This phase I/II dose-escalation study investigated the all-oral ixazomib-melphalan-prednisone regimen, followed by single-agent ixazomib maintenance, in elderly, transplant-ineligible patients with newly diagnosed multiple myeloma. Primary phase I objectives were to determine the safety and recommended phase II dose of ixazomib-melphalan-prednisone. The primary phase II objective was to determine the complete plus very good partial response rate. In phase I, patients were enrolled to 4 arms investigating weekly or twice-weekly ixazomib (13 28-day cycles or nine 42-day cycles) plus melphalan-prednisone. In phase II, an expansion cohort was enrolled at the recommended phase II ixazomib dose. Of the 61 patients enrolled, 26 received the recommended phase II dose (ixazomib 4.0 mg [days 1, 8, 15] plus melphalan-prednisone 60 mg/m2 [days 1-4], 28-day cycles). Of the 61 enrolled patients, 36 (13 of 26 in the recommended phase II dose cohort) received single-agent ixazomib maintenance (days 1, 8, 15; 28-day cycles). In phase I, 10/38 patients reported dose-limiting toxicities in cycle 1, including grade 3 and/or 4 neutropenia (n=6) and thrombocytopenia (n=4). Complete plus very good partial response rate was 48% (48% at recommended phase II dose), including 28% (22%) complete response or better; responses deepened during maintenance in 34% (33%) of evaluable patients. After median follow up of 43.6 months, median progression-free survival was 22.1 months. Adverse events were mainly hematologic events, gastrointestinal events, and peripheral neuropathy. This study demonstrates the feasibility, tolerability, and activity of ixazomib-melphalan-prednisone induction and single-agent ixazomib maintenance in transplant-ineligible newly diagnosed multiple myeloma patients. clinicaltrials.gov identifier 01335685.

Cancer Clinical Research Unit Princess Margaret Cancer Center Toronto ON Canada

Clinica Universidad de Navarra Centro Investigación Medica Aplicada Pamplona Spain

Department of Haematooncology University Hospital Ostrava Faculty of Medicine Ostrava University Czech Republic

Department of Hematology Hospital Clínic de Barcelona Institut d'Investigacions Biomèdiques August Pi i Sunyer Spain

Department of Medicine West Virginia University Morgantown WV USA

Division of Hematology University of British Columbia Vancouver BC Canada

Hospital Universitario de Salamanca Instituto Biosanitario de Salamanca Spain

Hospital Universitario Donostia San Sebastián Spain

Medical Department Clinical Department of Haematology 1st Faculty of Medicine and General Teaching Hospital Charles University Prague Czech Republic

Millennium Pharmaceuticals Inc Cambridge MA USA a wholly owned subsidiary of Takeda Pharmaceutical Company Limited Atlanta GA USA

Winship Cancer Institute of Emory University Atlanta GA USA

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Genadieva Stavric S, Bonello F, Bringhen S, Boccadoro M, Larocca A. How is patient care for multiple myeloma advancing¿ Expert Rev Hematol. 2017;10(6):551–561. PubMed

Moreau P, de Wit E. Recent progress in relapsed multiple myeloma therapy: implications for treatment decisions. Br J Haematol. 2017;179(2):198–218. PubMed

Moreau P, San Miguel J, Sonneveld P, et al. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl_4):iv52–iv61. PubMed

Palumbo A, Rajkumar SV, San Miguel JF, et al. International Myeloma Working Group consensus statement for the management, treatment, and supportive care of patients with myeloma not eligible for standard autologous stem-cell transplantation. J Clin Oncol. 2014;32(6):587–600. PubMed PMC

Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014;28(5):1122–1128. PubMed PMC

Pawlyn C, Gay F, Larocca A, Roy V, Ailawadhi S. Nuances in the Management of Older People With Multiple Myeloma. Curr Hematol Malig Rep. 2016;11(3):241–251. PubMed

Wildes TM, Campagnaro E. Management of multiple myeloma in older adults: Gaining ground with geriatric assessment. J Geriatr Oncol. 2017;8(1):1–7. PubMed PMC

Dimopoulos MA, Kastritis E, Delimpasi S, et al. Multiple myeloma in octogenarians: clinical features and outcome in the novel agent era. Eur J Haematol. 2012;89(1):10–15. PubMed

Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1782–1791. PubMed

Brioli A, Tacchetti P, Zamagni E, Cavo M. Maintenance therapy in newly diagnosed multiple myeloma: current recommendations. Expert Rev Anticancer Ther. 2014;14(5):581–594. PubMed

Lipe B, Vukas R, Mikhael J. The role of maintenance therapy in multiple myeloma. Blood Cancer J. 2016;6(10):e485. PubMed PMC

Mateos MV, Oriol A, Martinez-Lopez J, et al. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood. 2012;120(13):2581–2588. PubMed

Palumbo A, Hajek R, Delforge M, et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012;366(19):1759–1769. PubMed

Mateos MV, Oriol A, Martinez-Lopez J, et al. GEM2005 trial update comparing VMP/VTP as induction in elderly multiple myeloma patients: do we still need alkylators¿ Blood. 2014;124(12):1887–1893. PubMed

Niesvizky R, Flinn IW, Rifkin R, et al. Community-based phase IIIB trial of three UPFRONT bortezomib-based myeloma regimens. J Clin Oncol. 2015;33(33):3921–3929. PubMed

San Miguel JF, Schlag R, Khuageva NK, et al. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol. 2013;31(4):448–455. PubMed

San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359(9):906–917. PubMed

Zangari M, Guerrero J, Cavallo F, Prasad HK, Esseltine D, Fink L. Hemostatic effects of bortezomib treatment in patients with relapsed or refractory multiple myeloma. Haematologica. 2008;93(6):953–954. PubMed

Palumbo A, Bringhen S, Rossi D, et al. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010;28(34):5101–5109. PubMed

Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22(2):414–423. PubMed

Sonneveld P, Avet-Loiseau H, Lonial S, et al. Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group. Blood. 2016;127(24):2955–2962. PubMed PMC

Dimopoulos MA, Terpos E, Niesvizky R, Palumbo A. Clinical characteristics of patients with relapsed multiple myeloma. Cancer Treat Rev. 2015;41(10):827–835. PubMed

Facon T, Lee JH, Moreau P, et al. Phase 3 study (CLARION) of carfilzomib, melphalan, prednisone (KMP) v bortezomib, melphalan, prednisone (VMP) in newly diagnosed multiple myeloma (NDMM). Clin Lymphoma Myeloma Leuk. 2017;17(suppl):e26–e27.

Hou J, Jin J, Xu Y, et al. Randomized, double-blind, placebo-controlled phase III study of ixazomib plus lenalidomide-dex-amethasone in patients with relapsed/refractory multiple myeloma: China Continuation study. J Hematol Oncol. 2017;10(1):137. PubMed PMC

Kumar SK, Berdeja JG, Niesvizky R, et al. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Lancet Oncol. 2014;15(13):1503–1512. PubMed

Moreau P, Masszi T, Grzasko N, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;374(17):1621–1634. PubMed

Millennium Pharmaceuticals Inc. NIN-LARO® (ixazomib) capsules, for oral use. United States Prescribing Information. https://www.ninlarocom/downloads/prescribing-informationpdf, 2016.

EMA. European Public Assessment Report: Ninlaro. http://www.emaeuropaeu/docs/en_GB/document_library/EPAR_-_Scientific_Conclusion/human/003844/WC500217622pdf, 2016.

Kumar SK, Berdeja J, Niesvizky R, et al. Deep and durable responses with weekly ixazomib, lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma: long-term follow-up of patients who did not undergo SCT. Haematologica. 2017;102(s2):142–143.

Richardson P, Hofmeister C, Rosenbaum C, et al. Twice-weekly ixazomib plus lenalidomide-dexamethasone in patients with newly diagnosed multiple myeloma: long-term follow-up data for patients who did not undergo stem cell transplantation Haematologica. 2017;102(s2):317–318.

Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20(9):1467–1473. PubMed

Mateos MV, Oriol A, Martinez-Lopez J, et al. Outcomes with two different schedules of bortezomib, melphalan, and prednisone (VMP) for previously untreated multiple myeloma: matched pair analysis using longterm follow-up data from the phase 3 VISTA and PETHEMA/GEM05 trials. Ann Hematol. 2016;95(12):2033–2041. PubMed

Mateos MV, Dimopoulos MA, Cavo M, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018;378(6):518–528. PubMed

Jagannath S, Roy A, Kish J, et al. Real-world treatment patterns and associated progression-free survival in relapsed/refractory multiple myeloma among US community oncology practices. Expert Rev Hematol. 2016;9(7):707–717. PubMed

Facon T, Dimopoulos MA, Dispenzieri A, et al. Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma. Blood. 2018; 131(3):301–310. PubMed PMC

Durie BG, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diag nosed myeloma without intent for immediate autologous stem-cell transplant (SWOGS0777): a randomised, open-label, phase 3 trial. Lancet. 2017;389(10068):519–527. PubMed PMC

Myeloma Trialists’ Collaborative Group. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. J Clin Oncol. 1998;16(12):3832–3842. PubMed

Facon T, Mary JY, Hulin C, et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomized trial. Lancet. 2007;370(9594):1209–1218. PubMed

Hulin C, Facon T, Rodon P, et al. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol. 2009;27(22):3664–3670. PubMed

Kumar SK, Bensinger WI, Zimmerman TM, et al. Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Blood. 2014; 124(7):1047–1055. PubMed PMC

Richardson PG, Baz R, Wang M, et al. Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients. Blood. 2014; 124(7):1038–1046. PubMed PMC

Kumar S, Moreau P, Hari P, et al. Management of adverse events associated with ixazomib plus lenalidomide/dexamethasone in relapsed/refractory multiple myeloma. Br J Haematol. 2017;178(4):571–582. PubMed PMC

Dimopoulos MA, Mateos MV, Richardson PG, et al. Risk factors for, and reversibility of, peripheral neuropathy associated with bortezomib-melphalan-prednisone in newly diagnosed patients with multiple myeloma: subanalysis of the phase 3 VISTA study. Eur J Haematol. 2011;86(1):23–31. PubMed

Gupta N, Yang H, Hanley MJ, et al. Dose and schedule selection of the oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma: clinical and modelbased analyses. Target Oncol. 2017; 12(5):643–654. PubMed PMC

Gupta N, Diderichsen PM, Hanley MJ, et al. Population pharmacokinetic analysis of ixazomib, an oral proteasome inhibitor, including data from the phase III TOURMALINEMM1 study to inform labelling. Clin Pharmacokinet. 2017;56(11):1355–1368. PubMed PMC

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NCT01335685