Duration of Therapy Is Independently Associated with Improved Progression Free and Overall Survival Following First Line Therapy for Non-Transplant Eligible Patients with Multiple Myeloma: Retrospective Analysis from a Single Centre
Authors: De-Silva Dunnya , Bloomfield Adam , Counsell Nicholas , Cheesman Simon , Rismani Ali , Rabin Neil , D'Sa Shirley , Kyriakou Charalampia , Galinsky Jayne , Richard Sarah , Popat Rakesh , Mehta Atul , Yong Kwee L 
Published: October 2019

Abstract
Background.
Survival for older patients with multiple myeloma (MM) has improved with novel agents such as Proteasome inhibitors (PIs) and Immunomodulatory drugs (IMiDs) . Outcomes in this heterogeneous population are also affected by pre-morbid fitness, comorbidities and tolerance of therapy. We analysed the outcomes of first line systemic therapy in this older patient group, aiming to explore the influence of patient, disease and regimen factors on outcomes.
Methods.
Non-transplant eligible patients undergoing first line therapy between April 2008 and April 2016 were identified retrospectively from electronic prescribing records; patient and disease features, toxicity and dose modifications were obtained from clinical records. FISH was performed on CD138+ cells using standard probes, and adverse risk was defined as per IMWG criteria. Survival was estimated using Kaplan-Meier methods and disease response by IMWG criteria. Cox Regression (univariate and multivariate) analysis was performed to identify factors influencing progression free (PFS) and overall survival (OS).
Results.
84 patients were identified with median age 76 years (range 52-97); 24(28.6%) had cardiac and 12(14.3%) had pulmonary comorbidities. There was an equal spread of ISS stage and 26(31.0%) patients had extramedullary disease (EMD). Of 44 patients with FISH results at diagnosis, 18 (40.9%) had high risk features including 9(20.5%) with del(17p).
Patients received a range of treatments; 51(60.7%) had PI-based regimens mainly with Bortezomib, 18(21.4%) received IMiDs (13 Thalidomide, 5 Lenalidomide) and 13(15.5%) chemotherapy. The median total duration of therapy including maintenance was 7.7months (range 0.7-24.1); this was longer (9.6months) in patients receiving IMiDs.
The median PFS was 13.1 months (95% CI 10.6-15.5) and median OS was 40.5months (95% CI 30.3-50.7). The overall response rate (ORR) was 70.2%, and was higher in patients treated with novel agents (IMiD 72.2%, PI 72.0%) compared to patients treated with chemotherapy (61.6%).
Younger age (70-80years vs. ≥80years), ISS stage 1, disease response ≥PR, maintenance therapy and longer total duration of therapy were associated with longer PFS in univariate analysis, and EMD was associated with shorter PFS(p's <0.1). On multivariate analysis, only total duration of therapy (HR=0.89; 0.81-0.96, p=0.005), ISS stage 1 (HR=0.28; 0.12 -0.63, p=0.002) and younger age (70-80years vs. ≥80years HR=0.50; 0.24-1.05, p=0.068) independently predicted longer PFS.
Looking at factors predicting OS on univariate analysis, ISS stage 1, IMiD therapy, maintenance therapy and longer duration of therapy were associated with prolonged OS (p's <0.1). Only longer duration of therapy (HR=0.84; 0.76-0.93, p=0.001) and ISS stage 1 (HR=0.25; 0.08-0.80, p=0.020) remained significantly associated with OS on multivariate analysis. Although adverse genetic risk was associated with shorter OS on univariate analysis, the effect was not seen after adjusting for ISS stage, induction regimen and duration of therapy, where only duration of therapy remained significant (HR=0.69; 0.56-0.87, p=0.001).
18 (21.7%) patients discontinued therapy early due to toxicity; this was more frequent with PI (23.5%) and chemotherapy regimens (20.5%) compared to IMiD regimens (16.7%). 48(57%) patients required dose alterations due to toxicity, and this was commoner with IMiD (72%) compared to chemotherapy (38%) or PI (55%) based regimens.
Conclusion.
We report a sequential cohort of non-transplant eligible patients undergoing first line therapy in the era of novel agents. Our results indicate a consistent benefit for PFS and OS with longer duration of therapy, independent of response, regimen or adverse risk disease. ISS 1 was also an independent predictor of prolonged PFS and OS. Treatment regimen type and response did not correlate independently with PFS or OS. Despite the presence of comorbidities and discontinuations for toxicity, the PFS and OS outcomes are encouraging. This review of real-world outcomes highlights the potential benefit of continuous therapy in older patients. Improved ways of identifying patients susceptible to toxicity and use of frailty-adjusted treatment schedules would further improve outcomes in this patient group.

Disclosures
Yong: Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor; Janssen: Research Funding.