Feasibility and Efficacy of Dose Adjusted Melphalan - Prednisone - Bortezomib (MPV) in Elderly Patients ≥ 75 Years of Age with Newly Diagnosed Multiple Myeloma; the Non-Randomised Phase II HOVON 123 Study
Authors: Zweegman Sonja , Levin Mark-David , Klein Saskia K. , De Waal Esther G.M. , Eeltink Corien M. , Ypma Paula F. , Dijk Amanda C. , Westerman Matthijs , Deenik Wendy , Tanis Bea , Slee-Valentijn Monique S. , Minnema Monique , Visser-Wisselaar Heleen , Stege Claudia , van de Donk Niels W.C.J. , Nasserinejad Kazem , Sonneveld Pieter 
Published: October 2019

Abstract
BACKGROUND
There is a high rate of toxicity-related discontinuation in elderly patients with NDMM, which in general is higher in patients ≥75 years. Therefore, we investigated the feasibility of a dose-adapted MPV scheme in patients ≥75 years and whether the International Myeloma Working Group frailty score (fit, unfit, and frail) predicts feasibility. Moreover, geriatric assessments, including functional assessments, were performed in order to design a model for more precise prediction of feasibility of treatment.
METHODS
Patients were treated with 9 cycles of MPV: Mel 6 mg/m2, day 1-4; Pred 30 mg/m2, day 1-4; and Bort 1.3 mg/m2 day 1,8,15 and 22 of a 35-day cycle. This first planned analysis on discontinuation rate was restricted to the first 100 eligible consecutive patients out of 240 planned patients. A preliminary analysis of grip strength and walking speed was performed, comparing tertiles.
RESULTS
Of the 96/100 evaluable patients, none were fit (because of age ≥75 years), 23/96 (24%) were unfit and 64/96 (67%) were frail (9/96 (9%) unknown). 28/64 (44%) frail patients were aged 75-80, and 8/64 (13%) patients were defined frail based on age >80 years only. Frail patients were found to have significantly less grip strength and lower walking speed as compared to unfit patients (see table 1), both for men and women. However, 19% (male) and 15% (female) of the patients with low grip strength were not frail, but unfit. For slow walking speed these percentages were 13% and 7% respectively, indicating these tools might be complementary to the IMWG frailty score in predicting outcome.
The median follow up was 16 months. The discontinuation rate of MPV in the total population was 49%; 30% in unfit and 55% (including 7% discontinuation of bortezomib only) in frail patients (p=0.055). In patients >80 years (by definition frail) discontinuation rate was higher (69% (including 11% bortezomib only)) than in patients aged 75-80 years (37%; p=0.003). Reasons for early discontinuation in unfit versus frail were: progressive disease 1/7 vs 4/31, toxicity 3/7 vs 10/31, death 0/7 vs 4/31, non-compliance 1/7 vs 8/31, other 2/7 vs 5/31. In 72% 6 cycles of MPV were found to be feasible, both in unfit (78%) and frail (73%) patients.
Response on protocol was ≥PR 69%, ≥VGPR 29% and ≥CR 7%, not significantly different in unfit versus frail patients. Median progression free survival (PFS) was 17 months: 22 for unfit and 17 months for frail patients (p=0.38). Overall survival (OS) at 18 months was 76%: 88% for unfit and 71% for frail (p=0.26) patients.
Conclusions
Treatment of elderly NDMM patients ≥75 years with 9 cycles of dose-adjusted MPV results in a high discontinuation rate of 49%: 30% in unfit versus 55% in frail patients, indicating the need for further treatment adjustment and more precise selection of patients. Concerning the first; 6 cycles were found to be feasible in the majority of both unfit and frail patients. Concerning the latter; a preliminary analysis of functional geriatric assessments showed significantly lower performance in frail compared to unfit patients. Moreover, the results of functional geriatric assessments were found to add to the IMWG frailty score, hopefully leading to a better prediction of the feasibility of treatment in elderly NDMM patients.
Functional assessments in unfit versus frail patients 1 p=0.18 2 p=0.012 3 p=0.037 4 p=0.014
Additional cognitive and nutritional geriatric assessments and biomarkers (sarcopenia and senescence markers) were performed in all patients.
FISH analysis of isolated plasma cells will be available in the majority of patients.
This trial was registered at www.trialregister.nl (NTR 4244), EudraCT 2013-000320-33, and supported by the Dutch Cancer Society (project number VU 2013-6411 ) and by an unrestricted grant from Janssen-Cilag.

Disclosures
Zweegman: Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Ypma:Advisory Board Sanofi (Plerixafor): Membership on an entity's Board of Directors or advisory committees. Minnema:Celgene: Consultancy; BMS: Consultancy; Amgen: Consultancy; Jansen Cilag: Consultancy. van de Donk:BMS: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Amgen: Research Funding. Sonneveld:Karyopharm: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.