research paper Patient-reported outcomes in relapsed/refractory multiple mye- loma treated with melflufen plus dexamethasone: analyses from the Phase II HORIZON study Alessandra Larocca,1 Xavier Leleu,2 Summary 3,4,5 Cyrille Touzeau, Joan Blade,6 7 Relapsed/refractory multiple myeloma (RRMM) is known to have a high Agne Paner, Marıa- Victoria Mateos,8 Michele Cavo,9 burden of disease and complications associated with refractoriness to prior Christopher Maisel, Adrıan Alegre,11 10 lines of therapy. Severe pain and fatigue symptoms and impairments in Albert Oriol,12 Anastasios Raptis,13 physical and emotional functioning have been strongly linked to reduced Paula Rodriguez-Otero,14 health-related quality of life (HRQoL) in patients with RRMM. Assessment Amitabha Mazumder,15 of patient reported-outcome measures from the pivotal, Phase II HORI- Jacob Laubach,16 Omar Nadeem,16 ZON study (OP-106; NCT02963493) in patients with RRMM (n = 64) Anna Sandberg, Marie Orre,17 17 demonstrated that melphalan flufenamide (melflufen) plus dexamethasone Anna Torr ang,18 Nicolaas A. Bakker17 treatment preserved HRQoL. Patients had clinically meaningful improve- and Paul G. Richardson16 ments, even after eight treatment cycles, in relevant scales such as global 1 Myeloma Unit, Division of Hematology, health status/QoL, physical functioning, emotional functioning, pain, and University of Torino, Azienda Ospedaliero – fatigue. Patients with triple-class–refractory disease (n = 50) displayed simi- Universitaria Citta della Salute e della lar improvements. Patient-reported outcome deterioration was delayed for Scienza, Turin, Italy, 2CHU de Poitiers, Poitiers, 3Centre de Recherche en a substantial amount of time in patients who experienced a response to Cancerologie et Immunologie Nantes- melflufen plus dexamethasone treatment relative to patients who did not Angers (CRCINA), Institut National de la experience a response. These findings support the notion that treatment Sante et de la Recherche Medicale with melflufen plus dexamethasone may sustain or improve HRQoL over (INSERM), Centre National de la time in patients with RRMM, including in patients with triple-class–refrac- Recherche Scientifique (CNRS), Universite tory disease for whom outcomes are generally worse. The clinical benefits d’Angers, Universite de Nantes, 4Site de observed in patients from the HORIZON trial are encouraging and sup- Recherche Integree sur le Cancer (SIRIC), portive of translation into real-world practice. Imaging and Longitudinal Investigations to Ameliorate Decision-making (ILIAD), Keywords: patient-reported outcomes, melflufen, melphalan flufenamide, 5 Service d’Hematologie Clinique, Centre health-related quality of life, relapsed/refractory multiple myeloma. Hospitalier Universitaire, Place Alexis Ricordeau, Nantes, France, 6Hematology Department, IDIBAPS, Hospital Clinic, Barcelona, Spain, 7Rush University Medical Center, Chicago, IL, USA, 8Hospital Clınico Universitario de Salamanca/IBSAL/ CIC, Salamanca, Spain, 9 IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seragnoli”, Bologna, Italy, 10Baylor Scott & White Charles A. Sammons Cancer Center, Dallas, TX, USA, 11Hospital Universitario La Princesa and Hospital Universitario Quironsalud, Madrid, 12Institut Catala d’Oncologia and Josep Carreras Research Institute, Hospital Germans Trias i Pujol, ª 2021 The Authors. British Journal of Haematology published by British Society for First published online 21 October 2021 Haematology and John Wiley & Sons Ltd. British Journal of Haematology, 2022, 196, 639–648 doi: 10.1111/bjh.17887 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. 13652141, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjh.17887 by Readcube (Labtiva Inc.), Wiley Online Library on [26/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License A. Larocca et al. Badalona, Spain, 13Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, 14 Clınica Universidad de Navarra, Pamplona, Spain, 15The Oncology Institute of Hope and Innovation, Glendale, CA, 16 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA, 17 Oncopeptides AB, Stockholm, and 18SDS Life Science, Danderyd, Sweden Received 4 August 2021; accepted for publication 26 September 2021 Correspondence: Paul G. Richardson, Dana- Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. E-mail: Paul_Richardson@dfci.harvard.edu [Correction added on 30 May 2022, after first online publication: Affiliation 9 was updated in this version.] survival of 116 months, and a manageable safety profile in Introduction patients with advanced RRMM.14 The present analysis Survival in multiple myeloma (MM) has improved substan- focusses on patient-reported outcomes (PROs) collected in a tially in recent years due to advances in therapeutic agents subset of patients in the HORIZON study. and approaches. Despite this, patients continue to relapse and survival after exposure to the three main classes of drugs [pro- Methods teasome inhibitors (PIs), immunomodulatory drugs, and anti- cluster of differentiation 38 (CD38) monoclonal antibodies Study design and participants (mAbs)] results in triple-class–exposed or –refractory disease, with suboptimal outcomes.1–3 Moreover, this improvement in The HORIZON study was a pivotal, single-arm, multicentre, survival has contributed to an increased proportion of Phase II study of melflufen plus dexamethasone in patients patients with relapsed/refractory MM (RRMM) living with with RRMM who received at least two prior lines of therapy, the burden of symptoms and complications associated with including an immunomodulatory agent and PI, and who the disease and prior lines of therapy.3,4 RRMM is associated were refractory to pomalidomide and/or an anti-CD38 mAb. with severe symptoms, of which pain, fatigue, physical func- Additional eligibility criteria have been previously tioning, and emotional functioning have been strongly linked described.14 to impairments in health-related quality of life (HRQoL) of In each 28-day cycle, patients received a 30-min central patients.5,6 Treatment goals for late-stage patients with intravenous infusion of melflufen 40 mg (starting dose) on RRMM should therefore not only include extending survival day 1 in combination with oral dexamethasone 40 mg but also managing disease and treatment-related symptoms (20 mg if aged ≥75 years) on days 1, 8, 15, and 22 until dis- and preserving, or potentially improving, HRQoL.4,7 ease progression, unacceptable toxicity, or withdrawal. Dose Melphalan flufenamide (melflufen) is a first-in-class reductions for melflufen-related toxicities were allowed after peptide-drug conjugate (PDC) that targets aminopeptidases the first cycle in 10-mg increments down to the lowest dose and thereby rapidly releases alkylating agents inside tumour of 20 mg, as previously described.14 Multiple dose reduction cells, and has been approved by the United States Food and steps for dexamethasone were permitted based on starting Drug Administration (FDA) for use in patients with dose. The 40 mg starting dose could be reduced to 20 mg in RRMM.8–13 In the pivotal, Phase II, HORIZON study (OP- step 1, then 12 mg in step 2, and the 20 mg starting dose 106; ClinicalTrials.gov identifier: NCT02963493), melflufen could be reduced to 12 mg in step 1, then 8 mg in step 2. plus dexamethasone showed clinically meaningful efficacy The primary end-point was ORR [partial response or better with an overall response rate (ORR) of 29%, median (≥PR)] assessed by the investigator and confirmed by inde- progression-free survival of 42 months, median overall pendent review. 640 ª 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd. British Journal of Haematology, 2022, 196, 639–648 13652141, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjh.17887 by Readcube (Labtiva Inc.), Wiley Online Library on [26/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Patient-reported Outcomes in RRMM from HORIZON The study was conducted in accordance with the Declara- minimal important difference thresholds, if the 95% CI were tion of Helsinki and International Conference on Harmoni- within 18 to 13 units for global health status/QoL, within sation guidelines for Good Clinical Practice. The protocol 18 to 10 for physical functioning, within 24 to 24 units was reviewed and approved by national regulatory authorities for pain, and within 20 to 15 units for fatigue.17 A lower and an independent ethics committee or institutional review bound of the 95% CI for global health status/QoL scale and board at each study centre. Each patient provided written physical functioning scale falling below 18 units, and an informed consent. upper bound of the 95% CI for pain and fatigue scales above Following protocol amendment 5, PRO assessments were 24 and 15 units, respectively, were seen as deterioration.17 An added to capture functional status and well-being. Analyses upper bound for the 95% CI for global health status/QoL and included patients with valid baseline and at least one post- physical functioning scale above 13 and 10 units, respectively, baseline assessment. Subgroup analyses were performed for and the lower bound of the 95% CI for the pain and fatigue patients with triple-class–refractory MM (MM that is refrac- scales falling below 24 and 20 units, respectively, were tory to or intolerant of one or more immunomodulatory seen as improvement.17 Outputs were shown using descriptive drug, one or more PI, and one or more anti-CD38 mAb). statistics and graphical representations for the proportion of patients with impairments or meaningful improvements. Analyses were performed based on data in all cycles, as Outcome measures the change from baseline using mixed models for repeated Two PRO measures were used to assess functional status and measures (MMRM). The models included baseline score as a well-being, as a prespecified secondary end-point in the covariate and visit (cycle). Least-square (LS) means for HORIZON study: the EuroQol five Dimensions-three Levels change from baseline at the different cycles and two-sided (EQ-5D-3L) questionnaire15 and the European Organisation 95% CIs were calculated. No imputation of missing values for Research and Treatment of Cancer Quality of Life was performed. Univariate analyses for the mean changes Questionnaire-Core 30 version 3 (EORTC QLQ-C30).16 The from baseline to cycle four, using 95% CI based on the EQ-5D-3L is a generic measure of health status. The EQ t-distribution, were also performed. visual analogue scale (VAS) is intended to rate ‘health today’ The proportion of patients with improvement from baseline with anchors ranging from 0 (worst imaginable health state) in EORTC QLQ-C30 scores over time was assessed. On indi- to 100 (best imaginable health state). The EORTC QLQ-C30 vidual scores, improvement cut-offs of 5–10 points (indicative is used to assess HRQoL of patients with cancer participating of small improvements) and ≥10 points (indicative of medium in international clinical trials, with a 1-week recall period, to large improvements) from baseline were defined using pre- with raw scores transformed to a range of 0–100 (higher viously established minimal important differences for MM.18–22 scores represent better functioning for functional status/QoL The relevant scales were examined at both cut-offs as the num- and functional scales, and an increase in symptoms for the ber of improved patients per cycle and the percentage of symptom scales), and calculated according to the QLQ-C30 improved patients of the total number per cycle. scoring manual.16 For the purpose of these analyses, fatigue Time until definite deterioration was assessed, defined as and pain were identified as the most relevant symptom scales the time interval between the baseline measurement and the for patients with RRMM from the EORTC QLQ-C30, in first ≥10 point deterioration from baseline (decrease for addition to global health status/QoL and physical and emo- functional scales and global health status/QoL, increase for tional functioning.5,6,17 symptom scales) in EORTC-QLQ-C30 score with no further Questionnaires were administered at baseline, before dos- improvement during the remaining assessments.23 A change ing at day 1 of cycles two, four, six and eight, at the end of of ≥10 points from baseline was selected as the threshold treatment, and at follow-up visits for progression-free and based on the minimal important difference established in overall survival. Completion rates were calculated as the pro- Osoba et al.20 Death was considered as an event when it portion of patients who completed each relevant PRO scale, occurred within a period of time defined by 15-times the out of the total number who were dosed (from the same period between two assessments (three treatment cycles or protocol amendment) at each cycle. Cycle four was consid- 12 weeks) as planned in the study protocol, and as previ- ered a relevant time interval for capturing important PRO ously established.23,24 Patients were considered lost to follow- changes and was of primary interest for the change from up for HRQoL and were censored at the last assessment if a baseline analyses. ≥10 point deterioration from baseline was not observed, or if a ≥10 point deterioration was followed by an improvement at a subsequent cycle.25 All patients with baseline and one or Statistical analyses more post-baseline PRO assessment were included in time To understand whether PRO results were stable over time, the until definite deterioration analyses. Patients were stratified mean changes from baseline were estimated and 95% confi- as responders [achieving ≥PR or a minimal response or bet- dence intervals (CIs) were calculated. The EORTC QLQ-C30 ter (≥MR)], or as non-responders [patients with stable dis- symptom scales were defined as stable, based on available ease (SD), progressive disease (PD), or not evaluable]. Time ª 2021 The Authors. British Journal of Haematology published by British Society for 641 Haematology and John Wiley & Sons Ltd. British Journal of Haematology, 2022, 196, 639–648 13652141, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjh.17887 by Readcube (Labtiva Inc.), Wiley Online Library on [26/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License A. Larocca et al. until definite deterioration was calculated using the Kaplan– cytogenetics at study entry, 30% had extramedullary disease, Meier method and described using medians and 95% CIs and patients had received a median of five prior lines of using a log( log(survival)) distribution. therapy (range, two to 10). In all, 50 patients had triple- class–refractory disease. At cycles two, four, six, and eight, 91%, 95%, 96%, and 100% of patients with ongoing treat- Results ment completed EQ VAS PRO assessments, and 96%, 95%, Of the 72 patients who enrolled after the protocol amend- 96%, and 100% completed global health status/QoL PRO ment to allow PRO assessment, 64 had valid baseline and assessments, respectively (Table SI). Completion rates were post-baseline PRO assessments. At the data cut-off date of similar for other scales assessed from the EORTC-QLQ-C30. 25 August 2020 used for the analyses, 11 patients remained on therapy. Baseline characteristics were generally compara- Patient-reported outcomes and treatment with melflufen ble between patients from whom PROs were collected and plus dexamethasone those in the overall population (Table I). The median (range) age was 67 (46–84) years), 19% had International The mean baseline EQ VAS score was 614 in the overall Staging System Stage III disease, 36% had high-risk group and was slightly lower in the triple-class–refractory subgroup at 598. The EQ VAS scores were generally consis- Table I. Baseline characteristics of the patient reported outcome tent throughout the course of treatment with melflufen plus group and overall HORIZON patient population. dexamethasone, with an LS mean change from baseline at Patient-reported treatment cycle six of –04 in the overall group and 11 in outcome group Overall the triple-class–refractory subgroup (Fig 1A). The proportion Characteristics (n = 64) (N = 157) of patients in the overall group with impairments across EQ- Age, years, median (range) 67 (46–84) 65 (35–86) 5D-3L dimensions of anxiety/depression, mobility, pain/dis- Male sex, n (%) 33 (52) 89 (57) comfort, self-care, and usual activities remained relatively Time since diagnosis 70 (07–171) 65 (07–246) stable over time from baseline through treatment cycle eight at study entry, years, (Fig 1B). Worsening pain/discomfort and impairment with median (range)* usual activities were the most frequent across all treatment International Staging 48/32/19 40/31/25 cycles examined. System Stage I/II/III, %† The baseline EORTC QLQ-C30 global health status/QoL ECOG PS 0/1/2, % 27/63/11 25/59/16 score in the triple-class–refractory subgroup was 567, slightly Baseline albumin, 39 (19–47) 38 (19–52) lower than the overall group score of 586. The overall LS median (range), g/l‡ mean changes from baseline in EORTC QLQ-C30 global <35 g/l, n (%) 11 (17) 47 (30) health status/QoL, emotional functioning, physical function- ≥35 g/l, n (%) 53 (83) 110 (70) High LDH (≥15 9 ULN) 6 (10) 24 (15) ing, and fatigue scores were relatively stable in the overall at study entry, n (%) group and in the triple-class–refractory subgroup (Fig 2A). High risk cytogenetics 23 (36) 59 (38) Pain was also relatively stable across treatment in the overall at study entry, n (%) group and the triple-class–refractory subgroup. The MMRM Extramedullary disease 19 (30) 55 (35) LS mean change from baseline results was comparable to the at study entry, n (%) univariate analyses by cycle. Overall, these data indicate that No. prior lines of therapy, 5 (2–10) 5 (2–12) PRO measures were stable over time in patients treated with median (range) melflufen plus dexamethasone. Triple-class–refractory, 50 (78) 119 (76) A closer examination of LS mean change from baseline of n (%)§ the EORTC QLQ-C30 scales at cycle four was performed to Refractory to prior 34 (53) 92 (59) investigate the stability of PROs after patients had completed alkylators, n (%) several cycles of treatment. In the overall group and the ECOG PS, Eastern Cooperative Oncology Group Performance Status; triple-class–refractory subgroup, LS mean change from base- LDH, lactate dehydrogenase; ULN, upper limit of normal. line scores across all scales were stable, and 95% CIs did not *Time since initial diagnosis is calculated relative to first dose of exceed previously established minimal important difference study drug. limits for MM (Fig 2B).17 The univariate analysis for change †In the patient reported outcome group and the overall population, from baseline at cycle four for patients who completed and two patients and six patients had unknown/missing International tolerated three treatment cycles revealed similar results. Staging System stage, respectively. ‡Baseline laboratory values are defined as the most recent assessment The proportion of patients with meaningful improvements prior to administration of the first dose of study drug. in EORTC QLQ-C30 was assessed using two relevant mini- §Triple-class–refractory is defined as refractory or intolerant to one mal important difference cut-offs of 5–10 points for a small or more proteasome inhibitor, one or more immunomodulatory improvement22,26 and ≥10 points for a medium-to-large drug, and one or more anti-CD38 monoclonal antibody. improvement19,21 from baseline through cycle eight. In the 642 ª 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd. British Journal of Haematology, 2022, 196, 639–648 13652141, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjh.17887 by Readcube (Labtiva Inc.), Wiley Online Library on [26/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Patient-reported Outcomes in RRMM from HORIZON (A) (B) LS mean change from baseline (95% CI) 40 100 Overall Triple-class–refractory Anxiety/ Mobility Pain/ Self-Care Usual Depression Discomfort Activities Improvement Patients with impairment (%) 20 75 0 50 Deterioration -20 25 -40 0 2 4 6 8 Cycle Baseline 2 4 6 8 Patients (n) Cycle Overall 52 37 25 20 Patients (n/N ) Triple- Anxiety/ class–refractory 39 28 18 12 depression 26/64 21/54 16/37 10/25 6/19 Mobility 32/63 29/54 22/37 16/24 12/20 Pain/discomfort 50/63 41/53 28/36 18/25 15/20 Self-care 10/64 8/54 5/37 5/25 4/20 Usual activities 43/64 35/53 24/37 18/24 13/20 Fig 1. EQ-5D-3L change from baseline and proportion of patients with impairments as assessed by EQ-5D-3L domains over treatment cycles. (A) LS mean change from baseline in EQ visual analogue scale over time for the overall group (black) and triple-class–refractory subgroup (grey). Numbers underneath (A) and denominators underneath (B) represent non-missing patients who completed the patient-reported outcome mea- sure in each respective cycle. (B) Proportion of total patients with detectable impairments in EQ-5D-3L scales per treatment cycle. CI, confidence interval; EQ-5D-3L, EuroQol five Dimensions-three Levels. [Colour figure can be viewed at wileyonlinelibrary.com] overall group, the total proportion of patients with improve- a ≥MR had a median time until definite deterioration of ments, as assessed by both cut-offs, was relatively stable 138 months compared with 29 months in patients who did across treatment cycles for each scale (Fig 3A). Among those not achieve an MR (Fig 4A). A similar trend was observed patients in the overall group who showed improvement, a for the pain scale, with patients achieving a ≥MR having a majority improved by ≥10 points in the global health status/ median time until definite deterioration of 138 months QoL scale in all treatment cycles, and by ≥10 points in the compared with 31 months for patients who did not achieve emotional functioning scale in cycles four to eight. The an MR (Fig 4B). Similar results were observed for other opposite trend was observed in the physical functioning EORTC QLQ-C30 scales of focus and when evaluating scale, with a greater proportion of patients improving by a patients who achieved a ≥PR compared with those who did measure of 5–10 points in cycles four to eight (Fig 3A). The not (Figure S1A, B; Table SII). When patients who did not trend in the magnitude of improvements in global health sta- achieve a ≥MR were separated into those with PD or SD/not tus/QoL and emotional functioning scales in the triple-class– evaluable, the median time until definite deterioration for refractory subgroup was similar to that observed in the over- global health status/QoL and pain were similar, but slightly all population (Fig 3B). worse for those with PD compared with SD/not evaluable Improvements in pain and fatigue across both the overall (Figure S1C, D). group and the triple-class–refractory subgroup were only detected at the medium to large cut-off of ≥10 points. Discussion Improvements in pain and fatigue were observed across nearly all treatment cycles; however, there were few patients Relapsed/refractory multiple myeloma is a late-stage disease with these improvements in the triple-class–refractory sub- often associated with advanced patient age, frailty and an group at cycle eight (Fig 3B). Together, these findings indi- increased likelihood of comorbidities.27 Patients with RRMM cate that in patients who experienced improvements in in HORIZON had similar baseline HRQoL as in other stud- PROs, these improvements were clinically meaningful over ies in RRMM,18,26,28–32 with a mean baseline EQ VAS score multiple cycles of treatment. of 614 in HORIZON, compared with 631 and 576 reported in USA28 and European Union + Russia29 daratumumab early access programme analyses, respectively. Patients with Time until definite deterioration analysis for EORTC RRMM in HORIZON had poor baseline HRQoL relative to QLQ-C30 scales of focus other advanced cancers, including cancers of the bladder, A time until definite deterioration analysis was performed to brain, breast, colon/rectum, head/neck, hepatobiliary assess the time until definite deterioration in score using tract/pancreas, kidney, lung, lymphoma, ovary or prostate, EORTC global health status/QoL and pain scales as measures for which mean EQ VAS scores ranged from 618 to 720.33 (Fig 4). For global health status/QoL, patients who achieved In addition to having the highest percentage of patients ª 2021 The Authors. British Journal of Haematology published by British Society for 643 Haematology and John Wiley & Sons Ltd. British Journal of Haematology, 2022, 196, 639–648 13652141, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjh.17887 by Readcube (Labtiva Inc.), Wiley Online Library on [26/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License A. Larocca et al. (A) Emotional Functioning Physical Functioning Global Health Status/QoL 40 Improvement LS mean change from baseline (95% CI) 20 0 Deterioration -20 -40 2 4 6 8 2 4 6 8 2 4 6 8 Cycle Cycle Cycle Patients (n) Overall 55 37 25 20 55 37 25 19 55 37 25 20 Triple-class–refractory 41 28 18 12 41 28 18 11 41 28 18 12 Pain Fatigue 40 Improvement Deterioration LS mean change from baseline (95% CI) 20 Overall 0 Triple-class–refractory -20 -40 2 4 6 8 2 4 6 8 Cycle Cycle Patients (n) Overall 55 37 25 20 55 37 25 20 Triple-class–refractory 41 28 18 12 41 28 18 12 (B) Overall (n =64) Triple-class–refractory (n =50) Fatigue Pain Global Health Status/QoL Physical Functioning Emotional Functioning -20 -10 0 10 20 -20 -10 0 10 20 LS mean change from baseline (95% CI) Fig 2. The LS mean change from baseline in EORTC QLQ-C30. (A) LS mean change from baseline in EORTC QLQ-C30 over treatment cycles in the overall group (black) and the triple-class–refractory subgroup (grey). (B) Stability of scales assessed by change from baseline at cycle four. Higher scores represent improvement for global health status/QoL, emotional functioning, and physical functioning scales, and lower scores rep- resent improvement for pain and fatigue symptom scales. Numbers underneath each plot represent non-missing patients who completed the patient-reported outcome measure in each respective cycle. Shaded area represents 95% confidence interval where no minimal important differ- ence is observed.17 CI, confidence interval; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; LS, least squares; QoL, quality of life. 644 ª 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd. British Journal of Haematology, 2022, 196, 639–648 13652141, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjh.17887 by Readcube (Labtiva Inc.), Wiley Online Library on [26/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Patient-reported Outcomes in RRMM from HORIZON (A) Global Health Status/QoL Emotional Functioning Physical Functioning 100 Patients with improvement in each cycle (%) 75 50 25 0 2 4 6 8 2 4 6 8 2 4 6 8 Cycle Cycle Cycle Patients (n/N ) >10 point improvement 11/55 14/37 8/25 7/20 11/55 11/37 8/25 5/20 10/55 3/37 2/25 1/19 5-10 point improvement 6/55 5/37 3/25 2/20 10/55 4/37 1/25 2/20 11/55 9/37 4/25 4/19 Pain Fatigue 100 Patients with improvement in each cycle (%) 75 50 Improvement level 25 10 points and above from 5 to 10 points 0 2 4 6 8 2 4 6 8 Cycle Cycle Patients (n/N ) >10 point improvement 13/55 10/37 10/25 6/20 12/55 12/37 5/25 5/20 (B) Global Health Status/QoL Emotional Functioning Physical Functioning 100 Patients with improvement in each cycle (%) 75 50 25 0 2 4 6 8 2 4 6 8 2 4 6 8 Cycle Cycle Cycle Patients (n/N ) >10 point improvement 10/41 13/28 7/18 5/12 9/41 9/28 6/18 4/12 8/41 2/28 1/18 0/11 5-10 point improvement 5/41 3/28 1/18 1/12 8/41 4/28 1/18 1/12 9/41 6/28 2/18 1/11 Pain Fatigue 100 Patients with improvement in each cycle (%) 75 50 Improvement level 25 10 points and above from 5 to 10 points 0 2 4 6 8 2 4 6 8 Cycle Cycle Patients (n/N ) >10 point improvement 8/41 8/28 6/18 1/12 9/41 9/28 2/18 1/12 Fig 3. Proportion of patients with meaningful improvements from baseline in EORTC QLQ-C30 scales across treatment cycles. Proportion of patients with improvements in EORTC QLQ-C30 scales, assessed by minimal clinically important differences of 5–10 points (grey) or ≥10 points (black) in (A) the overall group and (B) the triple-class–refractory subgroup. EORTC QLQ-C30, European Organisation for Research and Treat- ment of Cancer Quality of Life Questionnaire-Core 30; QoL, quality of life. ª 2021 The Authors. British Journal of Haematology published by British Society for 645 Haematology and John Wiley & Sons Ltd. British Journal of Haematology, 2022, 196, 639–648 13652141, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjh.17887 by Readcube (Labtiva Inc.), Wiley Online Library on [26/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License A. Larocca et al. (A) (B) Response Median Response Median 1·00 Group Events, n (95% CI) 1·00 Group Events, n (95% CI) Definite deterioration probability Definite deterioration probability ≥MR 15 13·8 (6·9–15a0) ≥MR 12 13·8 (9·4–NE) No response 18 2·9 (1·9–3·5) No response 16 3·1 (1·9–5·0) 0·75 0·75 0·50 0·50 0·25 0·25 0·00 0·00 0 5 10 15 20 0 5 10 15 20 Time (months) Time (months) Patients at risk (n) Patients at risk (n) Achieved ≥MR 37 27 8 2 0 Achieved ≥MR 37 25 9 2 0 No response 27 5 1 1 0 No response 27 4 1 1 0 Fig 4. Time until definite deterioration analysis for EORTC QLQ-C30 global health status/QoL and pain scales. Time until definite deterioration for patients who achieved an ≥MR versus non-responders (i.e. patients with SD, not evaluable, or PD) for the EORTC QLQ-C30 (A) global health status scale and (B) pain scale. Black, patients who achieved a ≥MR; grey, non-responders (patients with SD, not evaluable, or PD). CI, confi- dence interval; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; MR, minimal response; NE, not evaluable; PD, progressive disease; SD, stable disease. (79%) reporting pain/discomfort compared with other cancer patients with RRMM,34,35 representing an area of high unmet types, 51% of patients in HORIZON reported mobility therapeutic need. Despite these prognoses, patients with impairment; second only to those with prostate cancer triple-class–refractory disease in HORIZON displayed rela- (58%).33 The finding that patients in HORIZON are repre- tively stable PRO measures over time. Our present finding sentative of broader RRMM populations is supportive of the that melflufen plus dexamethasone treatment can sustain utility of the analyses in the present study, and the finding HRQoL in this subgroup is encouraging and warrants further that RRMM has similar, and potentially higher, disease bur- investigation in a larger population. den relative to other advanced cancers further supports the The present study has several limitations. Because PRO unmet needs for HRQoL and symptom management in assessments were added as an addendum to protocol version patients with RRMM. 5, the populations in these analyses were relatively small. In HORIZON, the proportion of patients in the overall Given that 85% of all patients in HORIZON received study group with EQ-5D-3L impairments, the change from baseline medication at cycle two, but 48% received study medication in EORTC QLQ-C30 function and symptom scales, and the at cycle four, the subset included in the PRO analyses is percentage of patients with some improvement in EORTC inherently biased towards patients with better outcomes. QLQ-C30 function and symptom scales were generally stable Lastly, only patients with a baseline and a post-baseline PRO across treatment cycles. Previous examinations of improve- assessment were included, given that analyses focussed on ments in EORTC QLQ-C30 function and symptom scales changes in PRO scores from baseline. have typically used one of two accepted cut-offs, at ≥5 or Collectively, these findings support the notion that treat- ≥10 points of improvement from baseline.20–22,26 Our analy- ment with melflufen plus dexamethasone may sustain or ses reveal that although patient improvements in later cycles improve HRQoL over time in patients with RRMM, despite may be smaller in magnitude (5–10 points), these improve- the high disease burden of this patient population as well as ments are still clinically meaningful. In addition, time until the associated morbidity and should help augment the suc- definite deterioration analyses indicate that PRO deteriora- cessful translation of the clinical benefit seen in those tion is delayed for a substantial amount of time in patients patients participating in the HORIZON trial across to real- with RRMM who experience a response to melflufen plus world practice.36 dexamethasone treatment. Patient-reported outcome data in the literature are limited Acknowledgements for patients with triple-class–refractory disease in RRMM. Our present findings that patients with RRMM and triple- This work is supported by Oncopeptides AB. Medical writing class–refractory disease have slightly worse baseline PRO support was provided Elizabeth G. Wheatley, PhD, and measures than the overall group are not surprising, given Katherine Mills-Lujan, PhD, CMPP, of Team 9 Science, with that this population has particularly poor prognoses among funding from Oncopeptides AB. 646 ª 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd. British Journal of Haematology, 2022, 196, 639–648 13652141, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjh.17887 by Readcube (Labtiva Inc.), Wiley Online Library on [26/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Patient-reported Outcomes in RRMM from HORIZON Author contributions Supporting Information Alessandra Larocca, Xavier Leleu, Cyrille Touzeau, Joan Blade, Additional supporting information may be found online in Agne Paner, Marıa-Victoria Mateos, Michele Cavo, Christo- the Supporting Information section at the end of the article. pher Maisel, Adrıan Alegre, Albert Oriol, Anastasios Raptis, Paula Rodriguez-Otero, Amitabha Mazumder, Jacob Laubach, Table SI. Completion rates per cycle for patient-reported Omar Nadeem and Paul G. Richardson performed the outcome measures. research. Marıa-Victoria Mateos and Paul G. Richardson Table SII. Median and confidence limits for time until designed the research study; and Anna Sandberg, Marie Orre, definite deterioration analysis of scores of focus. Anna Torr ang and Nicolaas A. Bakker performed PRO analyses Fig S1. Time until definite deterioration analysis of and analysed the data. All authors had access to the data and patients who achieved a response versus those who did not all authors contributed to the writing and editing of the paper. achieve an MR or PR. Time until definite deterioration for patients who achieved a ≥PR (black) versus non-responders Conflict of interest (i.e. patients with SD, PD, or not evaluable; grey) for the EORTC-QLQ-C30 (A) global health status/QoL scale and (B) Alessandra Larocca reports honoraria and personal fees from pain scale. Time until definite deterioration for patients who Bristol Myers Squibb, Celgene, Janssen, and Takeda and per- achieved an ≥MR (black) versus non-responders, with sonal fees from Amgen and GlaxoSmithKline. Cyrille Touzeau patients with SD or not evaluable grouped (grey) separately reports consultancy and honoraria from AbbVie, Amgen, Cel- from patients with PD (teal) for the EORTC QLQ-C30 (C) gene, GlaxoSmithKline, Jannsen, Novartis, and Takeda, hono- global health status scale and (D) pain scale. raria from Sanofi, and research support from AbbVie. Albert Oriol reports consultancy for Amgen, Celgene/Bristol Myers Squibb, Sanofi, GlaxoSmithKline and Janssen. Joan Blade References reports honoraria from Amgen, Celgene, Janssen, Oncopep- 1. Laubach J, Richardson P, Anderson K. Multiple myeloma. Annu Rev Med. tides, and Takeda. Agne Paner reports honoraria from Amgen 2011;62:249–64. and Celgene and consultancy/advisory fees from AbbVie, Cel- 2. Thorsteinsdottir S, Dickman PW, Landgren O, Blimark C, Hultcrantz M, lectar, Janssen, Karyopharm, and Takeda. Marıa-Victoria Turesson I, et al. Dramatically improved survival in multiple myeloma Mateos received personal fees from AbbVie, Adaptive, Amgen, patients in the recent decade: results from a Swedish population-based study. Haematologica. 2018;103: e412–e415. Celgene, GlaxoSmithKline, Janssen, Roche, Seattle Genetics, 3. Gandhi UH, Cornell RF, Lakshman A, Gahvari ZJ, McGehee E, Jagosky and Takeda. Michele Cavo received personal fees from AbbVie, MH, et al. Outcomes of patients with multiple myeloma refractory to Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Jans- CD38-targeted monoclonal antibody therapy. Leukemia. 2019;33:2266–75. sen, Sanofi, and Takeda. Christopher Maisel received hono- 4. Vogl DT, Delforge M, Song K, Guo S, Gibson CJ, Ervin-Haynes A, et al. Long-term health-related quality of life in transplant-ineligible patients raria from Amgen, Celgene, Incyte, Janssen, Karyopharm, Kite, with newly diagnosed multiple myeloma receiving lenalidomide and dex- Takeda, and Verastem and consulting fees from Bayer. Adrıan amethasone. Leuk Lymphoma. 2018;59:398–405. Alegre received honoraria from Amgen, Bristol Myers Squibb, 5. LeBlanc MR, Hirschey R, Leak Bryant A, LeBlanc TW, Smith SK. How are Celgene, GlaxoSmithKline, Janssen, Oncopeptides, Sanofi, and patient-reported outcomes and symptoms being measured in adults with Takeda. Albert Oriol reports consultancy or advisory role and relapsed/refractory multiple myeloma? A systematic review. Qual Life Res. 2020;29:1419–31. speakers’ bureau for Bristol Myers Squibb, Sanofi, and Amgen. 6. Rosinol L, Ocio EM, Grande M, Fernandez-Nistal A, Ruiz-Zorrilla A, Paula Rodriguez-Otero reports honoraria from AbbVie, Montoto C. Impact of patients characteristics on health-related quality of Amgen, Celgene/Bristol Myers Squibb, GlaxoSmithKline, Jans- life in patients with relapsed or refractory multiple myeloma: results from sen, Kite, Oncopeptides, and Sanofi. Omar Nadeem reports the Charisma study. Poster presented at the 24th European Hematology personal fees from Amgen, Celgene, Janssen, Sanofi, and Association (EHA) Annual Congress; June 13–16, 2019; Amsterdam, The Takeda. Xavier Leleu, Anastasios Raptis, Amitabha Mazumder, Netherlands; Poster PF615. 7. Jordan K, Proskorovsky I, Lewis P, Ishak J, Payne K, Lordan N, et al. and Jacob Laubach have nothing to disclose. Anna Sandberg, Effect of general symptom level, specific adverse events, treatment pat- Marie Orre, and Nicolaas A. Bakker are employees of and own terns, and patient characteristics on health-related quality of life in stock and stock options in Oncopeptides. Anna Torr ang is a patients with multiple myeloma: results of a European, multicenter cohort consultant at Oncopeptides. Paul G. Richardson received grant study. Support Care Cancer. 2014;22:417–26. 8. Chauhan D, Ray A, Viktorsson K, Spira J, Paba-Prada C, Munshi N, et al. support from Bristol Myers Squibb, grant support and hono- In vitro and in vivo antitumor activity of a novel alkylating agent, raria from Celgene, Karyopharm, Oncopeptides, and Takeda, melphalan-flufenamide, against multiple myeloma cells. Clin Cancer Res. and honoraria from Janssen, Sanofi, and Secura Bio. 2013;19:3019–31. 9. Ray A, Ravillah D, Das DS, Song Y, Nordstr€ om E, Gullbo J, et al. A novel alkylating agent melflufen induces irreversible DNA damage and cytotoxic- Funding ity in multiple myeloma cells. Br J Haematol. 2016;174:397–409. 10. Gullbo J, Wickstrom M, Tullberg M, Ehrsson H, Lewensohn R, Nygren P, This study was sponsored by Oncopeptides AB, which also et al. Activity of hydrolytic enzymes in tumour cells is a determinant for provided support for manuscript editorial assistance. ª 2021 The Authors. British Journal of Haematology published by British Society for 647 Haematology and John Wiley & Sons Ltd. British Journal of Haematology, 2022, 196, 639–648 13652141, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjh.17887 by Readcube (Labtiva Inc.), Wiley Online Library on [26/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License A. Larocca et al. anti-tumour efficacy of the melphalan containing prodrug J1. J Drug Tar- compared with cisplatin and fluorouracil from a phase III trial for get. 2003;11:355–63. advanced gastric or gastroesophageal adenocarcinoma: the V-325 Study 11. Wickstr€om M, Haglund C, Lindman H, Nygren P, Larsson R, Gullbo J. Group. J Clin Oncol. 2007;25:3210–6. The novel alkylating prodrug J1: diagnosis directed activity profile 25. Anota A, Hamidou Z, Paget-Bailly S, Chibaudel B, Bascoul-Mollevi C, ex vivo and combination analyses in vitro. Invest New Drugs. 2008;26: Auquier P, et al. Time to health-related quality of life score deterioration 195–204. as a modality of longitudinal analysis for health-related quality of life 12. Wickstr€om M, Nygren P, Larsson R, Harmenberg J, Lindberg J, Sj€ oberg P, studies in oncology: do we need RECIST for quality of life to achieve stan- et al. Melflufen - a peptidase-potentiated alkylating agent in clinical trials. dardization? Qual Life Res. 2015;24:5–18. Oncotarget. 2017;8:66641–55. 26. Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Spicka I, Oriol A, 13. PEPAXTO (melphalan flufenamide) [package insert]. Waltham, MA: et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple Oncopeptides Inc; 2021. myeloma. N Engl J Med. 2015;372:142–52. 14. Richardson PG, Oriol A, Larocca A, Blade J, Cavo M, Rodriguez-Otero P, 27. Hari P, Romanus D, Luptakova K, Blazer M, Yong C, Raju A, et al. The et al. Melflufen and dexamethasone in heavily pretreated relapsed and impact of age and comorbidities on practice patterns and outcomes in refractory multiple myeloma. J Clin Oncol. 2021;39:757–67. patients with relapsed/refractory multiple myeloma in the era of novel 15. van Reenen M, Oppe M, Secnik Boye K, Herdman M, Kennedy-Martin therapies. J Geriatr Oncol. 2018;9:138–44. M, Kennedy-Martin T, et al. EuroQol Research Foundation. EQ-5D-3L 28. Chari A, Mark TM, Krishnan A, Stockerl-Goldstein K, Usmani SZ, Londhe User Guide; 2018. Available from: https://euroqol.org/publications/user- A, et al. Results of an early access treatment protocol (EAP) of daratu- guides. mumab in United States patients with relapsed or refractory multiple mye- 16. Fayers P, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A. loma. Blood. 2016;128:Abstract 2133. On behalf of the EORTC Quality of Life Group. EORTC QLQ-C30 scor- 29. Cook G, Corso A, Streetly M, Mendeleeva LP, Ptushkin V, Couturier C, ing manual. 3rd edn. Brussels: European Organisation for Research and et al. Results of the daratumumab monotherapy early access treatment Treatment of Cancer; 2001. protocol (EAP) in patients from Europe and Russia with relapsed or 17. Kvam AK, Fayers P, Wisloff F. What changes in health-related quality of refractory multiple myeloma. 24th EHA Abstract Book. 2019:PS1425. life matter to multiple myeloma patients? A prospective study. Eur J Hae- 30. Leleu X, Kyriakou C, Vande Broek I, Murphy P, Bacon P, Lewis P, et al. matol. 2010;84:345–53. Prospective longitudinal study on quality of life in relapsed/refractory 18. Stewart AK, Dimopoulos MA, Masszi T, Spicka I, Oriol A, Hajek R, et al. multiple myeloma patients receiving second- or third-line lenalidomide or Health-related quality-of-life results from the open-label, randomized, bortezomib treatment. Blood Cancer J. 2017;7:e543. phase III ASPIRE trial evaluating carfilzomib, lenalidomide, and dexam- 31. Richardson PG, Schlossman RL, Roy AN, Panneerselvam A, Acharyya S, ethasone versus lenalidomide and dexamethasone in patients with relapsed Sopala M, et al. Patient-reported outcomes of multiple myeloma patients multiple myeloma. J Clin Oncol. 2016;34:3921–30. treated with panobinostat after ≥2 lines of therapy based on the 19. Royle K-L, Gregory WM, Cairns DA, Bell SE, Cook G, Owen RG, et al. international phase 3, randomized, double-blind, placebo-controlled Quality of life during and following sequential treatment of previously PANORAMA-1 trial. Br J Haematol. 2018;181:628–36. untreated patients with multiple myeloma: findings of the Medical 32. Robinson D Jr, Esseltine DL, Regnault A, Meunier J, Liu K, van de Velde Research Council Myeloma IX randomised study. Br J Haematol. H. The influence of baseline characteristics and disease stage on health- 2018;182:816–29. related quality of life in multiple myeloma: findings from six randomized 20. Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the signifi- controlled trials. Br J Haematol. 2016;174:368–81. cance of changes in health-related quality-of-life scores. J Clin Oncol. 33. Pickard AS, Jiang R, Lin HW, Rosenbloom S, Cella D. Using patient- 1998;16:139–44. reported outcomes to compare relative burden of cancer: EQ-5D and 21. Ludwig H, P€ onisch W, Knop S, Egle A, Hinke A, Schreder M, et al. Qual- functional assessment of cancer therapy-general in eleven types of cancer. ity of life in patients with relapsed/refractory multiple myeloma during Clin Ther. 2016;38:769–77. ixazomib-thalidomide-dexamethasone induction and ixazomib mainte- 34. Usmani S, Ahmadi T, Ng Y, Lam A, Desai A, Potluri R, et al. Analysis of nance therapy and comparison to the general population. Leuk Lymphoma. real-world data on overall survival in multiple myeloma patients with ≥3 2020;61:377–86. prior lines of therapy including a proteasome inhibitor (PI) and an 22. Ludwig H, Moreau P, Dimopoulos MA, Mateos M-V, Kaiser M, Hajek R, immunomodulatory drug (IMiD), or double refractory to a PI and an et al. Health-related quality of life in the ENDEAVOR study: carfilzomib- IMiD. Oncologist. 2016;21:1355–61. dexamethasone vs bortezomib-dexamethasone in relapsed/refractory multi- 35. Kumar SK, Dimopoulos MA, Kastritis E, Terpos E, Nahi H, Goldschmidt ple myeloma. Blood Cancer J. 2019;9:23. H, et al. Natural history of relapsed myeloma, refractory to immunomod- 23. Balakrishnan N, Rao CR. Advances in survival analysis, Volume 23, 1st ed. ulatory drugs and proteasome inhibitors: a multicenter IMWG study. Leu- (Handbook of Statistics series). Amsterdam, The Netherlands: Elsevier; kemia. 2017;31:2443–8. 2004. 36. Richardson PG, San Miguel JF, Moreau P, Hajek R, Dimopoulos MA, 24. Ajani JA, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Laubach JP, et al. Interpreting clinical trial data in multiple myeloma: et al. Quality of life with docetaxel plus cisplatin and fluorouracil translating findings to the real-world setting. Blood Cancer J. 2018;8:109. 648 ª 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd. British Journal of Haematology, 2022, 196, 639–648