Bortezomib, Melphalan, Prednisone (VMP) and Lenalidomide Plus Dexamethasone (Rd) Is the Optimal Combination for Patients with Newly Diagnosed Multiple Myeloma (MM) Patients Between 65 and 80 Years
Authors: Mateos Maria-Victoria , Martínez-López Joaquín , Hernandez Miguel T , Ocio Enrique M , Rosiñol Laura , Martinez Rafael , Teruel Ana Isabel , Gutierrez Norma C , Martín María-Luisa , Oriol Albert , Bargay Joan , Bengoechea Enrique , Gonzalez Yolanda , Perez de Oteyza Jaime , Gironella Mercedes , Encinas Cristina , Cabrera Carmen , Paiva Bruno , Cedena Maria Teresa , Puig Noemi , Blade Joan , Lahuerta Juan José , San Miguel Jesus 
Published: October 2019

Abstract
Background: MM usually affects elderly patients and although novel agents-based combinations have substantially improved MM outcome, it is possible that this benefit would be particularly relevant for the "youngest-elderly" patients (65-80y). According to the frailty score published by IMWG, the chronological age ≥80 years identifies itself a frail patient population with poor outcome and we have here evaluated the efficacy, safety and outcome of patients included in the GEM2010 trial according to the age to identify the group of patients who benefit most of this total therapy approach.
Patients and methods: 242 patients were randomized to receive a sequential scheme consisting on 9 cycles of VMP followed by 9 cycles of Rd or the same regimens in an alternating approach (one cycle of VMP alternating with one Rd, up to 18 cycles. VMP included the iv administration of weekly bortezomib (except in the first cycle that was given twice weekly) at 1.3 mg/m2 in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2 once daily on days 1-4. Rd treatment consisted on lenalidomide 25 mg daily on days 1-21 plus dexamethasone 40 mg weekly.
Results: 233 pts were evaluable for safety and efficacy (118 in the sequential and 115 in the alternating arm). One hundred and fifteen patients (49%) were between 65-75 years, 69 patients (30%) were aged between 75-80 years and 49 patients (21%) were older than 80 years. The allocation in both sequential and alternating arms was well balanced. There were not significant differences in the baseline characteristics of the three subgroups of patients. The ORR was similar in both patients aged 65-75 and 75-80 (80% and 83%), but significantly lower in patients older than 80 years (68%) (p=0.007). The CR rate was also almost identical in patients between 65-75 (45%) and 75-80 (49%), but significantly lower in those aged over 80 years (10%) (p<0.0001).
The median PFS was 35 m and 32 m in the group of patients aged between 65-75 and 75-80, respectively (p=NS), but PFS was only 25 months in patients older than 80 (p=0.02). In terms of OS, 75% of the patients between 65-75 years remained alive at 4 years, 60% of patients between 75-80 years (p=0.05), as compared to only 30% of patients older than 80 years (p=0.003). There were no significant differences between the sequential and alternating arms.
Hematological and non-hematological toxicity was not different in the different groups according to the age, but it is important to note that 63% of patients older than 80 years early discontinued the trial due to toxicity or informed consent withdrawal, while this occurred in only 30% of patients aged 65-75 and 75-80. Sixty-eight percent and 59% of the patients aged 65-75 and 75-80, respectively, completed the 18 planned cycles, as compared to only 36% of patients aged over 80 years. The median cumulative dose of bortezomib and lenalidomide was significantly higher in the group of patients aged 65-75 (44 mg/m2 for bz and 4410 mg for len) and 75-80 (41 mg/m2 for bz and 4078 mg for len) compared to patients over 80 years (33 mg/m2 for bz and 1783 mg for len). These differences were maintained in both sequential and alternating arms.
Conclusions: The present therapeutic approach, based on VMP and Rd for newly diagnosed elderly MM patients probably represents the optimal therapeutic option for elderly patients between 65 and 80 years in a sequential or alternating approach. By contrast, further optimization for the patient population over 80 years is still required.

Disclosures
Mateos: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ocio:Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy, Honoraria; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy; Mundipharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; MSD: Research Funding; Pharmamar: Consultancy, Research Funding; Janssen: Honoraria. Oriol:Celgene, Janssen, Amgen: Consultancy, Speakers Bureau. Gironella:Celgene Corporation: Consultancy, Honoraria. Paiva:Celgene: Consultancy; Binding Site: Consultancy; Millenium: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; EngMab AG: Research Funding; BD Bioscience: Consultancy; Onyx: Consultancy. Puig:Janssen: Consultancy; The Binding Site: Consultancy. San Miguel:Celgene: Honoraria; Janssen-Cilag: Honoraria; Novartis: Honoraria; Sanofi-Aventis: Honoraria; Bristol-Myers Squibb: Honoraria; Millennium: Honoraria; Onyx: Honoraria.