; therefore the need for a front-line therapy that can be dose-extended for maintenance with minimal cumulative toxicity remains an unmet need for patients with NDMM.2 The oral proteasome inhibitor, ixazomib, is approved by the US Food and Drug Administration (FDA), European Medicines Agency (EMA), and National Institute for Health and Care Excellence (NICE) for patients with previously treated MM in combination with lenalidomide and dexamethasone.

Professor Shaji Kumar, a member of our Steering Committee, from the Mayo Clinic, Rochester, US, and colleagues, conducted this multicenter, open-label, dose-escalation, phase I/II trial (NCT01217957) aimed to assess the long-term safety and efficacy of weekly oral ixazomib in combination with lenalidomide and dexamethasone, followed by ixazomib single-agent consolidation, in enrolled adult patients (n = 65, median age = 66; range, 34–86) with NDMM.3 During induction, patients (n = 53) were administered oral ixazomib (4 mg, days 1, 8, and 15), in combination with standard doses of lenalidomide (25 mg daily, days 1–21) and dexamethasone (40 mg, weekly), following a 28-day cycle for up to 12 cycles. For patients completing 12 full cycles of induction, consolidation therapy with ixazomib was administered at the final tolerated dose during induction.

Key findings:

Data shown as total population (n = 65) versus patients receiving induction and not proceeding to stem cell transplantation (SCT, n = 42) versus patients receiving consolidation (n = 25), where applicable

Safety
  • Among 65 patients enrolled, 53 received ixazomib induction therapy
    • Twenty-three patients proceeded to SCT and discontinued induction therapy
    • In patients receiving induction therapy (n = 42), treatment discontinued due to: adverse events (AEs) (n = 9), patient withdrawal (n = 4), progressive disease (n = 2), unsatisfactory response (n = 1), and other (n = 1)
    • Twenty-five patients completed 12 cycles of induction, and continued to single-agent consolidation therapy
  • Patients experiencing any grade ≥ 3 AE: 78% (n = 51) vs 86% (n = 36) vs 68% (n = 17, during induction) and 48% (n = 12, during maintenance)
  • Most common treatment-emergent grade ≥ 3 AE in the total population (n = 65), include: neutropenia (22%), thrombocytopenia (11%), diarrhea (9%), and fatigue (9%)
  • Patients experiencing any serious AE: 46% (n = 30) vs 52% (n = 22) vs 36% (n = 9, during induction) and 28% (n = 7, during maintenance)
Efficacy
  • Median follow-up: 55 months
  • Overall response rate in response-evaluable patients (n = 41): 80%
  • Median progression-free survival: 35.4 months (95% CI, 17.84–44.12) vs 29.4 months (95% CI, 17.71–41.13) vs 37.2 months (95% CI, 20.93–46.00)

In conclusion, the results from the long-term follow-up study show that the combination of ixazomib with lenalidomide and dexamethasone has a manageable toxicity profile, allowing for the convenient oral single-agent ixazomib maintenance therapy to be used in patients with no significant cumulative toxicities.

References
  1. Durie B.G. et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem cell-transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017 Feb 4; 389(10068): 519–527. DOI: 10.1016/S0140-6736(16)31594-X.
  2. Ludwig H. et al. IMWG consensus on maintenance therapy in multiple myeloma. Blood. 2012 Mar 29; 119(13): 3003–3015. DOI: 10.1182/blood-2011-11-374249.
  3. Kumar S.K. et al. Ixazomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma: long-term follow-up including ixazomib maintenance. Leukemia. 2019 Jan 29. DOI: 10.1038/s41375-019-0384-1. [Epub ahead of print]
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