Reduced Dose-Intensity Subcutaneous Bortezomib Plus Prednisone (VP) Or Plus Cyclophosfamide (VCP) Or Plus Melphalan (VMP) For Newly Diagnosed Multiple Myeloma Patients Older Than 75 Years Of Age
Authors: Larocca Alessandra , Cavallo Federica , Magarotto Valeria , Offidani Massimo , Federico Vincenzo , Innao Vanessa , Falcone Antonietta Pia , Romano Alessandra , Caravita Tommaso , Rossi Davide , Mansueto Giovanna , Mina Roberto , Nozzoli Chiara , Benevolo Giulia , Guglielmelli Tommasina , Liberati Anna Marina , Derudas Daniele , Oliva Stefania , Morabito Fortunato , Carella Angelo Michele , Gentili Silvia , Saraci Elona , Petrucci Maria Teresa , Sonneveld Pieter , Boccadoro Mario , Palumbo Antonio 
Published: November 2019

Abstract

Background
Frail patients represent 30% of the myeloma population, and are more susceptible to adverse events (AEs) with subsequent treatment discontinuations that significantly affect efficacy and dose-intensity. This community-based, phase II, multicenter trial aims to assess the efficacy and safety of 3 reduced-dose intensity subcutaneous (sc) bortezomib-based treatments in newly diagnosed elderly multiple (MM) patients.

Methods
Patients with symptomatic, measurable MM, older than 75 years were enrolled. No exclusion criteria were planned in the protocol, to avoid patient selection bias. Patients with abnormal cardiac, pulmonary, renal or hepatic function were included.
Treatment consisted of nine 28-day cycles with sc bortezomib 1.3 mg/m2 days 1, 8, 15, 22 plus oral prednisone 50 mg every other day (VP) or VP plus oral cyclophosphamide 50 mg every other day (VCP) or oral melphalan 2 mg every other day (VMP) for 28 days, followed by maintenance with sc bortezomib every 2 weeks until progression.
A geriatric assessment was performed, including the Charlson index for estimating comorbidities, the Activity of Daily Living (ADL) and the Instrumental Activity of Daily Living (IADL) questionnaires to assess self-care and independence status. Combining these factors with age, patients were classified as fit (<80 years, ADL= 6, IADL=8, Charlson score= 0), unfit (fit patients >80 years or ADL=5, IADL=6-7, Charlson score=1), or frail (unfit patients >80 years or ADL≤4, IADL ≤5 and Charlson score ≥2).

Results
A total of 152 patients were enrolled, including 51 patients in the VP, 51 in the VCP and 50 in the VMP group. Median age was 78 years and 30% of patients were older than 80 years. Overall, 53%, 47% and 32% of the patients had ISS stage III disease, 21%, 20% and 24% had an unfavourable FISH profile [at least one chromosomal abnormality: del17, or t(4;14), or t(14;16)], and 88%, 84% and 78% were defined as unfit/frail in the VP, VCP, and VMP groups, respectively.
Patients received a median of 9 treatment cycles and 44% of patients started maintenance. All three induction regimens exhibited substantial activity, with an overall response rate (≥partial response) of 67% in the VP, 63% in the VCP, and 80% in the VMP group. After a median follow-up of 17 months, median progression-free survival (PFS) was 14, 16 and 16 months and 1-year overall survival (OS) estimates were 80%, 82% and 80% in the VP, VCP and VMP group, respectively.
The incidence of Serious Adverse Events (SAEs) was 22%, 20% and 30% and the discontinuation rate due to AEs was 14%, 16% and 26% in the VP, VCP and VMP groups, respectively. The most common non hematologic grade ≥3 AEs were infections (12%), cardiovascular events (8%), and neurologic events (7%), including 5% of peripheral neuropathy.
According to the geriatric classification, and specifically in the fit, unfit and frail patients, the overall response rate was 92%, 67% and 65%, the 1 year OS was 100%, 88% and 73%, rate of SAEs was 4%, 22%, 30% and discontinuation due to toxicity was 40%, 58% and 67%, respectively.

Conclusions
In this community-based population of elderly newly diagnosed MM patients low-dose intensity VP, VCP and VMP showed similar PFS and OS estimates, while SAEs and discontinuations were higher with VMP, suggesting that a melphalan-free regimen should be preferred in these patients. Geriatric assessment is mandatory, since both efficacy and toxicities are significantly different in fit, unfit and frail patients.

Disclosures:
Larocca: Janssen and Cilag: Honoraria. Cavallo:Janssen-Cilag: Honoraria. Caravita:Janssen-Cilag: Honoraria. Petrucci:Janssen-Cilag: Honoraria. Sonneveld:Janssen-Cilag: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Research Funding; Millenium: Research Funding; Onyx: Research Funding; Celgene: Research Funding. Boccadoro:Janssen-Cilag: Membership on an entity’s Board of Directors or advisory committees; Janssen-Cilag: Research Funding; Janssen-Cilag: Consultancy. Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria.