Page 317 - Haematologica Vol. 109 - July 2024

LETTER TO THE EDITOR
Health-related quality of life in relapsed/refractory multiple myeloma treated with melflufen and dexamethasone: analyses from the phase III OCEAN study
Relapsed or refractory multiple myeloma (RRMM) is asso- ciated with severe symptoms, some of which have been strongly linked to impairments in health-related quality of life (HRQoL), notably pain, fatigue, and a decline in physical and emotional functioning.1 Furthermore, HRQoL deteri- orates with each subsequent line of therapy in RRMM.2 Hence, treatment goals, particularly in later lines of therapy, should include preserving HRQoL. Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively re- lease potent alkylating agents inside tumor cells. Melflufen is approved in Europe for the treatment of patients with triple-class refractory RRMM with ≥3 prior lines of ther- apy and time to progression (TTP) >36 months after prior autologous stem cell transplant (ASCT), if received. Ap- proval was based on the results of the phase II HORIZON study and further supported by those of the phase III OCEAN study.3-5 OCEAN met its primary endpoint with melflufen plus dexamethasone demonstrating superior progression-free survival compared with pomalidomide plus dexamethasone in RRMM.4 Across trials, the safety profile of melflufen plus dexamethasone has been characterized primarily by hematologic adverse events that are clinically manageable, with infrequent grade 3/4 non-hematologic adverse events.3,4,6 HRQoL over time was preserved with melflufen plus dexamethasone in patients with advanced RRMM in the HORIZON trial..7 Pomalidomide plus dexa- methasone has also been shown to be safe and effective without negatively affecting HRQoL, including in later lines of therapy.8 In this letter, we report HRQoL based on pa- tient-reported outcomes (PRO) in a subset of patients from OCEAN receiving either melflufen plus dexamethasone or pomalidomide plus dexamethasone. Overall, melflufen plus dexamethasone treatment resulted in HRQoL comparable to that of pomalidomide plus dexamethasone, further supporting the use of melflufen plus dexamethasone in heavily pretreated patients with RRMM.
The OCEAN study design has been previously published.4 The study was conducted in compliance with the ethical principles set forth in the Declaration of Helsinki and In- ternational Conference on Harmonization Good Clinical Practice Guidelines and was approved by national regu- latory authorities and independent ethics committees/ review boards. All patients provided written consent to participate. PRO assessments were added as an exploratory endpoint on May 24, 2019 (protocol v4.1), approximately 2 years after the study started.4 Only patients enrolled on/
after protocol v4.1 and who completed ≥1 PRO question- naires were included in this analysis.. PRO questionnaires were administered before dosing at baseline and day 1 of each treatment cycle, at the end-of-treatment visit, dis- ease progression, and the start of a new treatment. Three PRO assessments were used: the European Organization for Research and Treatment of Cancer Quality of Life Ques- tionnaire-Core 30 (EORTC QLQ-C30) version 3, scored from 0-100, with higher scores indicating better functional status/ QoL and functional scales, and an increase in severity of symptoms for the symptom scales;9,10 the EORTC Quality of Life Questionnaire-Multiple Myeloma module (EORTC MY20), scored from 0-100 with higher scores indicating greater symptom severity;10 and the European Quality of Life 5 Di- mensions 3-Level (EQ-5D-3L) questionnaire that evaluates generic health status, also with scores ranging from 0-100 (death=0; perfect health=100) with higher scores indicating a better health state.11 PRO results were compared between the treatment groups (melflufen and pomalidomide), and also within the melflufen group – between patients with TTP >36 months after prior ASCT or without prior ASCT (target population) and those with TTP <36 months after ASCT (non-target population). Mean scores at baseline, at each treatment cycle up to cycle 6, and mean change from baseline through cycle 6 were analyzed. Responder analysis was conducted, defined as the proportion of patients with improved, stable, or worsening EORTC QLQ-C30 and MY20 scores at cycle 6. We used a cutoff of a 10-point change for improvement or worsening scores, since this is the minimal important difference resulting in clinical benefit.12
Of the 495 patients enrolled and randomized in OCEAN, 158 with PRO assessments were included in the pre-specified PRO analysis (melflufen group, n=77; pomalidomide group, n=81). Forty-four patients in the melflufen group had not received previous ASCT or had TTP >36 months after previous ASCT, and 33 had TTP <36 months after previous ASCT.
Baseline characteristics were generally well matched between treatment groups for patients with PRO data. Both treatment groups showed similar PRO scores at baseline with respect to general health and well-being, as measured by the EORTC QLQ-C30 multi-item scales, including global health status/QoL and physical and emo- tional functioning; symptom burden, as measured by the EORTC QLQ-C30 fatigue and pain scales; EORTC MY20 disease symptom scale and side effects of treatment score; and “health today,” as measured by the EQ-5D-3L visual analog scale (VAS) score (Table 1). Importantly, mean
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