Abstract
Lenalidomide (Len) and dexamethasone (dex) therapy is a standard therapy in patients with multiple myeloma. Elderly or unfit patients may reduce Len or dex doses to prevent toxicities that lead to treatment discontinuation. However, there have been few studies evaluating the efficacy and safety of lower doses of Len and dex. We conducted a phase II study of 1.5-year low-dose Len and dex therapy following melphalan and prednisolone (MP), the number of which cycles was determined by a response within 9 cycles. The Len dose was 10 mg daily and the dex dose was 20 mg weekly, which were continued for 1.5 years. Twenty-one patients were enrolled. The median number of cycles of MP was 3 (range, 2–9). The overall response rate was 81% and a very good partial response or better was achieved in 33.3% of patients. The median follow-up time for survivors was 70.5 months (range, 42–83 months), the median progression-free survival (PFS) was 27 months (95% CI, 21–33 months), and the median overall survival was not reached. Grade 3 or 4 adverse events were observed in 28.6% of patients. In conclusion, the low-dose Len and dex therapy safely achieved comparable efficacies to the standard-dose regimen in elderly patients with newly diagnosed multiple myeloma. UMIN000007889.
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Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, Pinto A, Weisel K, Ludwig H, Bahlis N, Banos A, Tiab M, Delforge M, Cavenagh J, Geraldes C, Lee JJ, Chen C, Oriol A, de la Rubia J, Qiu L, White DJ, Binder D, Anderson K, Fermand JP, Moreau P, Attal M, Knight R, Chen G, Van Oostendorp J, Jacques C, Ervin-Haynes A, Avet-Loiseau H, Hulin C, Facon T, Team FT (2014) Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med 371(10):906–917. https://doi.org/10.1056/NEJMoa1402551
Facon T, Dimopoulos MA, Dispenzieri A, Catalano JV, Belch A, Cavo M, Pinto A, Weisel K, Ludwig H, Bahlis NJ, Banos A, Tiab M, Delforge M, Cavenagh JD, Geraldes C, Lee JJ, Chen C, Oriol A, De La Rubia J, White D, Binder D, Lu J, Anderson KC, Moreau P, Attal M, Perrot A, Arnulf B, Qiu L, Roussel M, Boyle E, Manier S, Mohty M, Avet-Loiseau H, Leleu X, Ervin-Haynes A, Chen G, Houck V, Benboubker L, Hulin C (2018) Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma. Blood 131(3):301–310. https://doi.org/10.1182/blood-2017-07-795047
Palumbo A, Bringhen S, Ludwig H, Dimopoulos MA, Blade J, Mateos MV, Rosinol L, Boccadoro M, Cavo M, Lokhorst H, Zweegman S, Terpos E, Davies F, Driessen C, Gimsing P, Gramatzki M, Hajek R, Johnsen HE, Leal Da Costa F, Sezer O, Spencer A, Beksac M, Morgan G, Einsele H, San Miguel JF, Sonneveld P (2011) Personalized therapy in multiple myeloma according to patient age and vulnerability: a report of the European Myeloma Network (EMN). Blood 118(17):4519–4529. https://doi.org/10.1182/blood-2011-06-358812
Palumbo A, Anderson K (2011) Multiple myeloma. N Engl J Med 364(11):1046–1060. https://doi.org/10.1056/NEJMra1011442
Palumbo A, Bringhen S, Mateos MV, Larocca A, Facon T, Kumar SK, Offidani M, McCarthy P, Evangelista A, Lonial S, Zweegman S, Musto P, Terpos E, Belch A, Hajek R, Ludwig H, Stewart AK, Moreau P, Anderson K, Einsele H, Durie BG, Dimopoulos MA, Landgren O, San Miguel JF, Richardson P, Sonneveld P, Rajkumar SV (2015) Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood 125(13):2068–2074. https://doi.org/10.1182/blood-2014-12-615187
Bartlett JB, Dredge K, Dalgleish AG (2004) The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer 4(4):314–322. https://doi.org/10.1038/nrc1323
Gandhi AK, Kang J, Capone L, Parton A, Wu L, Zhang LH, Mendy D, Lopez-Girona A, Tran T, Sapinoso L, Fang W, Xu S, Hampton G, Bartlett JB, Schafer P (2010) Dexamethasone synergizes with lenalidomide to inhibit multiple myeloma tumor growth, but reduces lenalidomide-induced immunomodulation of T and NK cell function. Curr Cancer Drug Targets 10(2):155–167. https://doi.org/10.2174/156800910791054239
Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, Tai YT, Lin B, Podar K, Gupta D, Chauhan D, Treon SP, Richardson PG, Schlossman RL, Morgan GJ, Muller GW, Stirling DI, Anderson KC (2001) Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood 98(1):210–216. https://doi.org/10.1182/blood.v98.1.210
Haslett PA, Hanekom WA, Muller G, Kaplan G (2003) Thalidomide and a thalidomide analogue drug costimulate virus-specific CD8+ T cells in vitro. J Infect Dis 187(6):946–955. https://doi.org/10.1086/368126
Hayashi T, Hideshima T, Akiyama M, Podar K, Yasui H, Raje N, Kumar S, Chauhan D, Treon SP, Richardson P, Anderson KC (2005) Molecular mechanisms whereby immunomodulatory drugs activate natural killer cells: clinical application. Br J Haematol 128(2):192–203. https://doi.org/10.1111/j.1365-2141.2004.05286.x
Dimopoulos MA, Hussein M, Swern AS, Weber D (2011) Impact of lenalidomide dose on progression-free survival in patients with relapsed or refractory multiple myeloma. Leukemia 25(10):1620–1626. https://doi.org/10.1038/leu.2011.126
Palumbo A, Bringhen S, Kumar SK, Lupparelli G, Usmani S, Waage A, Larocca A, van der Holt B, Musto P, Offidani M, Petrucci MT, Evangelista A, Zweegman S, Nooka AK, Spencer A, Dimopoulos MA, Hajek R, Cavo M, Richardson P, Lonial S, Ciccone G, Boccadoro M, Anderson K, Barlogie B, Sonneveld P, McCarthy PL (2014) Second primary malignancies with lenalidomide therapy for newly diagnosed myeloma: a meta-analysis of individual patient data. The lancet oncology 15(3):333–342. https://doi.org/10.1016/S1470-2045(13)70609-0
Musto P, Anderson KC, Attal M, Richardson PG, Badros A, Hou J, Comenzo R, Du J, Durie BGM, San Miguel J, Einsele H, Chen WM, Garderet L, Pietrantuono G, Hillengass J, Kyle RA, Moreau P, Lahuerta JJ, Landgren O, Ludwig H, Larocca A, Mahindra A, Cavo M, Mazumder A, McCarthy PL, Nouel A, Rajkumar SV, Reiman A, Riva E, Sezer O, Terpos E, Turesson I, Usmani S, Weiss BM, Palumbo A, International Myeloma Working G (2017) Second primary malignancies in multiple myeloma: an overview and IMWG consensus. Annals of Oncology 28(2):228–245. https://doi.org/10.1093/annonc/mdw606
Kumar SK, Callander NS, Hillengass J, Liedtke M, Baljevic M, Campagnaro E, Castillo JJ, Chandler JC, Cornell RF, Costello C, Efebera Y, Faiman M, Garfall A, Godby K, Holmberg L, Htut M, Huff CA, Kang Y, Landgren O, Malek E, Martin T, Omel J, Raje N, Sborov D, Singhal S, Stockerl-Goldstein K, Tan C, Weber D, Johnson-Chilla A, Keller J, Kumar R (2019) NCCN guidelines insights: multiple myeloma, version 1.2020. J Natl Compr Cancer Netw 17(10):1154–1165. https://doi.org/10.6004/jnccn.2019.0049
Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, Gertz M, Dimopoulos M, Westin J, Sonneveld P, Ludwig H, Gahrton G, Beksac M, Crowley J, Belch A, Boccadaro M, Cavo M, Turesson I, Joshua D, Vesole D, Kyle R, Alexanian R, Tricot G, Attal M, Merlini G, Powles R, Richardson P, Shimizu K, Tosi P, Morgan G, Rajkumar SV, International Myeloma Working G (2006) International uniform response criteria for multiple myeloma. Leukemia 20(9):1467–1473. https://doi.org/10.1038/sj.leu.2404284
Kanda Y (2013) Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant 48(3):452–458. https://doi.org/10.1038/bmt.2012.244
Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, Gisslinger H, Wiktor-Jedrzejczak W, Zodelava M, Weisel K, Cascavilla N, Iosava G, Cavo M, Kloczko J, Blade J, Beksac M, Spicka I, Plesner T, Radke J, Langer C, Ben Yehuda D, Corso A, Herbein L, Yu Z, Mei J, Jacques C, Dimopoulos MA, Investigators MM (2012) Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med 366(19):1759–1769. https://doi.org/10.1056/NEJMoa1112704
Quach H, Fernyhough L, Henderson R, Corbett G, Baker B, Browett P, Blacklock H, Forsyth C, Underhill C, Cannell P, Trotman J, Neylon A, Harrison S, Link E, Swern A, Cowan L, Dimopoulos MA, Miles Prince H (2017) Upfront lower dose lenalidomide is less toxic and does not compromise efficacy for vulnerable patients with relapsed refractory multiple myeloma: final analysis of the phase II RevLite study. Br J Haematol 177(3):441–448. https://doi.org/10.1111/bjh.14562
Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, San Miguel J, Hellmann A, Facon T, Foa R, Corso A, Masliak Z, Olesnyckyj M, Yu Z, Patin J, Zeldis JB, Knight RD, Multiple Myeloma Study I (2007) Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 357(21):2123–2132. https://doi.org/10.1056/NEJMoa070594
Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, Siegel D, Borrello I, Rajkumar SV, Chanan-Khan AA, Lonial S, Yu Z, Patin J, Olesnyckyj M, Zeldis JB, Knight RD, Multiple Myeloma Study I (2007) Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 357(21):2133–2142. https://doi.org/10.1056/NEJMoa070596
Nakaya A, Fujita S, Satake A, Nakanishi T, Azuma Y, Tsubokura Y, Hotta M, Yoshimura H, Ishii K, Ito T, Nomura S (2017) Realistic lenalidomide dose adjustment strategy for transplant-ineligible elderly patients with relapsed/refractory multiple myeloma: Japanese real-world experience. Acta Haematol 138(1):55–60. https://doi.org/10.1159/000477792
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The authors thank all of the clinical staff members at the collaborating centers.
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YO and HH designed the study. YO performed statistical analyses and wrote the manuscript. HY, YK, TI, TK, JY, SN, OS, TA, KM, OF, NK, HN, and SO enrolled patients and reported clinical data. All authors interpreted data and reviewed and approved the final manuscript.
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YO and HH received speaker honoraria from Celgene whose product was discussed in this article. The remaining authors declare that they have no conflict of interest.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Onishi, Y., Yokoyama, H., Katsuoka, Y. et al. Low-dose lenalidomide and dexamethasone therapy after melphalan-prednisolone induction in elderly patients with newly diagnosed multiple myeloma. Ann Hematol 99, 2351–2356 (2020). https://doi.org/10.1007/s00277-020-04240-x
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DOI: https://doi.org/10.1007/s00277-020-04240-x