Subcutaneous Bortezomib, Melphalan and Prednisone in Elderly Newly Diagnosed Multiple Myeloma Patients
Authors: Herbaux Charles , Joao Cristina M. , Plocque Alexia , Richez Valentine , Gay Francesca , Renaud Loic , Legros Laurence , Garderet Laurent , Ikhlef Souhila , Pegourie Brigitte , Escoffre-Barbe Martine , Royer Bruno , Voillat Laurent , Hulin Cyrille , Banos Anne , Voog Eric G. , Karlin Lionel , Stoppa Anne-Marie , Benboubker Lotfi , Zweegman Sonja , De Jongh Eva , Abildgaard Niels , Le Dû Katell , Jurczyszyn Artur J. , Moreau Philippe , Facon Thierry , Caillot Denis , Terpos Evangelos , Leleu Xavier 
Published: October 2019

Abstract
Background. Bortezomib-melphalan-prednisone (VMP) is a standard of care upfront in Multiple Myeloma (MM) ineligible for transplantation, where bortezomib was given twice weekly intra veinously. Based on the VISTA study, the median TTP was 24.0 months, the median OS 56.4 months, the ORR (IMWG) 71% and the CR rate 30%. This regimen was then improved with a weekly administration of bortezomib starting at cycle 1 (called Palumbo design) or cycle 2 (called Mateos design). In the once-weekly schedule, the median PFS was 33.1 months, the median OS was not reached, the ORR 85% and the CR rate 30%.
Recently, subcutaneous bortezomib was approved in association to dexamethasone in relapsed MM that proved non-inferior to standard intravenous administration in terms of efficacy, with an improved safety profile, particularly with regard to the rate of neuropathy. As a consequence, physicians have switched to Bortezomib subcutaneous administration in the VMP regimen in many countries.
We aimed to study the impact of subcutaneous bortezomib in the VMP regimen (VscMP) in elderly MM newly diagnosed (NDMM).
Method. A total of 40 patients were recruited for the current study. Patients were required to be aged ≥65 years, NDMM treated with subcutaneous Bortezomib, Melphalan and Prednisone. Patients had VscMP either according to VISTA schedule or to Palumbo (weekly) schedule. Response rate was determined according to IMWG. All survival endpoints were evaluated using Kaplan-Meier estimates and compared with the log-rank test.
Results. The median age was 79 years (range, 67 - 90), with 28 patients (70%) aged >75 and 18 patients (45%) aged >80. The m:f ratio was 1.2, 77% of the patients were ISS 2 or 3, 32% had an ECOG score ≥ 2, and 10% had adverse FISH (del17p and/or t(4;14)). 15 patients were treated in the VISTA schedule and 25 in the weekly schedule (Palumbo design). No patients have had Mateos design.
For the cohort as a whole, the median TTP was 32 months, the median OS is not reached with 81% 5-years estimate, the ORR 75% and the CR rate 17,5%; that demonstrated that subcutaneous bortezomib is non-inferior to IV data reported in historical studies for the VMP regimen.
Similarly, there was not much difference in terms of efficacy between patients that had bortezomib subcutaneous weekly versus twice a week: weekly: the median OS is not reached, the ORR 80% and the CR rate 13%; twice a week: the median OS is not reached, the ORR 84% and the CR rate 20%.
With regards to the safety profile of VMP given with bortezomib subcutaneous, it seemed to offer an improved safety profile: 12.5% of grade 3 or 4 hematologic toxicity versus 47% in the literature. It does not seem to be any difference in neurological toxicity, with 5% of grade ≥2 peripheral neuropathy in our study, as to the VISTA study. Interestingly, we have seen no clear difference in terms of safety profile between the two schedule designs, VMP twice a week versus weekly using bortezomib sub cutaneous, which tend to confirm the improved safety profile of VMP with bortezomib used subcutaneously.
Conclusion. The use of subcutaneous bortezomib in the standard of care bortezomib-melphalan-prednisone regimen in elderly MM newly diagnosed had comparable efficacy than the intravenous administration. Importantly, the subcutaneous administration is associated to improved safety profile in comparison with previously published data. This dataset might encourage the use of the twice weekly subcutaneous bortezomib in the VMP regimen for patients considered fit.

Disclosures
No relevant conflicts of interest to declare.