Autologous stem cell transplantation (ASCT) is a standard treatment for eligible multiple myeloma (MM) patients, but many patients will relapse after ASCT and require subsequent therapy. The proteasome inhibitor carfilzomib is approved for relapsed or refractory MM (RRMM). In phase 3 trials, carfilzomib-based regimens (ASPIRE, carfilzomib-lenalidomide-dexamethasone; ENDEAVOR, carfilzomib-dexamethasone) demonstrated superior progression-free survival (PFS) compared with standard therapies for RRMM (ASPIRE: lenalidomide-dexamethasone; ENDEAVOR, bortezomib-dexamethasone). This subgroup analysis of ASPIRE and ENDEAVOR evaluated outcomes according to prior ASCT status. In total, 446 patients in ASPIRE and 538 in ENDEAVOR had prior ASCT. Median PFS was longer for carfilzomib-based regimens vs non-carfilzomib-based regimens for patients with prior ASCT (ASPIRE: 26.3 vs 17.8 months (hazard ratio (HR)=0.68); ENDEAVOR: not estimable vs 10.2 months (HR=0.61)), those with one prior line of therapy that included ASCT (ASPIRE: 29.7 vs 17.8 months (HR=0.70); ENDEAVOR: not estimable vs 11.2 months (HR=0.46)), and those without prior ASCT (ASPIRE: 26.4 vs 16.6 months (HR=0.76); ENDEAVOR: 17.7 vs 8.5 months (HR=0.43)). Overall response rates also favored the carfilzomib-based regimens. No new safety signals were detected. This analysis suggests that carfilzomib-based treatment may lead to improvement in PFS and response rates regardless of prior transplant status. Further evaluation is warranted.

Amgen Inc Thousand Oaks CA USA

Department of Hematology University of Nantes Nantes France

Fred Hutchinson Cancer Research Center Seattle WA USA

Hematology Hospital Clinico Universitario de Salamanca IBSAL Salamanca Spain

Indiana University Simon Cancer Center Indianapolis IN USA

John Theurer Cancer Center at Hackensack University Hackensack NJ USA

Leukemia Bone Marrow Transplant Program of British Columbia Vancouver British Columbia Canada

Medical College of Wisconsin Milwaukee WI USA

Medizinische Klinik der Universitat Wurzburg Wurzburg Germany

Universitatsklinikum Heidelberg Heidelberg Germany

University Hospital Ostrava and Faculty of Medicine University of Ostrava Ostrava Czech Republic

Zobrazit více v PubMed

Ludwig H, Miguel JS, Dimopoulos MA, Palumbo A, Garcia Sanz R, Powles R et al. International Myeloma Working Group recommendations for global myeloma care. Leukemia 2014; 28: 981–992. PubMed

Attal M, Lauwers-Cances V, Hulin C, Facon T, Caillot D, Escoffre M et al. Autologous transplantation for multiple myeloma in the era of new drugs: a phase III study of the Intergroupe Francophone Du Myelome (IFM/DFCI 2009 Trial). Blood 2015; 125: 391 (abstract).

Korde N, Roschewski M, Zingone A, Kwok M, Manasanch EE, Bhutani M et al. Treatment with carfilzomib-lenalidomide-dexamethasone with lenalidomide extension in patients with smoldering or newly diagnosed multiple myeloma. JAMA Oncol 2015; 1: 746–754. PubMed PMC

Zimmerman TM, Griffith KA, Jasielec J, Rosenbaum CA, McDonnell K, Waite-Marin J et al. Phase II MMRC trial of extended treatment with carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (DEX) plus autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (NDMM). J Clin Oncol 2015; 33: Abstract 8510.

Michaelis LC, Saad A, Zhong X, Le-Rademacher J, Freytes CO, Marks DI et al. Salvage second hematopoietic cell transplantation in myeloma. Biol Blood Marrow Transplant 2013; 19: 760–766. PubMed PMC

Sellner L, Heiss C, Benner A, Raab MS, Hillengass J, Hose D et al. Autologous retransplantation for patients with recurrent multiple myeloma: a single-center experience with 200 patients. Cancer 2013; 119: 2438–2446. PubMed

Holstein SA, Richardson PG, Laubach JP, McCarthy PL. Management of relapsed multiple myeloma after autologous stem cell transplantation. Biol Blood Marrow Transplant 2015; 21: 793–798. PubMed

Nooka AK, Kastritis E, Dimopoulos MA, Lonial S. Treatment options for relapsed and refractory multiply myeloma. Blood 2015; 125: 3085–3099. PubMed

Lemieux E, Hulin C, Caillot D, Tardy S, Dorvaux V, Michel J et al. Autologous stem cell transplantation: an effective salvage therapy in multiple myeloma. Biol Blood Marrow Transplant 2013; 19: 445–449. PubMed

Olin R, Vogl D, Porter D, Luger SM, Schuster SJ, Tsai DE et al. Second auto-SCT is safe and effective salvage therapy for relapsed multiple myeloma. Bone Marrow Transplant 2009; 43: 417–422. PubMed PMC

NCCN Multiple Myeloma. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) version 3 2016. Available at: https://www.nccn.org/professionals/physician_gls/f_guidelines.asp.

EMEAVelcade: Product Information. EMEA: London, UK, 2008.

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: 2133–2142. PubMed

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: 2123–2132. PubMed

US FDAKyprolis: Product Information. US FDA: Maryland, USA, 2016.

EMEAKyprolis: Product Information. EMEA: London, UK, 2016.

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; 373: 142–152. PubMed

Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hájek R et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol 2016; 17: 27–38. PubMed

Rosinol L, Kumar S, Moreau P, Cavo M. Initial treatment of transplant-eligible patients in multiple myeloma. Expert Rev Hematol 2014; 7: 43–53. PubMed

Cavo M, Rajkumar SV, Palumbo A, Moreau P, Orlowski R, Blade J et al. International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation. Blood 2011; 117: 6063–6073. PubMed PMC

Attal M, Harousseau JL. Role of autologous stem-cell transplantation in multiple myeloma. Recent Results Cancer Res 2011; 183: 189–206. PubMed

Feyler S, Selby PJ, Cook G. Regulating the regulators in cancer immunosuppression in multiple myeloma (MM). Blood Rev 2013; 27: 155–164. PubMed

Ribatti D, Moschetta M, Vacca A. Microenvironment and multiple myeloma spread. Thromb Res 2014; 133: S102–S106. PubMed

Pellat-Deceunynck C, Battaile R. Normal and malignant human plasma cells: proliferation, differentiation, and expansions in relation to CD45 expression. Blood Cells Mol Dis 2004; 32: 293–301. PubMed

Asosingh K, De Raeve H, Van Riet I, Van Camp B, Vanderkerken K. Multiple myeloma tumor progression in the 5T2MM murine model is a multistage and dynamic process of differentiation, proliferation, invasion, and apoptosis. Blood 2003; 101: 3136–3141. PubMed

Kraj M, Sokolowska U, Kopec-Szlezak J, Poglod R, Kruk B, Wozniak J et al. Clinicopathological correlates of plasma cell CD56 (NCAM) expression in multiple myeloma. Leuk Lymphoma 2008; 49: 298–305. PubMed

Hanamura I, Stewart J, Huang Y, Zhan F, Santra M, Sawyer JR et al. Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridization: incidence increases in MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell transplantation. Blood 2006; 108: 1724–1732. PubMed PMC

Moreau P, Robillard N, Avet-Loiseau H, Pineau D, Morineau N, Milipied N et al. Patients with CD45 negative multiple myeloma receiving high-dose therapy have a shorter survival than those with CD45 positive multiple myeloma. Haematologica 2004; 89: 547–551. PubMed

Avet-Loiseau H, Hulin C, Campion L, Rodon P, Marit G, Attal M et al. Chromosomal abnormalities are major prognostic factors in elderly patients with multiple myeloma: the intergroupe francophone du myelome experience. J Clin Oncol 2013; 31: 2806–2809. PubMed PMC

Lonial S, Anderson KC. Association of response endpoints with survival outcomes in multiple myeloma. Leukemia 2014; 28: 258–268. PubMed PMC

Majithia N, Rajkumar SV, Lacy MQ, Buadi A, Dispenzieri M, Hayman SR et al. Early relapse following initial therapy for multiple myeloma predicts poor outcomes in the era of novel agents. Leukemia 2016; 30: 2208–2213. PubMed PMC

Jimenez-Zepeda VH, Reece DE, Trudel S, Chen C, Tiedemann R, Kukreti V. Early relapse after single auto-SCT for multiple myeloma is a major predictor of survival in the era of novel agents. Bone Marrow Transplant 2015; 50: 2015–2018. PubMed

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: 621–631. PubMed

Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 2016; 374: 1621–1634. PubMed

Stadtmauer EA, Weber DM, Niesvizky R, Belch A, Prince MH, San Miguel JF et al. Lenalidomide in combination with dexamethasone at first relapse in comparison with its use as later salvage therapy in relapsed or refractory multiple myeloma. Eur J Haematol 2009; 82: 426–432. PubMed PMC

Dimopoulos MA, Stewart KA, Rajkumar SV, Masszi T, Oriol A, Hajek R et al. Effect of carfilzomib, lenalidomide, and dexamethasone (KRd) vs lenalidomide and dexamethasone (Rd) in patients with relapsed multiple myeloma (RMM) by line of therapy: secondary analysis from an interim analysis of the phase III study ASPIRE (NCT01080391). J Clin Oncol 2015; 33 (suppl): Abstract 8525.

Moreau P, Joshua D, Chng WJ, Palumbo A, Goldschmidt H, Hajek R et al. Impact of prior treatment on patients with relapsed multiple myeloma treated with carfilzomib and dexamethasone vs bortezomib and dexamethasone in the phase 3 ENDEAVOR study. Leukemia 2016; 19: 1782–1791. PubMed PMC

Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 2012; 366: 1782–1791. PubMed

McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 2012; 366: 1770–1781. PubMed PMC

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

Attal M, Palumbo A, Holstein SA, Lauwers-Cances V, Petrucci MT, Richardson PG et al. Lenalidomide (LEN) maintenance (MNTC) after high-dose melphalan and autologous stem cell transplant (ASCT) in multiple myeloma (MM): a meta-analysis (MA) of overall survival (OS). J Clin Oncol 2016; 34 (suppl): Abstract 8001.

Analysis of carfilzomib cardiovascular safety profile across relapsed and/or refractory multiple myeloma clinical trials