Abstract
This phase 1 study investigated the safety of the anthracycline amrubicin combined with lenalidomide and dexamethasone in adults with relapsed or refractory multiple myeloma. A standard 3 + 3 design was used. Patients received intravenous amrubicin 40–80 mg/m2 on day one, lenalidomide 15 mg orally on days 1–14, and dexamethasone 40 mg orally weekly on 21 day cycles. 14 patients were enrolled, and completed a median of three cycles. The maximum tolerated dose was not reached. One patient experienced dose limiting toxicity of dizziness and diarrhea. The most frequent non-hematologic toxicity was infection (79%). Serious adverse events included cord compression and sepsis. Three patients (21%) had a partial response or better, and seven (50%) had stable disease. The median duration of response was 4.4 months, and the median progression-free survival was 3 months. Amrubicin combined with lenalidomide and dexamethasone, was safe and demonstrated clinical activity in relapsed or refractory multiple myeloma.
Clinicaltrials.gov identifier: NCT01355705
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References
Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516–20.
Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357:2123–32.
Dimopoulos MA, Chen C, Spencer A, Niesvizky R, Attal M, Stadtmauer EA, et al. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia. 2009;23:2147–52.
Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357:2133–42.
Hussein MA, Wood L, Hsi E, Srkalovic G, Karam M, Elson P, et al. A Phase II trial of pegylated liposomal doxorubicin, vincristine, and reduced-dose dexamethasone combination therapy in newly diagnosed multiple myeloma patients. Cancer. 2002;95:2160–8.
Knop S, Gerecke C, Liebisch P, Topp MS, Platzbecker U, Sezer O, et al. Lenalidomide, adriamycin, and dexamethasone (RAD) in patients with relapsed and refractory multiple myeloma: a report from the German Myeloma Study Group DSMM (Deutsche Studiengruppe Multiples Myelom). Blood. 2009;113:4137–43.
Offidani M, Corvatta L, Piersantelli MN, Visani G, Alesiani F, Brunori M, et al. Thalidomide, dexamethasone, and pegylated liposomal doxorubicin (ThaDD) for patients older than 65 years with newly diagnosed multiple myeloma. Blood. 2006;108:2159–64.
Orlowski RZ, Nagler A, Sonneveld P, Blade J, Hajek R, Spencer A, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007;25:3892–901.
Popat R, Oakervee HE, Hallam S, Curry N, Odeh L, Foot N, et al. Bortezomib, doxorubicin and dexamethasone (PAD) front-line treatment of multiple myeloma: updated results after long-term follow-up. Br J Haematol. 2008;141:512–6.
Samson D, Gaminara E, Newland A, Van de Pette J, Kearney J, McCarthy D, et al. Infusion of vincristine and doxorubicin with oral dexamethasone as first-line therapy for multiple myeloma. Lancet, 1989; 882–5.
Segeren CM, Sonneveld P, van der Holt B, Baars JW, Biesma DH, Cornellissen JJ, et al. Vincristine, doxorubicin and dexamethasone (VAD) administered as rapid intravenous infusion for first-line treatment in untreated multiple myeloma. Br J Haematol. 1999;105:127–30.
Singh P, Wilson I, Gupta V, Buadi F, Lacy M, Dispenzieri A, et al. Clinical outcomes after intensive VDT-PACE therapy for relapsed multiple myeloma. J Clin Oncol, 2013; (31:(abstr 8600)).
Thanendrarajan S, Alapat D, Zangari M, Schinke C, Heuck C, van Rhee F, et al. Upfront 28-day metronomic therapy for high-risk multiple myeloma (HRMM). Blood, 2015; (126:(abstr 1843)).
Baz R, Walker E, Karam MA, Choueiri TK, Jawde RA, Bruening K, et al. Lenalidomide and pegylated liposomal doxorubicin-based chemotherapy for relapsed or refractory multiple myeloma: safety and efficacy. Ann Oncol. 2006;17(12):1766–71.
Hahn VS, Lenihan DJ, Ky B. Cancer therapy-induced cardiotoxicity: basic mechanisms and potential cardioprotective therapies. J Am Heart Assoc. 2014;3:e000665.
Morisada S, Yanagi Y, Noguchi T, Kashiwazaki Y, Fukui M. Antitumor activities of a novel 9-aminoanthracycline (SM-5887) against mouse experimental tumors and human tumor xenografts. Jpn J Cancer Res, 1989; 80:69–76.
Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011;117:4691–5.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41.
Onoda S, Masuda N, Seto T, Eguchi K, Takiguchi Y, Isobe H, et al. Phase II Trial of amrubicin for treatment of refractory or relapsed small-cell lung cancer: thoracic oncology research group study 0301. J Clin Oncol. 2006;24(34):5448–53.
Leleu X, Attal M, Arnulf B, Moreau P, Traulle C, Marit G, et al. Pomalidomide plus low-dose dexamethasone is active and well tolerated in bortezomib and lenalidomide-refractory multiple myeloma: intergroupe Francophone du Myelome 2009-02. Blood. 2013;121:1968–75.
Richardson PG, Siegel DS, Vij R, Hofmeister CC, Baz R, Jagannath S, et al. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014;123:1826–32.
Siegel DS, Martin T, Wang M, Vij R, Jakubowiak AJ, Lonial S, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120:2817–25.
Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Spicka I, Oriol A, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372:142–52.
Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373:621–31.
Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015;373:1207–19.
Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani S, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. NEJM. 2016;375:1319–31.
Palumbo A, Chanan-Khan A, Weisel K, Nooka A, Masszi T, Beksac M, et al. Daratumumab, bortezomib and dexamethasone for multiple myeloma. NEJM. 2016;375:754–66.
Acknowledgements
ML was the principal investigator for this study; TJD, SD, BCM, SC, JG, CB, and ML contributed to patient enrollment and care; SD, and ML coordinated the research. SD, BCM, and ML contributed to acquisition, analysis, and interpretation of data. SD, EP, GK, and ML wrote the paper. All authors reviewed the manuscript and approved the final submitted version.
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Drs. Liedtke, Medeiros and Coutre have received research support funding from Celgene. The remaining authors declare no conflicts of interest, financial or otherwise.
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Dinner, S., Dunn, T.J., Price, E. et al. A phase I, open-label, dose-escalation study of amrubicin in combination with lenalidomide and weekly dexamethasone in previously treated adults with relapsed or refractory multiple myeloma. Int J Hematol 108, 267–273 (2018). https://doi.org/10.1007/s12185-018-2468-5
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DOI: https://doi.org/10.1007/s12185-018-2468-5