Melflufen and Dexamethasone in Heavily original reports Pretreated Relapsed and Refractory Multiple Myeloma Paul G. Richardson, MD1; Albert Oriol, MD2; Alessandra Larocca, MD, PhD3; Joan Bladé, MD, PhD4; Michele Cavo, MD5; Paula Rodriguez-Otero, MD, PhD6; Xavier Leleu, MD, PhD7; Omar Nadeem, MD1; John W. Hiemenz, MD8; Hani Hassoun, MD9; Cyrille Touzeau, MD, PhD10,11,12; Adrián Alegre, MD, PhD13; Agne Paner, MD14; Christopher Maisel, MD15; Amitabha Mazumder, MD16; Anastasios Raptis, MD17; Jan S. Moreb, MD18; Kenneth C. Anderson, MD1; Jacob P. Laubach, MD, MPP1; Sara Thuresson, MSc19; Marcus Thuresson, PhD19; Catriona Byrne, RN19; Johan Harmenberg, MD19; Nicolaas A. Bakker, MD, PhD19; and Marı́a-Victoria Mateos, MD, PhD20; on behalf of the HORIZON (OP-106) Investigators PURPOSE Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets amino- abstract peptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need. PATIENTS AND METHODS Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing. RESULTS Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class–refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class–refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade $ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predom- inantly grade 1/2 (93%); none were grade 4. ASSOCIATED CONCLUSION Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile CONTENT in patients with heavily pretreated RRMM, including those with triple-class–refractory and extramedullary disease. See accompanying article on page 836 J Clin Oncol 39:757-767. © 2020 by American Society of Clinical Oncology Appendix Creative Commons Attribution Non-Commercial No Derivatives 4.0 License Data Supplement Protocol INTRODUCTION Outcomes are particularly poor for patients with high- Author affiliations Despite the introduction of novel therapies and regi- risk cytogenetics, extramedullary disease, and MM and support mens that have improved outcomes in multiple my- resistant to multiple drug classes, including those information (if with triple-class–refractory disease who represent applicable) appear eloma (MM),1,2 almost all patients will relapse.1,3 After at the end of this groups with a high unmet need.1,3,4 Furthermore, relapse, treatment choice is usually determined by the article. patients with relapsed and refractory multiple mye- class of and response to previous treatment and pa- Accepted on October loma (RRMM) may have comorbidities because of 15, 2020 and tient characteristics.2,3 Although class switching is age, disease symptoms, and cumulative toxicities published at generally prioritized, this is becoming increasingly stemming from previous therapies.5,6 There is an ascopubs.org/journal/ difficult, not least because novel agents are commonly urgent requirement for agents with novel mechanisms jco on December 9, administered in combination in earlier treatment lines, of action that are effective, safe, and tolerable and that 2020: DOI https://doi. org/10.1200/JCO.20. resulting in disease resistant to multiple drug classes maintain quality of life in patients with aggressive and 02259 as early as second-line therapy.2,3 resistant disease. Volume 39, Issue 7 757 Downloaded from ascopubs.org by 62.83.88.102 on June 15, 2021 from 062.083.088.102 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. Richardson et al CONTEXT Key Objective To evaluate whether melphalan flufenamide (melflufen) plus dexamethasone is effective and safe in patients with heavily pretreated relapsed and refractory multiple myeloma (RRMM), a population with a high unmet medical need. Knowledge Generated In this pivotal, phase II study, melflufen plus dexamethasone showed meaningful efficacy in heavily pretreated patients with RRMM, including patients with triple-class–refractory disease and those with extramedullary disease. The safety profile of melflufen plus dexamethasone was consistent with previously reported data and was characterized primarily by clinically manageable hematologic toxicities. Relevance As new combinations of antimyeloma drugs are introduced in earlier lines of therapy, patients with RRMM often have disease that is refractory to multiple drugs. Therefore, drugs with novel mechanisms of action are urgently needed. Melflufen, when combined with dexamethasone, has the potential to fill this unmet medical need by providing a novel mechanism of action, clinically meaningful efficacy, and manageable safety in patients with RRMM. Melphalan flufenamide (melflufen) is a first-in-class peptide- melflufen was characterized primarily by hematologic drug conjugate that targets aminopeptidases and rapidly toxicities that were clinically manageable with appropriate and selectively releases alkylating agents into tumor cells.7-12 dose delays, dose reductions, and supportive care. Based Melflufen is rapidly and passively taken up by cells because on these results, the efficacy and safety of melflufen plus of its high lipophilicity, thereby circumventing the develop- dexamethasone were therefore evaluated in the current ment of transporter-associated resistance.8,11,13 Intracellular study in a larger population with heavily pretreated, re- aminopeptidases hydrolyze melflufen to release hydro- sistant, and poor-risk RRMM, including those with triple- philic alkylating moieties.11 Melflufen and its metabolites class–refractory disease, for whom few effective treatment melphalan and desethyl-melflufen have equipotent options exist.3 alkylating potential.11 Unlike previous aminopeptidase- targeting therapies that directly inhibit aminopeptidase PATIENTS AND METHODS activity, melflufen takes a novel approach by leveraging Study Design and Participants increased aminopeptidase activity to selectively direct potent cytotoxic agents into tumor cells.11,14,15 Melflufen HORIZON (OP-106; ClinicalTrials.gov identifier: NCT02963493) and its metabolites trigger robust and irreversible DNA was a pivotal, single-arm, multicenter, phase II study of melflufen plus dexamethasone in patients with RRMM refractory to damage, have antiangiogenic effects, induce apoptosis— pomalidomide and/or an anti-CD38 monoclonal antibody. Pa- resulting in potent antitumor activity in myeloma cells, tients were enrolled from December 28, 2016, to October 14, including those with resistance to melphalan, bortezomib, 2019, at 17 sites (see the Data Supplement, online only). Eligible and dexamethasone—and, importantly, retain activity in adult patients had an Eastern Cooperative Oncology Group myeloma cells with absent or impaired p53 function.8-10,16 performance status score of 0-2, a previous diagnosis of MM Melflufen may also have activity in other hematologic ma- with disease progression, and measurable disease (serum lignancies (including immunoglobulin light chain amyloidosis monoclonal protein $ 5 g/L, urine monoclonal protein and leukemia) and solid tumors (including breast cancer and $ 200 mg per 24 hours, or serum immunoglobulin-free light ovarian cancer).11 chain $ 100 mg/L, and abnormal serum immunoglobulin The phase I/II, multicenter O-12-M1 trial established the kappa to lambda–free light chain ratio) at study entry. Patients dosage of melflufen plus dexamethasone in patients who had received at least two prior lines of therapy, including an had RRMM, received a median of four previous lines of immunomodulatory agent and proteasome inhibitor, and were therapy (including lenalidomide and bortezomib), and had refractory to pomalidomide and/or an anti-CD38 monoclonal disease refractory to their last line of therapy.17 In 45 pa- antibody. RRMM was defined as disease that was nonre- tients treated with infusional melflufen 40 mg administered sponsive (ie, did not achieve a minimal response or better, or on day 1 of each 28-day cycle and once weekly dexa- developed progressive disease with treatment) while on primary methasone dosed at 40 mg, the overall response rate or salvage therapy or progressed within 60 days of last therapy.18 (ORR) was 31%, the median duration of response (DOR) Please see the Data Supplement for full eligibility criteria. Patients was 8.4 months, the median progression-free survival received once-monthly melflufen 40 mg as a 30-minute central (PFS) was 5.7 months, and the median overall survival (OS) intravenous infusion on day 1 of each 28-day cycle in combi- was encouraging at 20.7 months. The safety profile of nation with oral dexamethasone 40 mg (20 mg for patients 758 © 2020 by American Society of Clinical Oncology Volume 39, Issue 7 Downloaded from ascopubs.org by 62.83.88.102 on June 15, 2021 from 062.083.088.102 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. Melflufen and Dexamethasone in Relapsed and Refractory Myeloma age $ 75 years) once-weekly administered on days 1, 8, Terminology Criteria for Adverse Events, version 4.03. AE 15, and 22 of each 28-day cycle until disease progression, frequency and relationship to study treatment were unacceptable toxicity, or the patient or treating physician summarized. determined it was not in the patient’s best interest to continue. Melflufen dose reduction for drug-related tox- Statistical Analysis icities was allowed in 10 mg increments each cycle from Planned enrollment was 150 patients. ORR and associated 40 mg down to 30 mg and from 30 mg down to 20 mg (see two-sided exact 95% CI19 were estimated for all patients the Data Supplement). treated (all-treated population). With a sample size of 150 patients and an assumed ORR of 30%, the exact 95% CI This study was conducted in accordance with the Decla- was estimated to range between 23% and 38%. CBR and ration of Helsinki and International Conference on Har- disease stabilization were also summarized. Time-to-event monisation guidelines for Good Clinical Practice. The end points were summarized using the Kaplan-Meier Protocol was reviewed and approved by national regulatory method in the all-treated population. Median and esti- authorities and an independent ethics committee or in- mated 95% CIs were constructed using the methods of stitutional review board at each study center. Each patient Brookmeyer and Crowley20; duration of follow-up was es- provided written informed consent. timated by the reverse Kaplan-Meier methods of Schemper Outcomes and Smith.21 See the Data Supplement for patient cen- soring and handling of missing data. The primary end point was ORR, defined as the pro- portion of patients achieving a confirmed response of A preplanned subgroup analysis was performed in pa- stringent complete response (sCR), complete response tients with triple-class–refractory MM (refractory to or (CR), very good partial response (VGPR), or partial re- intolerant of at least one immunomodulatory drug, at least sponse (PR) as their best response per International one proteasome inhibitor, and at least one anti-CD38 Myeloma Working Group (IMWG) uniform response monoclonal antibody). With a sample size of 150 pa- criteria, as assessed by the investigator.18 Response, tients, 104-120 patients with triple-class–refractory dis- confirmed response, and confirmed progression were ease were expected; the primary end point was subsequently verified by an independent review com- considered met if the lower bound of the 95% CI for the mittee.18 Secondary end points included DOR, PFS, OS, ORR was higher than 15%. Additional subgroup analyses, clinical benefit rate (CBR), best response, time to re- including extramedullary disease, are described in the sponse, time to progression, time to next treatment, and Data Supplement. Extramedullary disease was assessed safety (defined in the Data Supplement). All response at baseline for patients with known or suspected extra- categories required confirmation with two consecu- medullary disease and to confirm a response achieved by tive assessments (see the Data Supplement). Adverse M-protein or for suspected progression per IMWG uniform events (AEs) were graded according to the Common response criteria.18 157 Patients enrolled and treated (intention-to-treat population) 131 Patients completed 26 Patients active on study treatment study treatment Primary reasons for 5 Patients in 35 Patients in treatment discontinuation PFS follow-up OS follow-up • Progressive disease (n = 88) • Adverse event (n = 26) • Withdrawal by patient (n = 7) • Lack of efficacy (n = 5) • Physician decision (n = 5) FIG 1. Trial profile. OS, overall survival; PFS, progression-free survival. Journal of Clinical Oncology 759 Downloaded from ascopubs.org by 62.83.88.102 on June 15, 2021 from 062.083.088.102 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. Richardson et al TABLE 1. Baseline Demographics and Clinical Characteristics in the TABLE 1. Baseline Demographics and Clinical Characteristics in the Overall Population Overall Population (continued) All-Treated Triple-Class– All-Treated Triple-Class– Population Refractory Population Refractory Characteristica (N 5 157) (n 5 119) Characteristica (N 5 157) (n 5 119) Median age (range), years 65 (35-86) 65 (35-86) Refractory to the last line of 154 (98) 117 (98) Male 89 (57) 70 (59) therapy ECOG performance status Previous stem-cell transplant scoreb $1 108 (69) 81 (68) 0 39 (25) 26 (22) $2 33 (21) 24 (20) 1 93 (59) 75 (63) NOTE. Data are expressed as no. (%) unless otherwise indicated. 2 25 (16) 18 (15) Abbreviation: ECOG, Eastern Cooperative Oncology Group. a High-risk cytogeneticsc,d 59 (38) 41 (34) Baseline is defined as the most recent assessment before administration of the first dose of study drug. $ 2 High-risk abnormalities 21 (13) 14 (12) b ECOG performance status scores range from 0 to 5, with 0 Del(17p) 18 (11) 10 (8) indicating no symptoms and higher scores indicating increasing International Staging System disability, and were established at baseline (most recent assessment staged,e before administration of the first dose of study drug). I 63 (40) 41 (34) c High-risk cytogenetics at study entry was based on fluorescence in situ hybridization defined as t(4; 14), del(17/17p), and t(14; 16) per II 49 (31) 36 (30) Sonneveld et al22; 31 patients (20%) had unknown cytogenetics. III 39 (25) 36 (30) Cytogenetic assessments were not centralized. d Unknown 4 (3) 4 (3) At study entry. e International Staging System stages were defined as follows: stages I, Missing 2 (1) 2 (2) serum B2-microglobulin , 3.5 mg/L, serum albumin $ 3.5 g/dL; stage d,f Extramedullary disease 55 (35) 50 (42) II, not stage I or stage III; stage III, serum B2-microglobulin $ 5.5 mg/L. Median time since initial 6.5 (0.7-24.6) 6.2 (0.7-24.6) Patients with unknown status were coded as unknown; patients without diagnosis (range), yearsg an entry into the case report form were coded as missing. f Median no. of prior lines of 5 (2-12) 5 (2-12) Extramedullary disease was defined as a multiple myeloma disease therapy (range) originating either in, but extending beyond, the cortical bone or as a separate soft tissue mass. Previous anti-CD38 125 (80) 119 (100) monoclonal antibody g Time since initial diagnosis is calculated relative to the first dose of study drug. Refractory (any) 125 (80) 119 (100) h Includes patients refractory to carmustine (6 [7%] in the all-treated Refractory to daratumumab 117 (75) 112 (94) population; 6 [5%] in the triple-class–refractory population), refractory Previous immunomodulatory 157 (100) 119 (100) to high-dose melphalan (3 [3%] in the all-treated population; 2 [2%] in drug the triple-class–refractory population), and refractory to busulfan (1 [1%] each in the all-treated and triple-class–refractory population). Refractory (any) 153 (97) 116 (97) i Defined as refractory to or intolerant of $ 1 proteasome inhibitor, Refractory to pomalidomide 140 (89) 104 (87) $ 1 immunomodulatory drug, and $ 1 anti-CD38 monoclonal Previous proteasome inhibitor 157 (100) 119 (100) antibody. Refractory (any) 145 (92) 115 (97) Refractory to bortezomib 101 (64) 80 (67) RESULTS Previous alkylator therapy 138 (88) 105 (88) Patients Refractory (any) 92 (59) 76 (64) In total, 157 patients were enrolled in the study, received Refractory to 80 (51) 65 (55) at least one dose of study medication, and were included cyclophosphamide in the all-treated population. At the data cutoff date Refractory to melphalan 21 (13) 19 (16) (January 14, 2020), 131 patients (83%) had discontinued Refractory to bendamustine 14 (9) 13 (11) treatment—the most common primary reasons for dis- Refractory to other h 10 (6) 7 (8) continuation were disease progression (n 5 88; 56%) and Triple-class refractoryi 119 (76) 119 (100) AEs (n 5 26; 17%)—and 26 patients (17%) remained on treatment (Fig 1). The median duration of treatment with (continued in next column) melflufen plus dexamethasone was 3.8 months (range, 0.9-22.7 months). At baseline, the median age was 65 years, patients had received a median of five prior lines of therapy, 154 patients (98%) had disease that was 760 © 2020 by American Society of Clinical Oncology Volume 39, Issue 7 Downloaded from ascopubs.org by 62.83.88.102 on June 15, 2021 from 062.083.088.102 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. Melflufen and Dexamethasone in Relapsed and Refractory Myeloma TABLE 2. Overall Response and Clinical Benefit Rate Response Category All-Treated Population (N 5 157) Triple-Class Refractory (n 5 119) Best overall responsea sCR 1 (1) 0 CR 0 0 VGPR 17 (11) 13 (11) PR 28 (18) 18 (15) Minimal response 25 (16) 16 (13) ORRb 46 (29) [22 to 37] 31 (26) [18 to 35] CBRc 71 (45) [37 to 53] 47 (39) [31 to 49] NOTE. Data are expressed as no. (%) [95% CI]. Abbreviations: CBR, clinical benefit rate; CR, complete response; ORR, overall response rate; PR, partial response; sCR, stringent complete response; VGPR, very good partial response. a Investigator assessed per the International Myeloma Working Group uniform response criteria.18 b Defined as the proportion of patients with a PR or better. c Defined as the proportion of patients with a minimal response or better. refractory to the last line of therapy received, 119 (76%) 37% to 53%). In the triple-class–refractory population, had triple-class–refractory disease, and 92 (59%) had the ORR was 26% (95% CI, 18% to 35%), with 13 pa- MM that was refractory to prior alkylator therapy (Table 1). tients achieving a VGPR and 18 a PR. The ORR per Overall, 59 patients (38%) had high-risk cytogenetics, 39 independent review committee was 30% (95% CI, 23% to (25%) had International Staging System stage III disease, 38%) overall and 26% (95% CI, 18% to 35%) in the and 55 (35%) had extramedullary disease. triple-class–refractory population (Data Supplement). Reduction in M-protein was observed in 118 of the 145 Efficacy patients (81.4%) (Data Supplement). In the all-treated The ORR per investigator assessment was 29% (95% CI, and triple-class–refractory populations, the median time 22% to 37%), with one patient achieving an sCR, 17 a to PR or better was 1.9 months (range, 1.0-7.4 months) VGPR, and 28 a PR (Table 2). An additional 25 patients and 1.9 months (range, 1.0-6.1 months), respectively, achieved a minimal response for a CBR of 45% (95% CI, and the median duration of PR or better was 5.5 months Patients With Best Response of Partial Response or Better SD MR PR VGPR CR sCR Latest dose Ongoing Progression-free survival event Patients with triple-class−refractory disease (n = 31) Patients with extramedullary disease (n = 13) 0 5 10 15 20 Time Since Start of Treatment (months) FIG 2. Duration of response to melflufen plus dexamethasone. Data on patients in the all-treated population (n 5 46), triple-class–refractory population (asterisk; n 5 31), and extramedullary subgroup (dagger; n 5 13) who achieved a PR or better as the best response. Open circles indicate the latest dose of melflufen received; arrows indicate patients still receiving treatment at the data cutoff date; orange Xs indicate progression-free survival events. CR, complete response; MR, minimal response; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response. Journal of Clinical Oncology 761 Downloaded from ascopubs.org by 62.83.88.102 on June 15, 2021 from 062.083.088.102 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. Richardson et al (95% CI, 3.9 to 7.6 months) and 4.4 months (95% CI, 3.4 to and triple-class–refractory populations, respectively (Data 7.6 months), respectively (Fig 2 and Data Supplement). Supplement). Among patients in the all-treated population and the triple-class–refractory group (n 5 70 and n 5 52, In the all-treated and triple-class–refractory populations, the respectively) who discontinued the study and initiated a new median PFS was 4.2 months (95% CI, 3.4 to 4.9 months) and myeloma therapy, the median time to next therapy was 3.9 months (95% CI, 3.0 to 4.6 months), respectively (Fig 3A). 8.2 months (95% CI, 7.2 to 10.8 months) and 7.9 months The median OS was 11.6 months (95% CI, 9.3 to (95% CI, 6.9 to 10.9 months), respectively. The median time 15.4 months) and 11.2 months (95% CI, 7.7 to 13.2 months), to next therapy or death was 5.8 months (95% CI, 4.8 to with an estimated 1-year event-free rate of 48.8% (95% CI, 7.1 months) in the all-treated population and 5.3 months 39.6% to 57.4%) and 41.9% (95% CI, 31.6% to 51.8%), (95% CI, 4.5 to 6.3 months) in the triple-class–refractory respectively (Fig 3B), at a median follow-up of 14 months group. (range, 10.8-18.7 months). Among responders, the median PFS was 8.5 months (95% CI, 5.4 to 13.4 months) and In a subgroup analysis, 19 of the 54 patients (35%) age 65- 8.5 months (95% CI, 5.3 to 13.4 months), and the median OS 74 years and 8 of the 25 patients (32%) older than 75 years was 17.6 months (95% CI, 13.2 to 28.9 months) and achieved a PR or better. In addition, a PR or better was 16.5 months (95% CI, 11.5 to 18.5 months) in the all-treated achieved in 13 of the 55 patients (24%) with extramedullary A 100 Progression-Free Survival (%) Events, Median PFS 80 Population n (%) (95% CI), months All-treated (N = 157) 121 (77.1) 4.2 (3.4-4.9) Triple-class–refractory (n = 119) 94 (79.0) 3.9 (3.0-4.6) 60 40 20 + Censored 0 3 6 9 12 15 18 21 24 Time From Start of Treatment (months) No. at risk (no. censored) All-treated 157 (0) 91 (9) 46 (13) 22 (23) 9 (31) 5 (33) 3 (34) 1 (35) 0 (36) Triple-class–refractory 119 (0) 64 (9) 26 (13) 15 (17) 6 (21) 3 (23) 2 (24) 0 (25) B 100 Events, Median OS Population n (%) (95% CI), months Overall Survival (%) 80 All-treated (N = 157) 88 (56.1) 11.6 (9.3-15.4) Triple-class–refractory (n = 119) 72 (60.5) 11.2 (7.7-13.2) 60 40 20 + Censored 0 3 6 9 12 15 18 21 24 27 30 33 Time From Start of Treatment (months) No. at risk (no. censored) All-treated 157 (0) 139 (1) 100 (12) 69 (30) 42 (46) 29 (53) 21 (56) 12 (61) 9 (63) 6 (65) 1 (68) 0 (69) Triple-class–refractory 119 (0) 104 (1) 70 (11) 49 (21) 29 (31) 17 (38) 11 (41) 6 (44) 5 (44) 2 (46) 0 (47) FIG 3. PFS and OS. Kaplan-Meier analysis of (A) PFS and (B) OS in the all-treated (N 5 157) and triple-class– refractory (n 5 119) populations. OS, overall survival; PFS, progression-free survival. 762 © 2020 by American Society of Clinical Oncology Volume 39, Issue 7 Downloaded from ascopubs.org by 62.83.88.102 on June 15, 2021 from 062.083.088.102 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. Melflufen and Dexamethasone in Relapsed and Refractory Myeloma disease and 12 of the 59 patients (20%) with high-risk general physical health deterioration was associated with cytogenetics (Data Supplement). Among patients with MM progressive disease (n 5 3; 2%) and respiratory failure refractory to previous alkylator therapy, the ORR was 21% (n 5 2; 1%; Data Supplement). None of the deaths were (19 of the 92 patients achieved a PR or better, including considered related to melflufen. one sCR, six VGPRs, and 12 PRs) and the CBR was 34% The average (standard deviation) monthly dose of melflufen (Data Supplement). Among patients refractory to an alky- received was 37.8 mg (6 4.0). TEAEs leading to melflufen lator in one previous line of therapy (n 5 60), the ORR was dose reductions occurred in 42 patients (27%), most 28% (CBR, 40%). In patients refractory to alkylators in commonly thrombocytopenia (n 5 22; 14%) and neu- multiple previous lines of therapy (n 5 32), the ORR was tropenia (n 5 5; 3%). While on study, 102 patients (65%) 6% (CBR, 22%). Median PFS and OS in the subgroups received concomitant RBC or platelet transfusion support, analyzed were consistent with those of the all-treated with 68 (43%) receiving platelet transfusion support only population (Data Supplement). and 106 (68%) receiving concomitant growth factor sup- Safety port (Data Supplement). Overall, 34 patients (22%) had at Treatment-emergent AEs (TEAEs) were reported in all 157 least one TEAE leading to melflufen treatment discontin- patients (100%) in the all-treated population, with 149 uation, most commonly thrombocytopenia (n 5 16) and (95%) reporting at least one melflufen-related TEAE neutropenia (n 5 5; Data Supplement). Overall, 95 patients (Table 3 and Data Supplement). Grade $ 3 TEAEs oc- (61%) experienced at least one dose delay, and the median curred in 150 patients (96%), most commonly neutropenia number of treatment cycles with a dose delay was one (124 [79%]), thrombocytopenia (120 [76%]), and anemia (range, 0-9). (67 [43%]). Any-grade and grade 3/4 bleeding events with concurrent grade 3/4 thrombocytopenia occurred in 25 DISCUSSION patients (16%) and four patients (3%), respectively. The In this study, melflufen plus dexamethasone demon- most common nonhematologic treatment-emergent grade strated meaningful efficacy and a manageable safety 3/4 events included pneumonia (16 [10%]; grade 3, 14 profile in patients with heavily pretreated RRMM. These [9%]; grade 4, two [1%]) and hypophosphatemia (eight findings build substantially on previously reported re- [5%]; grade 3, eight [5%]; grade 4, 0). Grade 3/4 neu- sults17 but in a population that is more aligned with current tropenia with concurrent grade 3/4 infections occurred in treatment practice in the relapsed and refractory as well as 18 patients (11%); of these, 11 (7%) had pneumonia (Data highly resistant disease setting (ie, patients refractory to an Supplement). GI events occurred in 97 patients overall and anti-CD38 monoclonal antibody and/or pomalidomide, were grade 1/2 in 90 of the 97 patients (93%) and grade 3 as well as exposed and refractory to prior lenalidomide, in seven of the 97 patients (7%). No grade 4 events were dexamethasone, and proteasome inhibitors). Durable reported. The most common any-grade GI events included responses were seen in this heavily pretreated population nausea (50 [32%]), diarrhea (42 [27%]), constipation (23 with a high proportion of extramedullary disease and high- [15%]), and vomiting (21 [13%]). Mucositis occurred in risk cytogenetic features. Although the median DOR was one patient (1%; grade 1 event), and there were no reports 5.5 months, the median PFS among responders was of alopecia or neuropathy. encouragingly longer at 8.5 months. Furthermore, the Serious TEAEs occurred in 77 patients (49%), most median time to first response was 1.9 months, but many commonly pneumonia (14 [9%]) and febrile neutropenia patients achieved their best response beyond 2 months of (eight [5%]; Data Supplement). Second primary malig- treatment. Altogether, these data support the notion that nancies occurred in five patients; of these, four had the clinical benefit of melflufen plus dexamethasone malignancies with cutaneous manifestations (two patients improves with longer treatment duration. with basal cell carcinoma, one patient with squamous cell The ORR of 29% was consistent among high-risk patient carcinoma, and one patient with basal cell carcinoma, subgroups, including those with triple-class–refractory squamous cell carcinoma, and malignant melanoma; see disease (26%), those with extramedullary disease (24%), the Data Supplement). One patient developed myelo- and patients age 75 years or older (32%), which is en- dysplasia after having received 17 cycles of study medi- couraging given the reported ORRs (10%-31%) in patients cation and in the context of multiple prior cycles of refractory to anti-CD38 monoclonal antibody therapy and/ alkylator-based therapy, including stem-cell transplant or with extramedullary disease at relapse.3,4,23-25 In fact, this prior to study entry. Moreover, the review of fluorescence is the largest population with extramedullary disease re- in situ hybridization studies from the screening bone ported to date in a prospective study.4,26,27 Subgroup an- marrow confirmed pre-existing abnormalities supporting a alyses showed sufficient efficacy in 60 patients refractory to subclinical myelodysplastic syndrome that was likely an alkylator in one previous line of therapy with an ORR of treatment-related and not otherwise apparent. No other 28%, while the ORR was only 6% in the 32 patients re- cases of myelodysplastic syndromes were seen. Overall, fractory to alkylators in two or more previous lines. Melflufen 10 patients (6%) died from TEAEs. Most commonly, may have a mechanism of action that is different from that Journal of Clinical Oncology 763 Downloaded from ascopubs.org by 62.83.88.102 on June 15, 2021 from 062.083.088.102 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. Richardson et al TABLE 3. TEAEs (Occurring in $ 10% of Patients) in the All-Treated Population Patients (N 5 157) a b TEAE Any-Grade Grade 1 Grade 2 Grade 3 Grade 4 c,d Any 157 (100) 0 7 (4) 40 (25) 100 (64) Hematologic Neutropeniae 129 (82) 1 (, 1) 4 (3) 50 (32) 74 (47) Thrombocytopeniae 128 (82) 5 (3) 3 (2) 40 (25) 80 (51) Anemiae 111 (71) 3 (2) 41 (26) 66 (42) 1 (, 1) Nonhematologic Nausea 50 (32) 31 (20) 18 (11) 1 (, 1) 0 Fatigue 46 (29) 17 (11) 25 (16) 4 (3) 0 Asthenia 42 (27) 13 (8) 23 (15) 5 (3) 1 (, 1) Diarrhea 42 (27) 24 (15) 18 (11) 0 0 Pyrexia 38 (24) 24 (15) 11 (7) 3 (2) 0 Cough 26 (17) 16 (10) 10 (6) 0 0 Upper respiratory tract infection 25 (16) 3 (2) 19 (12) 3 (2) 0 Constipation 23 (15) 18 (11) 4 (3) 1 (, 1) 0 Decreased appetite 22 (14) 10 (6) 11 (7) 1 (, 1) 0 Hypokalemia 22 (14) 14 (9) 6 (4) 2 (1) 0 Peripheral edema 22 (14) 15 (10) 5 (3) 2 (1) 0 Headache 21 (13) 13 (8) 8 (5) 0 0 Vomiting 21 (13) 12 (8) 9 (6) 0 0 Bone pain 20 (13) 9 (6) 8 (5) 3 (2) 0 Pain in extremity 20 (13) 7 (4) 10 (6) 3 (2) 0 f Pneumonia 20 (13) 0 3 (2) 14 (9) 2 (1) Back pain 19 (12) 9 (6) 9 (6) 1 (, 1) 0 Insomnia 18 (11) 14 (9) 3 (2) 1 (, 1) 0 Dizziness 17 (11) 14 (9) 3 (2) 0 0 Dyspnea 17 (11) 9 (6) 6 (4) 2 (1) 0 Arthralgia 16 (10) 11 (7) 5 (3) 0 0 Exertional dyspnea 16 (10) 13 (8) 3 (2) 0 0 Hypocalcemia 16 (10) 9 (6) 6 (4) 1 (, 1) 0 NOTE. Data are expressed as no. (%). Abbreviation: TEAE, treatment-emergent adverse event. a Adverse events are coded to the preferred term using MedDRA, version 19.1. b At each level of summarization (any event and preferred term), patients reporting more than one incidence of each adverse event are counted only once by maximum severity. c TEAEs were defined as adverse events with onset date/time or increase in the severity level after the initial dose of study drug and within 30 days (unless considered related to study drug) after the last dose of study drug or initiation of new multiple myeloma therapy, whichever occurred sooner. d Includes 10 patients who experienced grade 5 TEAEs. e Hematologic TEAEs of special interest were categorized by standardized MedDRA query. For anemia, the preferred terms under hematopoietic erythropenia were counted. For neutropenia, the preferred terms under hematopoietic leukopenia were combined. For thrombocytopenia, the preferred terms under hematopoietic thrombocytopenia were combined. f Includes one grade 5 event. of other alkylators.8,11 For example, melflufen induced cell of p53 function.8,11,16 Unlike other newer agents that death more effectively than melphalan in TP53-mutated work via immune-based mechanisms (including chimeric cell lines and in cells from patients with TP53-mutated antigen receptor T cell therapy, belantamab mafodotin, RRMM, suggesting that the mechanism of cytotoxicity of iberdomide, and isatuximab), melflufen adds a unique melflufen—but not that of other alkylators—is independent mechanism of action to the treatment landscape in 764 © 2020 by American Society of Clinical Oncology Volume 39, Issue 7 Downloaded from ascopubs.org by 62.83.88.102 on June 15, 2021 from 062.083.088.102 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. Melflufen and Dexamethasone in Relapsed and Refractory Myeloma relapsed disease as a potent and novel cytotoxic agent HORIZON in any patient. Encouragingly, alopecia and targeting myeloma more broadly while providing mean- treatment-emergent peripheral neuropathy were not ingful clinical efficacy and a manageable safety profile for reported. Patients were therefore able to tolerate treat- heavily pretreated RRMM.8,10,28-30 ment, with rates of discontinuation from AEs lower than The safety profile of melflufen primarily consisted of or comparable with other studies (which range from 6% hematologic AEs, consistent with previous results.17 to 33%) in this patient population and with a prolonged Despite cytopenias being common, the incidence of median duration of treatment, together with the added significant bleeding events or infections was low. He- convenience of monthly infusions, which is an especially matologic AEs were generally reversible and clinically important consideration in the current era of COVID- manageable with dose adjustments, dose delays, growth 19.23,27,28 factor use, platelet transfusions, and appropriate sup- In conclusion, the results from HORIZON suggest that portive care. Nonhematologic grade 3/4 AEs were in- melflufen has the potential to be an important therapeutic frequent, with infections being the most common. option in RRMM by providing a novel mechanism of action, Moreover, the frequency of infections was generally clinically meaningful efficacy, and manageable safety when consistent with the expected rates of infections in heavily combined with dexamethasone in heavily pretreated pa- pretreated patients.23,27,31 Specifically, the 10% rate of tients.32 Based on these results, the efficacy and safety of grade 3/4 pneumonia reported in HORIZON was similar melflufen plus dexamethasone versus pomalidomide plus to 9%-11% reported with pomalidomide plus dexa- dexamethasone are being further evaluated in OCEAN methasone, bortezomib plus dexamethasone, and seli- (OP-103), a randomized, global, phase III multicenter study nexor plus dexamethasone in RRMM.23,27,31 GI toxicities, (ClinicalTrials.gov identifier: NCT03151811) for patients in a common reason for treatment discontinuation with earlier relapse.33 Studies of melflufen plus dexamethasone in other agents,23 were infrequent, primarily grade 1/2, combination with bortezomib or daratumumab are also and did not lead to melflufen treatment cessation in ongoing, with promising results to date.34 AFFILIATIONS CORRESPONDING AUTHOR 1 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA Paul G. Richardson, MD, Dana-Farber Cancer Institute, 450 Brookline 2 Institut Català d’Oncologia and Josep Carreras Research Institute, Avenue, Boston, MA 02215; e-mail: Paul_Richardson@dfci.harvard.edu. Hospital Germans Trias i Pujol, Badalona, Spain 3 Myeloma Unit, Division of Hematology, University of Torino, Azienda PRIOR PRESENTATION Ospedaliero-Universitaria Città della Salute e della Scienza, Torino, Italy 4 Presented in part at the 25th European Hematology Association annual Hematology Department, IDIBAPS, Hospital Clinic, Barcelona, Spain 5 congress, virtual format, June 11-21, 2020; abstract EP945. Seràgnoli Institute of Hematology, Bologna University School of Medicine, Bologna, Italy 6 Clı́nica Universidad de Navarra, Pamplona, Spain SUPPORT 7 CHU de Poitiers, Poitiers, France This study was sponsored by Oncopeptides AB, which also provided 8 Division of Hematology-Oncology, Department of Medicine, University support for manuscript editorial assistance. of Florida, Gainesville, FL 9 Myeloma Service, Department of Medicine, Memorial Sloan Kettering CLINICAL TRIAL INFORMATION Cancer Center, New York, NY 10 NCT02963493 Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF Université d’Angers, Université de Nantes, Nantes, France INTEREST 11 Site de Recherche Intégrée sur le Cancer (SIRIC), Imaging and Disclosures provided by the authors are available with this article at DOI Longitudinal Investigations to Ameliorate Decision-making (ILIAD), https://doi.org/10.1200/JCO.20.02259. Nantes, France 12 Service d’hématologie Clinique, Centre Hospitalier Universitaire, Place Alexis Ricordeau, Nantes, France DATA SHARING STATEMENT 13 Hospital Universitario La Princesa and Hospital Universitario Oncopeptides commits to share clinical study data with qualified Quironsalud, Madrid, Spain researchers to enable enhancement of public health. As such, 14 Rush University Medical Center, Chicago, IL Oncopeptides will share anonymized patient-level data on request or if 15 Baylor Scott & White Charles A. Sammons Cancer Center, Dallas, TX required by law or regulation. Qualified scientific and medical researchers 16 The Oncology Institute of Hope and Innovation, Glendale, CA can request patient-level data for studies of Oncopeptides pharmaceutical 17 Division of Hematology-Oncology, Department of Medicine, University substances listed on ClinicalTrials.gov and approved by health authorities of Pittsburgh School of Medicine, Pittsburgh, PA in the United States and the EU. Patient-level data for studies of newly 18 Novant Health Hematology, Novant Health Forsyth Medical Center, approved pharmaceutical substances or indications can be requested Winston-Salem, NC 9 months after US Food and Drug Administration and European Medicines 19 Oncopeptides AB, Stockholm, Sweden Agency approval. Such requests are assessed at Oncopeptides’ discretion, 20 Hospital Clı́nico Universitario de Salamanca/IBSAL/CIC, Salamanca, and the decisions depend on the scientific merit of the proposed request, Spain data availability, and the purpose of the proposal. The applicants should be Journal of Clinical Oncology 765 Downloaded from ascopubs.org by 62.83.88.102 on June 15, 2021 from 062.083.088.102 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. Richardson et al willing to submit both positive and negative findings to a scientific journal. Xavier Leleu, Omar Nadeem, John W. Hiemenz, Hani Hassoun, Cyrille If Oncopeptides agrees to share clinical data for research purposes, the Touzeau, Adrián Alegre, Agner Paner, Christopher Maisel, Amitabha applicant is required to sign an agreement for data sharing before data Mazumder, Anastasios Raptis, Jan S. Moreb, Kenneth C. Anderson, release, to ensure that the patient data are de-identified. In case of any risk Jacob P. Laubach, Marcus Thuresson, Marı́a-Victoria Mateos of re-identification on anonymized data despite measures to protect patient Data analysis and interpretation: Paul G. Richardson, Albert Oriol, confidentiality, the data will not be shared. The patients’ informed consent Alessandra Larocca, Joan Bladé, Michele Cavo, Paula Rodriguez-Otero, will always be respected. If the anonymization process will provide futile Xavier Leleu, John W. Hiemenz, Cyrille Touzeau, Adrián Alegre, Agne data, Oncopeptides will have the right to refuse the request. Oncopeptides Paner, Anastasios Raptis, Jan S. Moreb, Kenneth C. Anderson, Jacob P. will provide access to patient-level clinical trial analysis datasets in a Laubach, Sara Thuresson, Marcus Thuresson, Catriona Byrne, Johan secured environment upon execution of the data sharing agreement. Harmenberg, Nicolaas A. Bakker, Marı́a-Victoria Mateos Oncopeptides will also provide the Protocol, statistical analysis plan, and Manuscript writing: All authors the clinical study report synopsis if needed. For additional information or Final approval of manuscript: All authors requests for access to Oncopeptides clinical trial data for research Accountable for all aspects for the work: All authors purposes, please contact us at medinfo@oncopeptides.com. ACKNOWLEDGMENT AUTHOR CONTRIBUTIONS The authors especially thank the patients and their families for Conception and design: Paul G. Richardson, Catriona Byrne, Johan participating in this trial and all the study investigators and Harmenberg, Marı́a-Victoria Mateos coordinators for their contributions to this work. The authors also Provision of study materials or patients: Paul G. Richardson, Albert Oriol, thank Jakob Obermüller and Hanan Zubair (Oncopeptides AB, Alessandra Larocca, Joan Bladé, Michele Cavo, Paula Rodriguez-Otero, Xavier Stockholm, Sweden) for data management as well as Katherine Mills- Leleu, Omar Nadeem, John W. Hiemenz, Hani Hassoun, Cyrille Touzeau, Lujan, PhD, CMPP, and Jennifer Leslie, PhD, CMPP, of Team 9 Adrián Alegre, Agner Paner, Christopher Maisel, Amitabha Mazumder, Science for providing medical editorial assistance under the guidance Anastasios Raptis, Jan S. Moreb, Kenneth C. Anderson, Jacob P. Laubach, of the authors, which was funded by Oncopeptides AB in accordance Marı́a-Victoria Mateos with Good Publications Practice (GPP3) guidelines. Collection and assembly of data: Paul G. Richardson, Albert Oriol, Alessandra Larocca, Joan Bladé, Michele Cavo, Paula Rodriguez-Otero, REFERENCES 1. Kumar SK, Dimopoulos MA, Kastritis E, et al: Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: A multicenter IMWG study. Leukemia 31:2443-2448, 2017 2. Moreau P, San Miguel J, Sonneveld P, et al: Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 28: iv52-iv61, 2017 3. Gandhi UH, Cornell RF, Lakshman A, et al: Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia 33:2266-2275, 2019 4. Jimenez-Segura R, Granell M, Gironella M, et al: Pomalidomide-dexamethasone for treatment of soft-tissue plasmacytomas in patients with relapsed/refractory multiple myeloma. Eur J Haematol 102:389-394, 2019 5. Sonneveld P: Management of multiple myeloma in the relapsed/refractory patient. Hematology Am Soc Hematol Educ Program 2017:508-517, 2017 6. Chim CS, Kumar SK, Orlowski RZ, et al: Management of relapsed and refractory multiple myeloma: Novel agents, antibodies, immunotherapies and beyond. Leukemia 32:252-262, 2018 7. Wickström M, Haglund C, Lindman H, et al: The novel alkylating prodrug J1: Diagnosis directed activity profile ex vivo and combination analyses in vitro. Invest New Drugs 26:195-204, 2008 8. Chauhan D, Ray A, Viktorsson K, et al: In vitro and in vivo antitumor activity of a novel alkylating agent, melphalan-flufenamide, against multiple myeloma cells. Clin Cancer Res 19:3019-3031, 2013 9. Strese S, Wickstrom M, Fuchs PF, et al: The novel alkylating prodrug melflufen (J1) inhibits angiogenesis in vitro and in vivo. Biochem Pharmacol 86:888-895, 2013 10. Ray A, Ravillah D, Das DS, et al: A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells. Br J Haematol 174:397-409, 2016 11. Wickström M, Nygren P, Larsson R, et al: Melflufen—A peptidase-potentiated alkylating agent in clinical trials. Oncotarget 8:66641-66655, 2017 12. Miettinen JJ, Kumari R, Traustadottir GA, et al: Aminopeptidase expression in multiple myeloma associates with disease progression and sensitivity to melflufen. Presented at the 25th European Hematology Association Annual Conference, June 11-21, 2020 (virtual poster EP897) 13. Pinto V, Bergantim R, Caires HR, et al: Multiple myeloma: Available therapies and causes of drug resistance. Cancers (Basel) 12:407, 2020 14. Wickström M, Larsson R, Nygren P, et al: Aminopeptidase N (CD13) as a target for cancer chemotherapy. Cancer Sci 102:501-508, 2011 15. Moore HE, Davenport EL, Smith EM, et al: Aminopeptidase inhibition as a targeted treatment strategy in myeloma. Mol Cancer Ther 8:762-770, 2009 16. Slipicevic A, Munawar U, Aschan J, et al: Melflufen efficacy in multiple myeloma with TP53 aberrations. Presented at the American Association for Cancer Research (AACR) Annual Meeting, June 22-24, 2020 (Virtual Annual Meeting II, abstr 1843) 17. Richardson P, Bringhen S, Voorhees P, et al: Melflufen plus dexamethasone in relapsed and refractory multiple myeloma (O-12-M1): A multicentre, in- ternational, open-label, phase 1-2 study. Lancet Haematol 7:e395-e407, 2020 18. Rajkumar SV, Harousseau JL, Durie B, et al: Consensus recommendations for the uniform reporting of clinical trials: Report of the International Myeloma Workshop Consensus Panel 1. Blood 117:4691-4695, 2011 19. Fleiss JL: Statistical methods for rates and proportions (ed 2). New York, NY, Wiley, 1981 20. Brookmeyer R, Crowley J: A confidence interval for the median survival time. Biometrics 38:29-42, 1982 21. Schemper M, Smith TL: A note on quantifying follow-up in studies of failure time. Control Clin Trials 17:343-346, 1996 22. Sonneveld P, Avet-Loiseau H, Lonial S, et al: Treatment of multiple myeloma with high-risk cytogenetics: A consensus of the International Myeloma Working Group. Blood 127:2955-2962, 2016 766 © 2020 by American Society of Clinical Oncology Volume 39, Issue 7 Downloaded from ascopubs.org by 62.83.88.102 on June 15, 2021 from 062.083.088.102 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. Melflufen and Dexamethasone in Relapsed and Refractory Myeloma 23. Chari A, Vogl DT, Gavriatopoulou M, et al: Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. N Engl J Med 381:727-738, 2019 24. Usmani SZ, Weiss BM, Plesner T, et al: Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood 128:37-44, 2016 25. Ichinohe T, Kuroda Y, Okamoto S, et al: A multicenter phase 2 study of pomalidomide plus dexamethasone in patients with relapsed and refractory multiple myeloma: The Japanese MM-011 trial. Exp Hematol Oncol 5:11, 2015 26. Raje N, Berdeja J, Lin Y, et al: Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med 380:1726-1737, 2019 27. Dimopoulos MA, Palumbo A, Corradini P, et al: Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): A phase 3b study in refractory multiple myeloma. Blood 128:497-503, 2016 28. Lonial S, Lee HC, Badros A, et al: Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): A two-arm, randomised, open-label, phase 2 study. Lancet Oncol 21:207-221, 2019 29. Lonial S, Van de Donk NW, Popat R, et al: A phase 1b/2a study of the CELMoD iberdomide (CC-220) in combination with dexamethasone in patients with relapsed/refractory multiple myeloma. Clin Lymphoma Myeloma Leuk 19:E52-E53, 2019 30. Attal M, Richardson PG, Rajkumar SV, et al: Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): A randomised, multicentre, open-label, phase 3 study. Lancet 394:2096-2107, 2019 31. San-Miguel JF, Hungria VT, Yoon SS, et al: Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: A multicentre, randomised, double-blind phase 3 trial. Lancet Oncol 15:1195-1206, 2014 32. Richardson PG, San Miguel JF, Moreau P, et al: Interpreting clinical trial data in multiple myeloma: Translating findings to the real-world setting. Blood Cancer J 8:109, 2018 33. Schjesvold F, Robak P, Pour L, et al: OCEAN: A randomized phase III study of melphalan flufenamide 1 dexamethasone to treat relapsed refractory multiple myeloma. Future Oncol 16:631-641, 2020 34. Ocio EM, Efebera YA, Granell M, et al: ANCHOR (OP-104): Updated efficacy and safety from a phase 1/2 study of melflufen and dexamethasone plus bortezomib or daratumumab in patients with relapsed/refractory multiple myeloma (RRMM) refractory to an IMiD or a proteasome inhibitor (PI). Blood 133, 2019 (abstr 3124) n n n Journal of Clinical Oncology 767 Downloaded from ascopubs.org by 62.83.88.102 on June 15, 2021 from 062.083.088.102 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. Richardson et al AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I 5Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Paul G. Richardson Christopher Maisel Consulting or Advisory Role: Celgene, Janssen, Takeda, Karyopharm Stock and Other Ownership Interests: Actinium Pharmaceuticals, Karyopharm Therapeutics, Oncopeptides, Sanofi, Jazz Pharmaceuticals, SecuraBio Therapeutics, Amgen Research Funding: Celgene, Takeda, Bristol-Myers Squibb, Oncopeptides Honoraria: Bristol-Myers Squibb, Karyopharm Therapeutics, Takeda, Janssen Albert Oriol Oncology, Kite/Gilead, Oncopetides, GlaxoSmithKline Consulting or Advisory Role: Celgene, Janssen, Amgen, Sanofi, GlaxoSmithKline Speakers’ Bureau: Amgen, Bristol-Myers Squibb, Karyopharm Therapeutics, Speakers’ Bureau: Amgen, Celgene Takeda, Janssen Oncology, Kite/Gilead Alessandra Larocca Amitabha Mazumder Honoraria: Amgen, Bristol-Myers Squibb, Celgene, Janssen, GlaxoSmithKline Honoraria: Karyopharm Therapeutics Consulting or Advisory Role: Bristol-Myers Squibb, Celgene, Janssen, Takeda Speakers’ Bureau: Karyopharm Therapeutics Joan Bladé Anastasios Raptis Honoraria: Janssen, Celgene, Amgen, Takeda, Oncopeptides Consulting or Advisory Role: intellisphere, integra Michele Cavo Jan S. Moreb Honoraria: Janssen, Bristol-Myers Squibb, Celgene, Sanofi, GlaxoSmithKline, Consulting or Advisory Role: Oncopeptide Takeda, Amgen, Oncopeptides, Abbvie, Karyopharm Therapeutics, Adaptive Kenneth C. Anderson Biotechnologies Stock and Other Ownership Interests: C4 Therapeutics, OncoPep Consulting or Advisory Role: Janssen, Bristol-Myers Squibb, Celgene, Sanofi, Consulting or Advisory Role: Celgene, Millennium, Gilead Sciences, Bristol- GlaxoSmithKline, Takeda, Amgen, Oncopeptides, Abbvie, Karyopharm Myers Squibb, Janssen Oncology, Sanofi, Tolero Pharmaceuticals, Precision Therapeutics, Adaptive Biotechnologies Biosciences Speakers’ Bureau: Janssen, Celgene Patents, Royalties, Other Intellectual Property: C4 Therapeutics, OncoPep Paula Rodriguez-Otero Jacob P. Laubach Honoraria: Janssen, Celgene, Amgen, Oncopeptides, Sanofi, Abbvie, Research Funding: Abbvie, Bristol-Myers Squibb, Genentech, Janssen GlaxoSmithKline, Kite Pharma Research & Development, Carsgen, Millennium Consulting or Advisory Role: Janssen, Celgene, Amgen, Takeda, Oncopeptides, Sara Thuresson Sanofi, AbbVie, GlaxoSmithKline, Kite Pharma Employment: Oncopeptides Xavier Leleu Stock and Other Ownership Interests: Oncopeptides Honoraria: Janssen-Cilag, Celgene, Amgen, Novartis, Bristol-Myers Squibb, Consulting or Advisory Role: Oncopeptides Takeda, Sanofi, Abbvie, Merck, Roche, Karyopharm Therapeutics, Carsgen Marcus Thuresson Therapeutics Ltd, Oncopeptides, GlaxoSmithKline Employment Oncopeptides Consulting or Advisory Role: Janssen-Cilag, Celgene, Amgen, Takeda, Bristol- Stock and Other Ownership Interests: Oncopeptides Myers Squibb, Novartis, Merck, Gilead Sciences, Abbvie, Roche, Karyopharm Consulting or Advisory Role: Oncopeptides Therapeutics, Oncopeptides, Carsgen Therapeutics Ltd, GlaxoSmithKline Travel, Accommodations, Expenses: Takeda Catriona Byrne Consulting or Advisory Role: Oncopeptides Omar Nadeem Travel, Accommodations, Expenses: Oncopeptides Consulting or Advisory Role: Janssen, Celgene, Sanofi, Takeda, Adaptive Biotechnologies Johan Harmenberg Leadership: Oncopeptides Hani Hassoun Stock and Other Ownership Interests: Oncopeptides Consulting or Advisory Role: Novartis Consulting or Advisory Role: Oncopeptides, Ectin AB Research Funding: Takeda, Janssen Travel, Accommodations, Expenses: Oncopeptides Cyrille Touzeau Nicolaas A. Bakker Honoraria: Abbvie, Celgene, Amgen, Takeda, Janssen, Sanofi, Novartis, Employment: Oncopeptides GlaxoSmithKline Stock and Other Ownership Interests: Oncopeptides Consulting or Advisory Role: Novartis, Amgen, Celgene, Abbvie, Takeda, Honoraria: Oncopeptides Janssen, GlaxoSmithKline Research Funding: Abbvie Marı́a-Victoria Mateos Honoraria: Janssen-Cilag, Celgene, Amgen, Takeda, GlaxoSmithKline, Abbvie/ Adrián Alegre Genentech, Adaptive Biotechnologies Leadership: Amgen, Janssen-Cilag, Celgene-BMS, Takeda, Sanofi, Consulting or Advisory Role: Takeda, Janssen-Cilag, Celgene, Amgen, Abbvie, GlaxoSmithKline, ONCOPETIDES GlaxoSmithKline, Pharmamar-zeltia Agne Paner No other potential conflicts of interest were reported. Honoraria: Amgen, Celgene, Janssen Consulting or Advisory Role: Takeda, Celgene, Amgen, Karyopharm Therapeutics, Oncopetides © 2020 by American Society of Clinical Oncology Volume 39, Issue 7 Downloaded from ascopubs.org by 62.83.88.102 on June 15, 2021 from 062.083.088.102 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. Melflufen and Dexamethasone in Relapsed and Refractory Myeloma APPENDIX TABLE A1. HORIZON (OP-106) Investigators and Recruitment Sites Principal Investigator Recruitment Site Paul Richardson Dana-Farber Cancer Institute Adrián Alegre Hospital Universitario La Princesa Joan Bladé Hospital Clı́nic de Barcelona Michele Cavo Ematologia “L. e A. Seragnoli”—PAD 8. Policlinico Sant’Orsola-Malpighi Hani Hassoun Memorial Sloan Kettering Cancer Center John Hiemenza University of Florida Health Cancer Center Maxim Norkin Jan Moreb Ramomohana Kancherlaa Hudson Valley Hematology and Oncology Associates Amitabha Mazumder Alessandra Larocca Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino Xavier Leleu CHU de Poitiers-Pole regional de cancerologie Christopher Maisel Baylor Scott & White Charles A. Sammons Cancer Center Marı́a-Victoria Mateos Hospital Clı́nico Universitario de Salamanca/IBSAL/CIC Amitabha Mazumder The Oncology Institute of Hope and Innovation Albert Oriol Hospital Germans Trias i Pujol Agne Paner RUSH University Medical Center Anastasios Raptis University of Pittsburgh School of Medicine Hillman Cancer Institute Paula Rodrı́guez-Otero Clinica Universidad de Navarra Cyrille Touzeau Service d’hématologie Clinique, Centre Hospitalier Universitaire a For institutions at which a principal investigator change occurred throughout the course of the study, the current principal investigator is listed in bold. Journal of Clinical Oncology Downloaded from ascopubs.org by 62.83.88.102 on June 15, 2021 from 062.083.088.102 Copyright © 2021 American Society of Clinical Oncology. All rights reserved.