Induction with Bortezomib Melphalan and Prednisolon (VMP) Is Associated with Unexpectedly High Discontinuation Rate in Elderly Multiple Myeloma Patients: First Analysis of the German Maintenance (GERMAIN) Trial
Authors: Brioli Annamaria , Manz Kirsi , Hänel Mathias , Pfirrmann Markus , Schwarzer Andreas Christoph , von Lilienfeld-Toal Marie , Prange-Krex Gabriele , Fabisch Christian , Knop Stefan , Illmer Thomas , Krammer-Steiner Beate , Hochhaus Andreas , Mügge Lars-Olof 
Published: October 2019

Abstract
Introduction
Based on improvement of overall survival (OS), lenalidomide (R) maintenance after up-front autologous stem cell transplantation has recently been approved for multiple myeloma (MM) patients (pts). Conversely, in transplant non-eligible (TNE) pts R maintenance after R-based induction improved progression free survival (PFS) but had no impact on OS. First-line treatment with VMP is considered a standard of care for newly diagnosed (ND) TNE pts, but whether maintenance therapy with R after VMP induction can further improve PFS and OS is currently unknown.
Aims
The prospective phase IIb GERMAIN trial (EudraCT-No: 2012-003023-38) aimed to evaluate the role of R maintenance after VMP induction in ND TNE MM pts. The trial, which planned to include 286 ND TNE MM pts, closed early in December 2017 due to insufficient accrual and high discontinuation rate. The present analysis focuses on the reasons for the high drop out rate.
Methods
After induction with 6 courses of VMP (Mateos et al., Lancet Oncology 2010), pts achieving at least a partial response (PR) were randomized 1:1 to R 10 mg or placebo (PCB) daily until progression (PD) or unacceptable toxicity. Pts with <PR could receive second line therapy with R 25 mg/day (three weeks on, one week off) and low dose dexamethasone until PD in the observational arm of the study. Pts with poor performance status (ECOG ≥3), creatinine clearance <15 ml/min, or other concomitant serious medical conditions were excluded, but no upper age limit was applied.
Results
From May 2014 to December 2017 85 pts were enrolled. Median age was 75 years (range 63-87). A significant proportion of pts presented with at least one concomitant illness: 75% were hypertensive, 29% had a cardiac disorder, 37% a metabolic disorder and 19% a chronic kidney disease.
Induction was completed by 53 pts and 40 pts entered maintenance randomization (Figure 1). Of patients completing induction therapy 77% achieved at least a PR, including 11% of sCR/CR and 26% of VGPR.
Overall 70% of pts discontinued the study; main reasons for trial discontinuation were PD (24%), unacceptable toxicity (17%), investigator decision (16%) and withdrawal of informed consent (12%). Of pts discontinuing treatment, 27 pts (47%) stopped during induction, and in 71% of these cases discontinuation was due to unacceptable toxicities (26%) or investigator (26%) and patients (19%) decision. Only one pt discontinued due to insufficient response during induction.
In total 745 adverse events (AE) and 71 serious AEs (SAE) were reported; of these 814 had complete data and were analyzed. During induction 571 AE occurred, of which 110 (19%) were of grade ≥3. Seventy-one pts (86%) reported at least one AE, and 49 (59%) at least one grade ≥3 AE. The most common grade ≥3 AE were: leukopenia (25%), thrombocytopenia (20%), cardiac toxicity (10%), infections (8%), peripheral neuropathy (6%), anemia and gastrointestinal toxicity (5% each). The cumulative probability of development of a grade ≥3 AE at 6 months was 59% (95% CI: 47 to 69%). SAEs during VMP were 54; 39% of pts experienced at least one SAE during induction. The cumulative probability for an SAE at 6 months was 41% (95% CI: 30 to 51%). During induction 4 deaths were recorded, all within the first month of treatment.
Of the pts randomized to maintenance treatment 37 received at least one dose of R/PCB and were considered evaluable. Twenty-one pts (36%) discontinued the study during maintenance. Main reason for discontinuation was PD (11 pts, 4 in R and 9 in PCB arm); only 2 pts (both in R arm) discontinued due to AE 2 and 21 months after start of maintenance, respectively. Of the AE recorded during maintenance (n=157, 92 in the R and 65 in the PCB group) 17% were grade ≥3 and 12 were considered SAE. At least one AE and at least one SAE were reported in 29 (78%) and 8 pts (22%), respectively. Four secondary malignancies (1 basal cell carcinoma, 1 AML, 1 bladder cancer and 1 lung cancer) were reported, 1 during VMP induction and 3 during maintenance.
Conclusions
In comparison to other studies focusing on ND TNE MM pts, our study investigated a remarkably elderly and frail population. In the cohort investigated, treatment with VMP resulted in increased toxicity and higher rate of discontinuation. Nevertheless, in those pts able to complete induction a promising ORR was observed. In elderly and frail MM pts, regimens other than VMP should be considered for induction.

Disclosures
Brioli: Celgene: Honoraria, Other: Travel support, Research Funding; Janssen: Honoraria. Hänel:Roche: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Amgen: Honoraria. Pfirrmann:Novartis: Research Funding. von Lilienfeld-Toal:Janssen: Honoraria, Other: Travel support, Research Funding; Celgene: Honoraria, Other: Travel support, Research Funding; Novartis: Honoraria, Other: Travel support, Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding. Fabisch:Novartis: Research Funding. Knop:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Hochhaus:Incyte: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding. Mügge:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Amgen: Honoraria.