Health-Related Quality of Life in Patients with Relapsed/Refractory Multiple Myeloma Treated with Isatuximab Plus Pomalidomide and Dexamethasone: Icaria-MM Study

Introduction: Isatuximab (Isa) is an IgG1 monoclonal antibody that targets a specific epitope on CD38 and has been investigated in combination with pomalidomide (P) and low-dose dexamethasone (d) (Isa-Pd) in a phase 3 trial compared to Pd in patients (pts) with relapsed/refractory multiple myeloma (RRMM). A significant and sustained progression free survival benefit was observed (Richardson et al., 2019). Since health-related quality of life (HRQL) is known to deteriorate with each subsequent line of therapy among RRMM pts, it is critical to determine the effect of adding Isa to the Pd regimen on HRQL. Symptoms such as pain, fatigue and physical functioning have been identified as key drivers of HRQL in oncology populations (Stull et al., 2016, 2017), including RRMM (Baz et al., 2015; FDA-ASCO, 2019; Gonzalez-McQuire et al., 2019; Osbourne 2014). Thus, maintaining or improving HRQL is dependent on managing symptoms and the impact of treatment on physical functioning (PF).

Aim: To assess the overall rate of change in patient-reported HRQL associated with adding Isa to the Pd regimen. Additionally, to assess the extent to which changes in patient-reported symptoms and PF predict HRQL.

Methods: A post hoc analysis of data from the ICARIA-MM study (NCT02990338) was performed. A total of 307 patients were randomized (154 Isa-Pd, 153 Pd) who received ≥2 prior lines with lenalidomide and a proteasome inhibitor, and were refractory to last therapy. Pts self-completed electronic versions of the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire 30-items (EORTC QLQ-C30) on day 1 of each treatment cycle (every 28 days) until progression or unacceptable toxicity. Domains are scored 0-100; for functional domains 0 = poor, 100 = excellent; whereas for symptom domains, 0 = symptom-free, 100 = worst symptoms. Mean scores within each treatment arm at each cycle were descriptively assessed. Flexible longitudinal analyses (latent growth modelling: LGM) were conducted to estimate true predicted rate of change over time in the following domains from the QLQ-C30: global health status/QoL (GHS/QoL), PF, pain, and fatigue. LGMs use all data from all pts at each time point simultaneously to estimate the true mean rate of change for each treatment arm. The focus was not on discrete change scores from one time point to another; but rather on overall trends across the treatment regimens. Joint (bivariate) LGMs were used to assess whether changes in PF, pain, or fatigue predicted changes in GHS/QoL. The models controlled for ECOG status at baseline, age group, prior number of therapy lines, death, and disease progression.

Results: Baseline scores were comparable between the treatment arms (Isa-Pd vs Pd: GHS/QoL 60.4 vs 59.5; PF 71.9 vs 72.0; Pain 34.5 vs 33.2; Fatigue 37.9 vs 35.0). No significant change in GHS/QoL was identified for Isa-Pd vs significant worsening for Pd: change at each cycle was a mean [SD] increase of 0.18 [0.03] points for Isa-Pd vs a decrement of 0.50 [0.05] for Pd (P<0.001). For pain and fatigue, no change was observed for Isa-Pd, while symptoms increased for Pd: pain per cycle: -0.12 [0.10] points vs +0.44 [0.06] points (P =0.04); fatigue per cycle: +0.04 [0.01] points vs +0.49 [0.07] (P =0.05). PF scores significantly worsened for Pd but not for Isa-Pd, and the decline was significantly greater for the Pd arm (per cycle: -0.27 [0.05] vs -0.75 [0.05]; P =0.01). The minimal important difference of 10-point change was not reached on any outcome, for either treatment arm. Changes in both pain and PF significantly predicted changes in GHS/QoL in both treatment arms (pain: both β = -0.9, P<0.01; PF: β =1.2 Isa-Pd and β = 0.8 Pd, both P <0.001). Changes in fatigue significantly predicted changes in GHS/QoL for the Pd arm (β = -1.0; P<0.01) but not the Isa-Pd arm (P =0.29).

Conclusions: The addition of Isa to Pd has previously been shown to significantly improve progression-free survival over Pd (Richardson et al., 2019). The analyses herewith demonstrated that the addition of Isa to Pd preserves HRQL among RRMM pts. This preservation is, in part, due to management of pain and the delay of physical functioning decrements. Thus, Isa-Pd is an important new treatment option for the management of RRMM.