Expert Opinion on Investigational Drugs ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ieid20 Melflufen for relapsed and refractory multiple myeloma Albert Oriol , Alessandra Larocca , Xavier Leleu , Roman Hajek , Hani Hassoun , Paula Rodríguez-Otero , Agne Paner , Fredrik H. Schjesvold , Joachim Gullbo & Paul G. Richardson To cite this article: Albert Oriol , Alessandra Larocca , Xavier Leleu , Roman Hajek , Hani Hassoun , Paula Rodríguez-Otero , Agne Paner , Fredrik H. Schjesvold , Joachim Gullbo & Paul G. Richardson (2020) Melflufen for relapsed and refractory multiple myeloma, Expert Opinion on Investigational Drugs, 29:10, 1069-1078, DOI: 10.1080/13543784.2020.1808884 To link to this article: https://doi.org/10.1080/13543784.2020.1808884 © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Published online: 29 Sep 2020. Submit your article to this journal Article views: 744 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ieid20 EXPERT OPINION ON INVESTIGATIONAL DRUGS 2020, VOL. 29, NO. 10, 1069–1078 https://doi.org/10.1080/13543784.2020.1808884 DRUG EVALUATION Melflufen for relapsed and refractory multiple myeloma Albert Oriola, Alessandra Laroccab, Xavier Leleu c, Roman Hajekd, Hani Hassoune, Paula Rodríguez-Oterof, Agne Panerg, Fredrik H. Schjesvoldh, Joachim Gullboi and Paul G. Richardsonj a Institut Josep Carreras and Institut Català d’Oncologia, Hospital Germans Trias I Pujol, Badalona, Spain; bAzienda Ospedaliero-Universitaria Città Della Salute E Della Scienza Di Torino, University of Torino, Torino, Italy; cDepartment of Hematology, Hôpital De La Milétrie, CHU De Poitiers, Poitiers, France; dDepartment of Hemato-Oncology, University of Ostrava and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic; e Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; fDepartment of Hematology, Clínica Universidad De Navarra, Pamplona, Spain; gDivision of Hematology, Oncology and Stem Cell Transplant, Rush University Medical Center, Chicago, IL, USA; hOslo Myeloma Center, Oslo University Hospital and K.G. Jebsen Centre for B-Cell Malignancies, University of Oslo, Oslo, Norway; i Department of Medical Sciences, Division of Clinical Pharmacology, Uppsala University, Uppsala, Sweden; jJerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA ABSTRACT ARTICLE HISTORY Introduction: The overall survival of patients with multiple myeloma has improved with the advent of Received 16 June 2020 novel agents; however, multiple myeloma remains incurable. Combinations of standard-of-care agents Accepted 8 August 2020 such as immunomodulators, proteasome inhibitors, and anti-CD38 monoclonal antibodies are increas­ KEYWORDS ingly used in earlier lines of therapy. Patients with disease that is refractory to multiple novel agents Melflufen; melphalan represent a population with high unmet medical need and for whom therapies with new mechanisms flufenamide; relapsed/ of action could be beneficial. Melphalan flufenamide (melflufen) has demonstrated encouraging activity refractory multiple myeloma in patients with relapsed and refractory multiple myeloma. Areas covered: This review provides an overview of the mechanism of action of melflufen, a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly delivers alkylating agents into tumor cells. It reviews key Phase I and II clinical trial data for melflufen in combination with dexamethasone as well as in triplet combinations with daratumumab or bortezomib. The safety profile of melflufen, which is characterized primarily by clinically manageable hematologic adverse events, is described. Expert opinion: Melflufen has potential to fill a gap in the myeloma treatment landscape by providing a new mechanism of action with clinically meaningful efficacy and a favorable safety profile in patients refractory to multiple novel agents. 1. Introduction mechanisms by exerting complementary antimyeloma effects [5,15]. Chemotherapy has historically been a mainstay of treat­ Multiple myeloma (MM), is a plasma cell neoplasia, characterized ment, but aside from melphalan as a conditioning agent prior to by an abnormal proliferation of aberrant plasma cells in the bone transplant or the use of alkylator-based regimens in older patients marrow and the production of a clonal immunoglobulin [1]. in certain regions, chemotherapy usage is decreasing based on the Median age at diagnosis is 69 years with a third of patients diag­ superiority of novel targeted agents [6,16]. Melphalan flufenamide nosed over the age of 75 years [2]. MM is associated with bone (melflufen) is a first-in-class peptide-drug conjugate (PDC) being lesions and fractures, infections, and end-organ damage [1,3]. evaluated in clinical trials in patients with relapsed/refractory MM Despite new treatment options that have improved outcomes (RRMM, Box 1) [17–20]. Agents such as melflufen with distinct for patients with MM, the disease remains incurable [4,5]. MOAs are needed to address growing unmet needs in RRMM. Approved and commonly used treatments for MM include immu­ nomodulatory drugs (IMiDs), proteasome inhibitors, alkylators, and monoclonal antibodies (mAbs) [6–10]. In addition, histone deace­ 1.1. Unmet needs in RRMM tylase inhibition using panobinostat in combination with bortezo­ In the last decade, combinations based on IMiDs, proteasome mib and dexamethasone as well as IMiDs confers meaningful inhibitors, anti-CD38 mAbs such as daratumumab, and anti- clinical benefit in the relapsed and refractory setting [11–13]. SLAMF7 mAbs such as elotuzumab have significantly Currently, patients who relapse after receiving prior IMiDs, protea­ improved outcomes and prolonged survival in patients with some inhibitors, anti-CD38 mAbs such as daratumumab, and anti- MM [21–25]. In the frontline setting, new combination strate­ signaling lymphocytic activation molecule F7 (SLAMF7) mAbs such gies with anti-CD38 mAbs have shown clinical benefit, includ­ as elotuzumab have limited treatment options [14]. The combina­ ing triplet and quadruplet regimens that contain IMiDs, tion of agents with distinct mechanisms of action (MOAs) has the proteasome inhibitors, and steroids to complement older potential to enhance efficacy and overcome resistance modalities of therapy and stem cell transplant [26,27]. While CONTACT Paul G. Richardson Paul_Richardson@dfci.harvard.edu Dana-Farber Cancer Institute, Boston, MA 02215, USA © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. 1070 A. ORIOL ET AL. reported in 2017, with a median OS of 13 months [31]. Among Article Highlights 249 patients in the MAMMOTH study who received therapy after ● Patients with multiple myeloma that are refractory to multiple agents becoming refractory to daratumumab or isatuximab, the overall with distinct mechanisms of action have limited treatment options, response rate (ORR) declined from 31% for the second line of face universally poor outcomes, and are in urgent need of novel treatment to 18% for the sixth [30]. This lack of efficacy high­ therapeutics. ● Melphalan flufenamide (melflufen) is a first-in-class peptide-drug lights the urgent need for additional therapies to treat patients conjugate (PDC) that targets aminopeptidases and rapidly releases with advanced RRMM. alkylating agents into tumor cells. ● Melflufen has demonstrated potent cytotoxic activity in vitro in multiple myeloma cells, including those with resistance to other 1.2. Therapies with new MOAs for RRMM treatments (e.g., immunomodulatory drugs, proteasome inhibitors, and alkylators), and induces irreversible DNA damage and apoptosis. Several novel drugs with new MOAs have been approved or ● Melflufen in combination with dexamethasone has demonstrated clinically meaningful efficacy in patients with heavily pretreated are in development for RRMM, including selective inhibitors of relapsed/refractory multiple myeloma, including in patients with nuclear export (selinexor), B-cell maturation antigen (BCMA)- triple-class–refractory disease and those with extramedullary disease. directed immunotherapies, and the PDC melflufen [23,32,33]. ● Melflufen has demonstrated a well-established safety profile with clinically manageable hematologic adverse events being most Selinexor is approved in the US in combination with dexa­ common. methasone to treat patients with RRMM who have received at least four prior therapies and who have disease that is refrac­ tory to at least two proteasome inhibitors, two IMiDs, and an anti-CD38 mAb [34,35]. Selinexor plus dexamethasone was evaluated in the Phase II STORM study in patients with RRMM and triple-class refractory disease [34]. In STORM, Box 1. Drug summary. patients (N = 122) had received a median of seven (range, Drug name (generic) Melphalan flufenamide (melflufen) 3–18) prior treatment regimens, 65 (53%) had high-risk cyto­ Phase (for indication under discussion) I, II, and III study genetics, including 32 (26%) with del(17p) [34]. In the primary Indication (specific to discussion) Multiple myeloma analysis, the ORR was 26% with a median progression-free Pharmacology description/mechanism of Peptide-drug conjugate action survival (PFS) and median OS of 3.7 months and 8.6 months, Route of administration 40 mg IV (on day 1 of each 28-day respectively [34]. Common grade ≥3 adverse events (AEs) with cycle) selinexor and dexamethasone were thrombocytopenia (59%), Chemical formula C24H30Cl2FN3O3 anemia (44%), fatigue (25%), hyponatremia (22%), and neutro­ Pivotal trial HORIZON [16] penia (21%). Among patients with grade ≥3 thrombocytope­ IV: intravenous. nia, grade ≥3 bleeding events were observed in 6 patients (5%) [34]. Idecabtagene vicleucel (bb2121; ide-cel), an investiga­ these combinations have potential to further improve patient tional autologous BCMA chimeric antigen receptor (CAR) outcomes, their use in frontline can result, at relapse, in T-cell therapy [36], was evaluated in a Phase I study (CRB- patients with disease that is refractory to several drugs with 401) in 33 patients with RRMM who had received at least different MOAs. Moreover, the choice of second-line treatment three prior therapies, including an IMiD, a proteasome inhi­ is largely dependent on prior therapy and prior response to bitor, or both, and in the expansion phase, patients had therapy, and a class switch is often prioritized [28,29]. prior daratumumab, and were refractory to their most MM is characterized by the emergence of therapy-resistant recent therapy [36]. The ORR was 85% and, with a median clones driven by selective pressure of treatment throughout the follow-up of 11.3 months (range, 6.2–22.8), the median PFS disease course [4,5,27]. Patients with RRMM with disease refrac­ was 11.8 months [36]. Common grade 3/4 AEs with ide-cel tory to multiple novel agents represent a population with high were anemia (45%/0%), leukopenia (18%/39%), thrombocy­ unmet medical need and limited effective treatment options as topenia (15%/30%), and neutropenia (6%/79%) [36]. Grade well as poor outcomes. In the retrospective MAMMOTH study, ≥3 cytokine release syndrome and neurotoxicity events 275 patients with RRMM refractory to an anti-CD38 mAb had were reported in 6% (n = 2) and 3% (n = 1) of patients received a median of four and a maximum of 16 lines of therapy treated with ide-cel, respectively, and no grade 4 cytokine [30]. Survival was dismal overall and for the subgroups of ‘not release syndrome was reported [36]. One death (cardiopul­ triple-refractory’ (refractory to 1 anti-CD38 mAb and not both of monary arrest) considered to be unrelated to treatment was a proteasome inhibitor and an IMiD), ‘triple- and quad- reported [36]. Results from the CRB-401 study suggest ide- refractory’ (refractory to 1 anti-CD38 mAb plus 1 proteasome cel is safe and yields high response rates in patients with inhibitor or IMiD plus 1 or 2 therapies of the other class), and RRMM with at least three prior therapies [36]. KArMMA, an ‘penta-refractory’ (refractory to 1 anti-CD38 mAb plus 2 protea­ ongoing, multicenter Phase II study of ide-cel, examining some inhibitors plus 2 IMiDs) patients. Median overall survival the efficacy and safety of a 150-to-450x106 dose of ide-cel, (OS) was 8.6 months for all patients, 11.2 months for patients has enrolled 128 patients with triple-exposed RRMM [37]. who were not triple-refractory, 9.2 months for those with triple- After a median follow up of 11.3 months, the study has met or quadruple-refractory disease, and 5.6 months for those with its primary endpoint, with an ORR of 73.4% [37]. The next- penta-refractory disease. Similarly, poor survival outcomes for generation anti-BCMA CAR T–cell therapy bb21217, which patients refractory to an IMiD and a proteasome inhibitor were adds a phosphoinositide 3-kinase inhibitor to enrich for EXPERT OPINION ON INVESTIGATIONAL DRUGS 1071 memory-like T cells, is currently in Phase I clinical stu­ belantamab mafodotin showed clinically meaningful activity dies [38]. consistent with that of previously reported data for the The anti-BCMA antibody-drug conjugate belantamab DREAMM-1 study. Despite higher-risk patients being more mafodotin (GSK857916) was evaluated in a two-arm, rando­ numerous in DREAMM-2 than in DREAMM-1, the AE profile mized, open-label, Phase II study in patients with RRMM who of DREAMM-2 was acceptable and no new safety signals had received three or more prior lines of therapy and who were identified [33,39]. were refractory to IMiDs, proteasome inhibitors, and refrac­ tory or intolerant (or both) to an anti-CD38 mAb (DREAMM-2) [33]. In DREAMM-2, 196 patients were randomized to receive 1.3. Emerging agents 2.5 mg/kg (n = 97) or 3.4 mg/kg (n = 99) doses of belanta­ mab mafodotin [33]. As of the 21 June 2019 data cutoff, ORR Bispecific antibodies are still in the earliest stages of develop­ was 31% and 34% in patients treated with the 2.5-mg/kg and ment, yet they have the potential to be a viable treatment 3.4-mg/kg dose of belantamab mafodotin, respectively. option for patients with RRMM. Clinical data have been Median PFS was 2.9 months and 4.9 months at the 2.5-mg/ reported for three BCMA:CD3 bispecific agents: AMG 420, kg and 3.4-mg/kg dose of belantamab mafodotin, respec­ CC-93269, and REGN5458 [40–42]. In a first-in-human study tively, and survival data were not mature at the data cutoff of AMG 420, among 42 patients who received 400 micro­ [33]. Common grade 3/4 AEs in the safety population receiv­ grams/day of AMG 420, the ORR was 70%, with only one ing the 2.5-mg/kg (n = 95) or 3.4-mg/kg (n = 99) dose of patient (2.4%) being treated for grade 3 cytokine release belantamab mafodotin, were keratopathy (27% and 21%), syndrome [43]. In a first-in-human study of CC-93269, 12 thrombocytopenia (20% and 33%), and anemia (20% and patients were treated with at least 6 mg of CC-93269 every 25%) [33]. Serious AEs (SAEs) occurred in 40% and 47% of week or biweekly which resulted in an ORR of 83.3% [44]. In patients treated at the 2.5-mg/kg and 3.4-mg/kg dose of this study, one of 19 patients (5.3%) died of cytokine release belantamab mafodotin, respectively, and two treatment- syndrome. A Phase 1 study of REGN5458 used a similar dosing related deaths were reported (1 with the 2.5-mg/kg dose regimen (6 mg every week/biweekly) in 4 patients, 75% of [due to sepsis] and 1 with the 3.4-mg/kg dose [due to whom responded [45]. No cases of grade ≥3 CRS were hemophagocytic lymphohistiocytosis]) [33]. In DREAMM-2, reported in seven patients. Figure 1. Clinical structure of melflufen hydrochloride and its metabolites melphalan and desethylmelflufen. Figure reproduced with permission from Schjesvold F, Robak P, Pour L, et al. Future Oncol. 2020;16(11):631–41 [32]. 1072 A. ORIOL ET AL. Figure 2. Melflufen mechanism of action. Melflufen targets aminopeptidases and rapidly releases alkylating agents into tumor cells. Peptidases are expressed in several types of cancer cells, including those of MM. Melflufen is rapidly taken up by mylema cells due to its high lipophilicity. Once inside the multiple myeloma cell, the activity of melflufen is dependent on its immediate hydrolysis by peptidases, which unleashes its more hydrophilic alkylator payloads that remain entrapped within the cell. 2. Melflufen 2.2. Overview of clinical trials 2.1. Mechanism of action 2.2.1. O-12-M1 Melflufen is a first-in-class peptide-drug conjugate (PDC) that O-12-M1 was a Phase I/II study to establish the dose and dosing targets aminopeptidases and rapidly releases alkylating agents schedule of melflufen in combination with dexamethasone and into tumor cells (Figure 1) [17,46]. Peptidases are expressed in to investigate initial treatment responses in patients with RRMM several types of cancer cells, including those of MM [47–49]. with disease refractory to the last line of therapy [18]. The Phase Melflufen is rapidly taken up by myeloma cells due to its high I portion of the study originally employed a 21-day cycle with no lipophilicity [17,46]. Once inside the myeloma cell, the activity dose-limiting toxicities occurring at the melflufen 40-mg dose of melflufen is dependent on its immediate hydrolysis by level. However, in the Phase II dose-expansion portion of the peptidases, which unleashes its more hydrophilic alkylator study, the cycle length was increased from 21 to 28 days, provid­ payloads that remain entrapped within the cell (Figure 2) ing additional time for recovery of the platelet and neutrophil [17,50,51]. Melflufen rapidly induces irreversible DNA damage counts, reducing the need for cycle delays and dose modifica­ and apoptosis via an alkylator-like, yet distinct mechanism of tions, and allowing patients to remain on treatment longer [18]. cytotoxicity that is independent of p53 function in MM cells Thus, O-12-M1 identified the maximum tolerated dose of mel­ [46,52,53]. Melflufen is 50-fold more potent than melphalan in flufen of 40 mg and the minimum acceptable cycle length of MM cells in vitro because the combined effects of its high 28 days in combination with dexamethasone as the recom­ lipophilicity and intracellular binding to aminopeptidases mended regimen for further evaluation in patients with RRMM results in increased intracellular alkylator exposure with mel­ [18]. Prior to the O-12-M1, a study of melflufen plus dexametha­ flufen (vs melphalan) [17,46,54]. Melflufen also has significant sone on patients with solid tumors demonstrated that the phar­ anti-myeloma activity, comparing favorably with melphalan macokinetic parameters of melflufen were not significantly in vivo with traditional xenografts [46] or genetically engi­ influenced by weight, thus, a fixed dosing schedule was used in neered transgenic models of the disease [55]. subsequent studies [56]. Table 1. Melflufen clinical trials summary table. Trial name No. of patients Key inclusion criteria Treatment(s) Efficacy 0–12-M1: Phase II study of melflufen + dexamethasone 45 RRMM Melflufen + dexamethasone Median follow-up: 27.9 mo in RRMM [18] ≥2 prior lines of therapy ORR: 31% Prior lenalidomide and bortezomib CBR: 49% Refractory to last line of therapy (relapsed ≤60 days mDOR: 8.4 mo after completing treatment) mPFS: 5.7 mo mOS: 20.7 mo HORIZON (OP-106): Pivotal phase II study of melflufen + 154 RRMM Melflufen + dexamethasone Follow-up (n = 125): ≥20 wks dexamethasone in RRMM refractory to pomalidomide anti-CD38 ≥2 prior lines, including an IMiD and a PI ORR: 29% mAb, or both [19] Refractory to pomalidomide, anti-CD38 mAb, or CBR: 44% both mDOR: 4.4 mo mPFS: 4.2 mo mOS: 11.6 mo ANCHOR (OP-104): Phase I/II study of melflufen + dexamethasone 33 RRMM Melflufen + dexamethasone + Median follow-up: 6.6 mo + bortezomib or daratumumab in RRMM [20] 1–4 prior lines of therapy daratumumab ORR: 76% Refractory (or intolerant) to IMiDs, PIs, or both CBR: 79% mPFS: 14.3 mo 6 RRMM Melflufen + dexamethasone + Median follow-up: 13.4 mo 1–4 prior lines of therapy bortezomib ORR: 67% Refractory (or intolerant) to IMiDs, PIs, or both CBR: 83% OCEAN (OP-103): Phase III study of melflufen + dexamethasone in ~450 RRMM Melflufen + dexamethasone vs – RRMM refractory to lenalidomide [32] 2–4 prior lines of therapy pomalidomide + Relapsed and refractory or refractory to last line of dexamethasone therapy Refractory to lenalidomide administered ≤18 mo prior to randomization LIGHTHOUSE [57] 170 RRMM Melflufen + daratumumab vs – (planned) Double refractory (or intolerant) to an IMiD and a PI daratumumab (2:1) or ≥3 prior lines of therapy including an IMiD and a PI CBR: clinical benefit rate; IMiD: immunomodulatory agent; mAb: monoclonal antibody; mDOR: median duration of response; mOS: median overall survival; mPFS: median progression-free survival; ORR: overall response rate; PI: proteasome inhibitor; RRMM: relapsed/refractory multiple myeloma. EXPERT OPINION ON INVESTIGATIONAL DRUGS 1073 1074 A. ORIOL ET AL. Table 2. Most common treatment-emergent AEs with melflufen and dexa­ 2–12) with 83% of patients having received prior alkylator methasone in O-12-M1 [18]. therapy; 32% had ISS stage III disease, 38% had high-risk Melflufen in combination with dexamethasone cytogenetics, 32% had extramedullary disease, 71% had triple- (n = 45) class refractory disease, and 69% had received ≥1 prior auto­ Adverse events, n (%) All grades Grade 3–4 Grade 5 logous stem cell transplant. Among 125 efficacy-evaluable Thrombocytopenia 33 (73) 28 (62) 0 (0) Neutropenia 31(69) 27 (60) 1 (2) patients, the ORR by investigator assessment was 29% (1 Anemia 29 (64) 20 (44) 0 (0) stringent complete response [CR], 12 VGPR, and 23 PR) and Pyrexia 18 (40) 2 (4) 0 (0) the CBR was 44% (Table 1) [19]. The median DOR was Asthenia 14 (31) 3 (7) 0 (0) Fatigue 13 (29) 2 (4) 0 (0) 4.4 months, median PFS was 4.2 months, and median OS Nausea 12 (27) 0 (0) 0 (0) was 11.6 months [19]. In patients with triple-class refractory Diarrhea 11 (24) 1 (2) 0 (0) disease and extramedullary disease, ORR was 24% and 24%, Pneumonia* 7 (16) 3 (7) 2 (4) median DOR was 7.5 and 5.1 months, median PFS was 4.0 and *There was one case each of a grade 3 and a grade 5 pneumonia overlapping with a grade 4 neutropenia. 3.0 months, and median OS was 11.3 and 8.1 months, respec­ tively. In the overall population (N = 154), 97% of patients experienced a treatment-emergent AE and 85% experienced In 45 patients treated in the Phase II portion of O-12-M1, a grade 3 or 4 treatment-emergent AE. The most common melflufen and dexamethasone demonstrated durable (≥20%) grade 3/4 treatment-emergent AEs were thrombocy­ responses with a manageable safety profile. Patients had topenia (21%/48%), neutropenia (31%/35%), and anemia received a median of four prior lines of therapy (interquartile (36%/1%) [19]. In addition, febrile neutropenia was also range, 3–5), 24 (53%) had received prior alkylator therapy, 30 observed (4%/1%), and the incidence of nonhematologic AEs (67%) were double-refractory (proteasome inhibitor and IMiD), was low [19]. As of the interim analysis data cutoff, five nine (20%) had International Staging System (ISS) stage III patients (3%) have died due to treatment-emergent AEs and disease, 20 (44%) had high-risk cytogenetics by fluorescence none of these deaths were treatment related [19]. These find­ in situ hybridization, and 26 (58%) had a prior autologous ings are highly encouraging because patients in whom lenali­ stem cell transplant [18]. ORR by investigator assessment was domide- and PI-based treatments have failed have limited 31%, including 5 patients who achieved very good partial remaining effective treatment options [28,30]. response (VGPR) and 9 who achieved partial response (PR), and the clinical benefit rate (CBR; ≥minimal response) was 2.2.3. ANCHOR 49% (Table 1) [18]. After a median follow-up of 27.9 months, ANCHOR (OP-104) is a Phase I/II study evaluating the safety the median duration of response (DOR) was 8.4 months, and and efficacy of melflufen and dexamethasone in triplet com­ median PFS and OS were 5.7 months and 20.7 months, respec­ binations in patients with RRMM [20]. Preliminary data from tively (Table 1) [18]. The most common AEs (all grades), ANCHOR showed activity of melflufen and dexamethasone regardless of relationship to study drug, included thrombocy­ with daratumumab or bortezomib. As of the data cutoff topenia (73%), neutropenia (69%), anemia (64%), pyrexia (8 October 2019), 33 patients had been treated with melflufen (40%), and asthenia (31%) (Table 2) [18]. Grade ≥3 AEs, regard­ (6 with a 30-mg dose; 27 with a 40-mg dose) in combination less of cause, occurred in 91% of patients, and melflufen- with daratumumab and dexamethasone, with a median treat­ related grade ≥3 AEs occurred in 58%. The most common ment duration of 6.2 months (range, 0.9–18.0) [20]. Patients melflufen-related grade 3/4 AEs were thrombocytopenia had a median of 2.5 (range, 1–3) and 2 (range, 1–4) prior lines (58%) and neutropenia (58%) [18]. Overall, seven bleeding of therapy in the 30-mg and 40-mg melflufen treatment events, all grade 1, were reported in association with grade 4 groups, respectively [20]. In addition, 83% and 89% of patients thrombocytopenia [18]. Treatment-emergent SAEs were had received prior alkylator therapy in the 30-mg and 40-mg reported in 38% of patients, with pneumonia being the most melflufen treatment groups, respectively. However, patients common (11%) and febrile neutropenia being observed in 4% must have been naïve to prior anti-CD38 mAb therapy [20]. of patients [18]. Overall, four deaths occurred in patients with The ORR (≥PR) was 76% (1 stringent CR, 11 VGPR, and 13 PR), rapidly progressing disease within 30 days of the last dose of the CBR was 79%, and median PFS was 14.3 months [20]. At melflufen, two of which (neutropenic sepsis and Escherichia data cutoff, six patients had been treated with melflufen (3 coli sepsis) were assessed as possibly treatment related. with 30 mg; 3 with 40 mg) plus dexamethasone and bortezo­ mib, with a median treatment duration of 9.3 months. Patients 2.2.2. HORIZON had a median of 2.5 prior lines of therapy (range, 2–4), and no HORIZON (OP-106) is a pivotal, single-arm, multicenter, Phase patient had achieved CR in any previous line [20]. Further, all II study evaluating the efficacy and safety of melflufen and patients had previously been exposed to a proteasome inhi­ dexamethasone in heavily pretreated and poor-risk patients bitor, but could not have been refractory to proteasome inhi­ with RRMM refractory to pomalidomide or an anti-CD38 mAb, bitors, and 5 patients had received prior alkylator therapy [20]. or both [19]. In an interim analysis of HORIZON, melflufen and ORR was 67%, and the CBR was 83% in these six patients, dexamethasone had efficacy and was generally safe and well including two patients each who achieved VGPR and PR [20]. tolerated in 154 patients with RRMM who had exhausted most No dose-limiting toxicities were observed at any of the eval­ salvage therapy options (data cutoff 1 October 2019) [19]. uated dose levels during dose-escalation with either daratu­ Patients had a median age of 64.5 years (range, 35–86) and mumab or bortezomib combinations. Among patients who had received a median of five prior lines of therapy (range, received melflufen 30 mg (n = 6) and 40 mg (n = 27) in the EXPERT OPINION ON INVESTIGATIONAL DRUGS 1075 daratumumab combination group, the most common grade a consequence, there is a growing need for novel agents 3/4 treatment-related AEs (≥2 patients) were neutropenia with alternative MOAs for patients with RRMM who are refrac­ (83%/56%), thrombocytopenia (50%/67%), and anemia (50%/ tory to IMiDs, proteasome inhibitors, and anti-CD38 mAbs. 7%) [20]. Six patients in this group experienced treatment- A major proportion of patients who do not enjoy related SAEs, including febrile neutropenia (n = 2), abdominal a prolonged response to frontline treatment are expected to pain, pancytopenia, pyrexia, respiratory failure, sepsis, and be triple-class refractory early in the course of disease, as upper respiratory tract infection (n = 1 each) [20]. In the six triplet or quadruplet combinations of effective agents are patients in the bortezomib combination group, grade 3/4 used both upfront and at first relapse. In contrast, the role of treatment-related AEs of thrombocytopenia (n = 5), neutrope­ alkylating agents in early MM is becoming relatively limited, nia (n = 3), anemia (n = 1), and pneumonia (n = 1) were except for the use of high dose melphalan in younger observed and one patient experienced treatment-related patients. The encouraging efficacy of melflufen and dexa­ SAEs (neutropenia and pneumonia) [20]. methasone in RRMM suggests this combination will provide an important option and translate successfully to real-world practice, strengthened by the convenience of a monthly infu­ 2.3. Safety and tolerability sion schedule [63]. Specifically, the activity of melflufen in the Patients with RRMM have depleted bone marrow reserves due triple-class refractory patient population is promising, given to the disease as well as side effects of prior therapy, and the otherwise poor prognosis in these patients. Melflufen as cytopenias are common [58]. Despite cytopenias being com­ a single agent appears to be not only effective in patients not mon with melflufen, particularly thrombocytopenia, they are exposed to alkylating agents but also to overcome prior che­ clinically manageable with a low incidence of bleeding events motherapy resistance. Its response rate in extramedullary dis­ [18]. However, it is important to vigilantly monitor cytopenias ease is of interest too, as extramedullary disease represents with melflufen and to provide appropriate management and a major issue in the context of aggressive MM progression. In supportive care for platelet count recovery including dose addition to its distinct MOA, melflufen has a manageable and reductions, growth factor support, and platelet transfusions a toxicity profile nonoverlapping with alternative agents. [59,60]. Despite working through an alkylator-dependent Although oral drugs are preferred options at early stages of mechanism, melflufen does not appear to cause alopecia the disease, gastrointestinal toxicity, mainly diarrhea and and incidence of mucositis is low, primarily grade 1/2 [18]. malabsorption, are present in a relevant proportion exposed to lenalidomide and pomalidomide. Patients with a prior his­ tory of gastrointestinal toxicity may not be ideal candidates for 2.4. Regulatory status selinexor therapy. Similarly, panobinostat may have a limited Melflufen is an investigational drug and has been granted role due to toxicity issues. Others may have limited options by orphan drug designation in the United States and Europe virtue of prior treatment-related toxicity such as peripheral [61]. The US Food and Drug Administration granted priority neuropathy, both features melflufen does not share. review to the New Drug Application for melflufen in combina­ Melflufen may also be more suitable than belantamab mafo­ tion with dexamethasone for the treatment of adult patients dotin and other investigational agents for a subset of patients with triple-class refractory MM, with a target date for review of given its otherwise limited nonhematologic toxicity, including the New Drug Application set for February 28, 2021 [62]. absence of alopecia and minimal mucositis as well as low rates of infection, an especially important consideration in the cur­ rent era. Its predictable hematologic toxicity and potency may 3. Conclusions further position melflufen as a preferred option for bridging To date, melflufen has demonstrated durable responses and therapy for other important emerging treatment strategies a manageable safety profile in patients with RRMM. such as CAR T-cell therapy. Moreover, significantly greater Treatment-related AEs associated with melflufen and dexa­ clinical activity is anticipated from the combination of melflu­ methasone are primarily hematologic, and rates of nonhema­ fen with proteasome inhibitors or mAbs in a less advanced tologic AEs are low. Based on the encouraging activity and setting, with preliminary data strongly supporting this [20]. acceptable safety profile of melflufen in RRMM, the rando­ Furthermore, if the efficacy and safety of melflufen in combi­ mized, head-to-head, superiority, open-label, global, Phase III nation with daratumumab is confirmed, melflufen could also OCEAN (OP-103) study is evaluating the efficacy and safety of be a potential partner for immunotherapeutic agents such as melflufen plus dexamethasone versus pomalidomide plus dex­ bispecific antibodies in the near future, providing an ideal amethasone in patients with RRMM who received two to four combination of drugs with high individual efficacy, MOAs prior therapies including lenalidomide within 18 months and not exhausted in previous treatment lines, and a potentially are refractory to the last line of therapy (Table 1) [32]. Top-line relatively favorable safety profile. results for OCEAN are expected in the first half of 2021 [32]. The remarkable progress observed in MM treatment may be able to provide a very prolonged disease-free period for a significant proportion of patients or even cure some of them. 4. Expert opinion However, it is expected that most individuals still relapsing will Current standards in the treatment of MM include combina­ present more aggressive and resistant disease. We need to tions of IMIDs, proteasome inhibitors, corticoids, and mAbs in increase our armamentarium to face the needs of such indivi­ frontline and early relapse treatment settings. As duals with drugs and combinations with alternative MOAs. 1076 A. ORIOL ET AL. Melflufen may become a preferred choice either in combina­ site, April 2019. https://seercancergov/statfacts/html/mulmyhtml tion with dexamethasone only or with third agents. Accessed Jan 28, 2020 3. Hussein MA. Multiple myeloma: most common end-organ damage and management. J Natl Compr Canc Netw. 2007;5(2):170–178. Acknowledgments 4. Keats JJ, Chesi M, Egan JB, et al. Clonal competition with alternating dominance in multiple myeloma. Blood. 2012;120(5):1067–1076. The authors received medical writing support from Jennifer Leslie PhD, 5. Robak P, Drozdz I, Szemraj J, et al. Drug resistance in multiple Team 9 Science. myeloma. Cancer Treat Rev. 2018;70:199–208. 6. Moreau P, San Miguel J, Sonneveld P, et al. Multiple myeloma: ESMO clinical practice guidelines for diagnosis, treatment and Funding follow-up. Ann Oncol. 2017;28(suppl_4):iv52–iv61. 7. Moreau P, Mateos MV, Berenson JR, et al. Once weekly versus twice This paper was funded by Oncopeptides, Sweden which is the company weekly carfilzomib dosing in patients with relapsed and refractory that is developing melflufen. multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study. Lancet Oncol. 2018;19(7):953–964. 8. Dimopoulos MA, Dytfeld D, Grosicki S, et al. Elotuzumab plus Declaration of interest pomalidomide and dexamethasone for multiple myeloma. N Engl J Med. 2018;379(19):1811–1822. A Oriol has consultancy/advisory roles with Amgen, Janssen, Takeda, and 9. Facon T, Kumar S, Plesner T, et al. Daratumumab plus lenalidomide Celgene; A Larocca has received honoraria from Amgen, Bristol-Myers and dexamethasone for untreated myeloma. N Engl J Med. Squib, Celgene, and Janssen-Cilag; X Leleu; has received honoraria from 2019;380(22):2104–2115. AbbVie, Amgen, Carsgen, Celgene, Gilead, Janssen, Karyopharm, 10. Mateos MV, Dimopoulos MA, Cavo M, et al. Daratumumab plus Mundipharma, Novartis, Oncopeptides, and Takeda; R Hajek has received bortezomib, melphalan, and prednisone for untreated myeloma. honoraria and has sconsultancy/advisory roles with Takeda, Amgen, N Engl J Med. 2018;378(6):518–528. Celgene, Janssen, and Bristol-Myers Squib and research funding from 11. San-Miguel JF, Hungria VT, Yoon SS, et al. Panobinostat plus bor­ Takeda, Amgen, Janssen, and Novartis; H Hassoun has Consultancy/advi­ tezomib and dexamethasone versus placebo plus bortezomib and sory roles with Novartis and receives research funding from Celgene and dexamethasone in patients with relapsed or relapsed and refrac­ Janssen; PR Otero received honoraria from Celgene, Janssen, Amgen, and tory multiple myeloma: a multicentre, randomised, double-blind Bristol-Myers Squib and consultancy/advisory roles with Celgene, Janssen, phase 3 trial. Lancet Oncol. 2014;15(11):1195–1206. Kite Pharma, Sanofi, Abbvie, Oncopeptides, GSK, and Takeda; A Paner 12. Richardson PG, Hungria VT, Yoon SS, et al. Panobinostat plus received honoraria from Amgen and Celgene and has consultancy/advisory bortezomib and dexamethasone in previously treated multiple roles with AbbVie, Cellectar, and Takeda; FH Schjesvold received honoraria myeloma: outcomes by prior treatment. Blood. 2016;127 from Amgen, Celgene, Takeda, Janssen, Novartis, and SkyliteDx and has (6):713–721. consultancy/advisory roles with Amgen, Celgene, Takeda, Janssen, 13. Popat R, Brown SR, Flanagan L, et al. Bortezomib, thalidomide, Oncopeptides, and MSD; J Gullbo is co-founder and is a minor shareholder dexamethasone, and panobinostat for patients with relapsed mul­ of Oncopeptides and has consultancy/advisory roles with Oncopeptides; PG tiple myeloma (MUK-six): a multicentre, open-label, phase 1/2 trial. Richardson has received a grant from Bristol-Myers Squib and grants and Lancet Haematol. 2016;3(12):e572–e580. honoraria (advisory committee member) from Oncopeptides, Celgene, 14. Oriol A, Abril L, Ibarra G, et al. Limited treatment options in refrac­ Takeda, and Karyopharm; and honoraria (advisory committee member) tory multiple myeloma: promising therapeutic developments. from Janssen, Sanofi, and SecuraBio. 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