Carfilzomib, cyclophosphamide and dexamethasone for newly diagnosed, high-risk myeloma patients not eligible for transplant: a pooled analysis of two studies

Roberto Mina, Francesca Bonello, Maria Teresa Petrucci, Anna Marina Liberati, Concetta Conticello, Stelvio Ballanti, Pellegrino Musto, Attilio Olivieri, Giulia Benevolo, Andrea Capra, Milena Gilestro, Piero Galieni, Michele Cavo, Agostina Siniscalchi, Antonio Palumbo, Vittorio Montefusco, Gianluca Gaidano, Paola Omedé, Mario Boccadoro, Sara Bringhen, Roberto Mina, Francesca Bonello, Maria Teresa Petrucci, Anna Marina Liberati, Concetta Conticello, Stelvio Ballanti, Pellegrino Musto, Attilio Olivieri, Giulia Benevolo, Andrea Capra, Milena Gilestro, Piero Galieni, Michele Cavo, Agostina Siniscalchi, Antonio Palumbo, Vittorio Montefusco, Gianluca Gaidano, Paola Omedé, Mario Boccadoro, Sara Bringhen

Abstract

Despite remarkable advances in the treatment of multiple myeloma in the last decades, the prognosis of patients harboring high-risk cytogenetic abnormalities remains dismal as compared to that of standard-risk patients. Proteasome inhibitors demonstrated to partially ameliorate the prognosis of high-risk patients. We pooled together data from two phase I/II trials on transplant-ineligible patients with multiple myeloma receiving upfront carfilzomib cyclophosphamide and dexamethasone followed by carfilzomib maintenance. The aim of this analysis was to compare treatment outcomes in patients with standard- versus high-risk cytogenetic abnormalities detected by fluorescence in situ hybridization (FISH) analysis. High risk was defined by the presence of at least one chromosomal abnormality, including t(4;14), del17p and t(14;16). Overall, 94 patients were included in the analysis: 57 (61%) in the standard-risk and 37 (39%) in the high-risk group. Median follow-up was 38 months. In standard- vs. high-risk patients, we observed similar progression-free survival (3-year PFS: 52% vs. 43%, respectively; p=0.50), overall survival (3-year OS: 78% vs. 73%; p=0.38), and overall response rate (88% vs 95%; p=0.47), with no statistical differences between the two groups. No difference in terms of progression-free survival was observed between patients with or without del17p. Carfilzomib, used both as induction and maintenance agent for transplant-ineligible newly diagnosed multiple myeloma patients, mitigated the poor prognosis carried by high-risk cytogenetics and resulted into similar progression-free survival and overall survival, as compared to standard-risk patients. ClinicalTrials.gov IDs: NCT01857115 (IST-CAR-561) and NCT01346787 (IST-CAR-506).

Figures

Figure 1.
Figure 1.
Standard-risk versus high-risk patients. (A) Progression-free survival (PFS), (B) PFS-2, and (C) overall survival (OS).
Figure 2.
Figure 2.
Median progression-free survival (PFS) according to del17p status.

References

    1. Greipp PR, San Miguel J, Durie BGM, et al. . International staging system for multiple myeloma. J Clin Oncol. 2005;23(15):3412-3420.
    1. Palumbo A, Bringhen S, Mateos M-V, et al. . Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood. 2015;125(13):2068-2074.
    1. Larocca A, Dold SM, Zweegman S, et al. . Patient-centered practice in elderly myeloma patients: an overview and consensus from the European Myeloma Network (EMN). Leukemia. 2018;32(8):1697-1712.
    1. Fonseca R, Bergsagel PL, Drach J, et al. . International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia. 2009; 23(12):2210-2221.
    1. Moreau P, Attal M, Garban F, et al. . Heterogeneity of t(4;14) in multiple myeloma. Long-term follow-up of 100 cases treated with tandem transplantation in IFM99 trials. Leukemia. 2007;21(9):2020-2024.
    1. Gertz MA, Lacy MQ, Dispenzieri A, et al. . Clinical implications of t(11;14)(q13;q32), t(4;14)(p16.3;q32), and -17p13 in myeloma patients treated with high-dose therapy. Blood. 2005;106(8):2837-2840.
    1. Fonseca R, Blood E, Rue M, et al. . Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood. 2003;101(11):4569-4575.
    1. Avet-Loiseau H, Malard F, Campion L, et al. . Translocation t(14;16) and multiple myeloma: is it really an independent prognostic factor? Blood. 2011;117(6):2009-2011.
    1. Palumbo A, Avet-Loiseau H, Oliva S, et al. . Revised International Staging System for Multiple Myeloma: a report from International Myeloma Working Group. J Clin Oncol. 2015;33(26):2863-2869.
    1. Howlader N, Noone A, Krapcho M, et al. . Cancer Statistics Review, 1975-2015, National Cancer Institute. Based on November 2018 SEER data submission, posted to the SEER web site, April 2019. [Last accessed 7 Jan 2019]
    1. 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.
    1. 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.
    1. 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.
    1. Benboubker L, Dimopoulos MA, Dispenzieri A, et al. . Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014; 371(10):906-917.
    1. 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.
    1. Chng W-J, Goldschmidt H, Dimopoulos MA, et al. . Carfilzomib-dexamethasone vs bortezomib-dexamethasone in relapsed or refractory multiple myeloma by cytogenetic risk in the phase 3 study ENDEAVOR. Leukemia. 2017;31(6):1368-1374.
    1. Avet-Loiseau H, Fonseca R, Siegel D, et al. . Carfilzomib significantly improves the progression- free survival of high-risk patients in multiple myeloma. Blood. 2016;128(9):1174-1180.
    1. Bringhen S, Petrucci MT, Larocca A, et al. . Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study. Blood. 2014;124(1):63-69.
    1. Bringhen S, D’Agostino M, De Paoli L, et al. . Phase 1/2 study of weekly carfilzomib, cyclophosphamide, dexamethasone in newly diagnosed transplant-ineligible myeloma. Leukemia. 2018;32(4):979-985.
    1. Bringhen S, Mina R, Petrucci MT, et al. . Once-weekly versus twice-weekly carfilzomib in patients with newly diagnosed multiple myeloma: a pooled analysis of two phase I/II studies. Haematologica. 2019; 104(8):1640-1647.
    1. Sonneveld P, Avet-Loiseau H, Lonial S, et al. . Treatment of multiple myeloma with highrisk cytogenetics: a consensus of the International Myeloma Working Group. Blood. 2016;127(24):2955-2962.
    1. Larocca A, Mina R, Offidani M, et al. . Firstline therapy with either bortezomib-melphalan- prednisone or lenalidomide-dexamethasone followed by lenalidomide for transplant-ineligible multiple myeloma patients: a pooled analysis of two randomized trials. Haematologica. 2020; 105(4):1074-1080.
    1. Sonneveld P, Goldschmidt H, Rosiñol L, et al. . Bortezomib-based versus nonbortezomib- based induction treatment before autologous stem-cell transplantation in patients with previously untreated multiple myeloma: a meta-analysis of phase III randomized, controlled trials. J Clin Oncol. 2013;31(26):3279-3287.
    1. Avet-Loiseau H, Bahlis NJ, Chng W-J, et al. . Ixazomib significantly prolongs progressionfree survival in high-risk relapsed/refractory myeloma patients. Blood. 2017; 130(24):2610-2618.
    1. Gay F, Cerrato C, Scalabrini DR, et al. . Carfilzomib-lenalidomide-dexamethasone (KRd) induction-autologous transplant (ASCT)-Krd consolidation vs KRd 12 cycles vs carfilzomib-cyclophosphamidedexamethasone (KCd) induction-ASCTKCd consolidation: analysis of the randomized FORTE trial in newly diagnosed multiple myeloma (NDMM). Blood. 2018;132(Suppl 1):Abstract #121 [ASH 2018 60th Meeting].
    1. Gay F, Rota Scalabrini D, Belotti A, et al. . Updated efficacy and MRD data according to risk status in newly diagnosed myeloma patients treated with carfilzomib plus lenalidomide or cyclophosphamide: results from the FORTE trial. HemaSphere. 2018;2(S1):6 [Abstract #S109, EHA 2018 23rd Congress].
    1. Facon T, Kumar SK, Plesner T, et al. . Phase 3 randomized study of daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma (NDMM) ineligible for transplant (MAIA). Blood. 2018;132(Suppl 1):Abstract #LBA-2 [ASH 2018 60th Meeting].
    1. Facon T, Kumar S, Plesner T, et al. . Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380(22):2104-2115.
    1. Mateos M-V, Dimopoulos MA, Cavo M, et al. . Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018;378(6):518-528.
    1. Lakshman A, Painuly U, Rajkumar SV, et al. . Impact of acquired del(17p) in multiple myeloma. Blood Adv. 2019;3(13):1930-1938.
    1. Thakurta A, Ortiz M, Blecua P, et al. . High subclonal fraction of 17p deletion is associated with poor prognosis in multiple myeloma. Blood. 2019;133(11):1217-1221.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner