Результаты лечения мелфлюфена у пациентов с повторной/отправленной миеломой.

Introduction

Multiple myeloma (MM) is a hematologic cancer that is characterized by the proliferation of monoclonal plasma cells into the bone marrow. In the last two decades, median overall survival (OS) in MM has improved from 3 years to approximately 8–10 years because of continued and numerous developments in MM treatment [ 1 ]. Mainstays of therapy such as immunomodulatory agents, proteasome inhibitors, and monoclonal antibodies, selinexor, belantamab mafodotin, chimeric antigen receptor (CAR) T cells, and bispecific antibodies have significantly improved patient outcomes [ 2 , 3 ]. Despite these advances and success in combining various classes of drugs, most patients eventually relapse and/or develop resistance to standard‐of‐care treatments as well as to newer immune therapies [ 4 , 5 , 6 , 7 ]. Further, MM is associated with immune exhaustion due to tumor burden and constant immune activation resulting from chronic disease, age, nutritional status, infection, and the impact of some MM treatments such as high‐dose chemotherapy, steroids, and proteasome inhibitors. Many current therapies, such as bispecific T‐cell engagers, anti‐CD38 antibodies, proteasome inhibitors, and CAR T cells, depend on the anti‐cancer activity of T cells [ 8 ]. Thus, there remains an urgent unmet need for effective and readily available treatment options with a different mechanism of action that are independent of immune exhaustion, especially for older and/or frailer patients who are ineligible for more intensive treatments and may be challenged by immune exhaustion [ 9 , 10 , 11 , 12 ].

Melphalan flufenamide (melflufen) is a first‐in‐class peptide‐drug conjugate targeting tumor cells through a unique mechanism of action. Melflufen readily crosses cell membranes due to its high lipophilicity and rapidly delivers an alkylating payload selectively to myeloma cells [ 13 , 14 ]. Once inside myeloma cells, melflufen is immediately cleaved by peptidases into hydrophilic alkylator payloads, melphalan and desethyl‐melflufen, which are cytotoxic agents that remain entrapped within myeloma cells [ 13 , 15 ]. In vitro, melflufen is 50‐fold more potent than melphalan in myeloma cells due to increased intracellular alkylator concentration [ 16 ]. Melflufen rapidly induces irreversible DNA damage, leading to apoptosis of myeloma cells and exhibiting cytotoxic activity against myeloma cell lines resistant to other treatments, including alkylators [ 17 ]. In preclinical studies, melflufen has also demonstrated inhibition of angiogenesis and DNA damage with a lack of functional DNA repair and can thus overcome resistance to both traditional chemotherapeutics and novel agents clinically, as well as show activity in high‐risk 17p deleted MM [ 12 , 13 , 16 , 17 , 18 , 19 ].

In March 2021, the clinical benefit of melflufen and dexamethasone observed in the Phase 2 HORIZON study (with an overall response rate [ORR] of 29% and a median OS of 11.6 months) [ 20 ] led to an accelerated approval of this combination by the United States Food and Drug Administration (FDA). The FDA subsequently withdrew approval of melflufen and dexamethasone on September 22, 2022, based on the results of the randomized, Phase 3 OCEAN study, which demonstrated a significant progression‐free survival (PFS) advantage associated with the combination for patients with 2–4 prior lines of therapy but a trend toward reduced OS [ 21 ]. The initial OS hazard ratio (HR) was 1.10, which, on subsequent analysis after longer follow‐up, improved to 1.09, with no safety signals identified [ 21 , 22 ]. Nevertheless, the combination is now fully approved in Europe for the treatment of adult patients with relapsed/refractory (RR)MM who have received ≥ 3 prior lines of therapy and whose disease is refractory to ≥ 1 proteasome inhibitor, ≥ 1 immunomodulatory agent, and one anti‐CD38 monoclonal antibody and have demonstrated disease progression on or after the last therapy [ 23 ]. Based upon subgroup analyses in older patients and in those with a time to progression of 3 years or longer after high‐dose melphalan and autologous stem cell transplant (ASCT) in the HORIZON and OCEAN studies, melflufen is approved to be used if the time from transplantation to when the cancer comes back is at least 3 years [ 20 , 21 ].

With the approval of the combination of melflufen and dexamethasone in Europe and considering that clinical trials restrict patient selection and may not fully reflect the patient population treated in clinical practice, it is important to assess the efficacy and safety of this combination in the real‐world RRMM setting. Therefore, we examined baseline features, as well as efficacy and safety outcomes, in patients with RRMM treated with melflufen plus dexamethasone as a standard therapy in the real‐world setting at the Dana‐Farber Cancer Institute, USA, prior to the withdrawal of FDA approval.

Materials and Methods

This retrospective analysis included all patients treated with at least one dose of melflufen combined with dexamethasone at the Dana‐Farber Cancer Institute between May 1, 2021 and February 1, 2022, who had MM that was refractory to (or who were unable to tolerate) at least one immunomodulatory drug, proteasome inhibitor, and anti‐CD38 antibody (triple‐class refractory). Patients enrolled in clinical trials were excluded. The study was approved by the Dana‐Farber Institutional Review Board. Patients were treated with once‐monthly melflufen 40 mg by central intravenous infusion over 30 min on Day 1 of each 28‐day cycle and oral dexamethasone 40 mg once weekly on Days 1, 8, 15, and 22 of each cycle, if the absolute neutrophil count was ≥ 1000/μL and platelet counts were ≥ 50,000/μL. If criteria to treat were not met, melflufen treatment could still be administered based on provider discretion and with supportive care. Data extracted from medical records included baseline patient and disease characteristics and prior treatments, as well as melflufen/dexamethasone dose intensity, responses, adverse events (AEs), and supportive care or growth factor use. Responses were assessed using the International Myeloma Working Group (IMWG) uniform response criteria [ 24 ]. Efficacy analyses included estimation of: (1) the ORR, defined as the proportion of patients achieving a stringent complete response + complete response (CR) + very good partial response (VGPR) + partial response (PR) per the IMWG uniform response criteria, (2) best response, defined as the deepest response achieved while on therapy or observation without the administration of additional therapies, (3) time to response (TTR), defined as the time from the first dose of melflufen received by the patient to the first response (PR or better) achieved, (4) time to treatment failure (TTF), defined as the time from the first dose of melflufen received by the patient to the time of the first dose of the next therapy or progressive disease, whichever was first, and (5) duration of response, calculated as TTF minus TTR. Treatment‐emergent AEs were collected as worst‐grade AEs occurring through the treatment period (i.e., recorded from Day 1 of Cycle 1 (C1D1) to 30 days after the last dose of melflufen or until initiation of new therapy).

Results

Patient Baseline Characteristics

The baseline characteristics are summarized in Table 1 and Table 4 . Twelve patients were included in the analysis, seven (58%) of whom were female. In patients with available Revised International Staging System scores, two (17%) and three (25%) were Stages I and II, respectively. Three patients (25%) were known to be high‐risk cytogenetically (17p deletion [ n = 1], 1q gain [ n = 1], and t [14;16; n = 1] as seen with fluorescence in situ hybridization). Three patients (25%) had extramedullary disease. The median time from diagnosis was 10.8 years, and patients had received a median of 5.5 prior lines of therapy. All patients had received prior lenalidomide, bortezomib, and daratumumab. Five (42%) had received an ASCT at a median of 10 years prior to melflufen administration. Additional prior therapies included pomalidomide (92%) and carfilzomib (75%) (Table 1 ).

The median number of melflufen doses received was three (range, 1–7), and the mean dose intensity was 89% (standard deviation, 12%). Reasons for melflufen discontinuation were progressive disease (five patients [42%]), market withdrawal of melflufen (four patients [33%]), AEs (two patients [17%]), and death (one patient [8%], due to cardiac arrest, considered unrelated to treatment by the treating physician, in a patient with a known history of significant cardiac disease).

Efficacy Data

Data for individual patients are presented in Table 2 . One patient (Patient 9) was not evaluable for response; therefore, the efficacy‐evaluable population consisted of 11 patients with a median follow‐up time of 218.5 days (range, 55–390). Six of the 11 efficacy‐evaluable patients (55%) responded to treatment, with three patients achieving CR (27%), one (9%) achieving VGPR, and two patients (18%) with PR as the best response. Five patients (45%) had stable disease as the best response. One patient (Patient 5) received two doses of melflufen but experienced hematologic toxicities that led to the discontinuation of treatment. The patient then went on to receive two doses of belantamab mafodotin but experienced ocular toxicities, prompting the re‐initiation of treatment with melflufen for an additional three doses. Thus, this patient received melflufen twice and had a response of SD at both response assessments (and was therefore only counted once during response assessment).

The median time to response in our study was 9.4 weeks (range, 4.0–18.9) and the median duration of response was 21.3 weeks (range, 4.7–33.0). Median TTF was 29.7 weeks (range, 4.4–53.7). Overall, 10 patients received a subsequent line of therapy. The most common subsequent therapies were belantamab mafodotin (four patients [36%]) and cyclophosphamide (four patients [36%]; Table 2 ). Among the eight patients for whom subsequent‐line TTF data were available, the median TTF for the next therapy was 7.6 weeks (range, 1.1–54.1).

Safety Data

None of the patients had mucositis, alopecia, or secondary malignancies. Two patients (17%) had documented infections, specifically, enterococcus sepsis associated with a pyelonephritis after an ablative procedure for left renal cell carcinoma in one patient and possible cellulitis in another patient. The pyelonephritis was determined to be associated with surgery, whereas the cellulitis was deemed possibly related to treatment, specifically, dexamethasone. Both patients were treated successfully with antibiotics. There were four hospitalizations (involving three patients); two were related to MM, one was related to a hematoma, and one was related to atrial fibrillation and shortness of breath in a patient with pre‐existing cardiac disease. The majority of AEs were otherwise hematologic in nature (Table 3 ), with the most common hematologic AEs being anemia (Grade 1/2: six patients [50%]; Grade 3: six patients [50%]), thrombocytopenia (Grade 1/2: four patients [33%]; Grade 3/4: eight patients [67%]), and neutropenia (Grade 1/2: three patients [25%]; Grade 3: six patients [50%]). Gastrointestinal AEs included Grade 1 or 2 nausea treated using ondansetron, prochlorperazine, or both (depending on provider/patient preference); no patients experienced Grade 3 nausea, and there was no mucositis seen. Also of note, no alopecia was reported, and to date, no secondary malignancy has been seen.

After study initiation, nine (75%) patients received supportive care for hematologic parameters throughout the course of their treatment. Three (25%) patients were treated with erythropoietin growth factors, two (17%) with romiplostim, and eight (67%) patients received granulocyte colony‐stimulating factors. Seven (58%) patients received blood transfusions, and three (25%) received platelet transfusions.

Discussion

Melflufen plus dexamethasone showed meaningful efficacy in patients with triple‐class refractory MM in this retrospective real‐world study, with an ORR of 55% and CR achieved in 27%. The median duration of response was 21.3 weeks, and, of note, median TTF was 29.7 weeks.

Reporting real‐world evidence from an approved therapy used as a standard therapy provides important insights on tolerability and effectiveness of a given treatment regimen that complement data derived from prospective trials [ 25 ]. In large part, this is necessary because patients who receive approved therapies in the real‐world setting are more heterogeneous than those treated as part of clinical trials, which have strict eligibility criteria that select participants with robust organ function and performance status [ 25 ].

For context, patients with triple‐class refractory MM in this real‐world analysis, albeit a small population ( N = 12), were older (median 73.5 and 65 years) and had been living with myeloma for a longer period of time (median 10.8 and 6.2 years) relative to patients with triple‐class refractory MM in the HORIZON study ( N = 119; Table 4 ). Both populations were heavily pretreated (5.5 and 5.0 prior therapies in this study and HORIZON, respectively), and a larger proportion of HORIZON patients had undergone prior ASCT (68% vs. 41.7%). The majority of patients in HORIZON were male (59%), whereas a higher percentage were female in this real‐world study (58%). Extramedullary disease (42% vs. 25%) and high‐risk cytogenetics (34% vs. 25%) were more common in the HORIZON triple‐class refractory population [ 20 ].

Encouragingly, response rates in our experience with real‐world use of melflufen and dexamethasone were favorable, as six patients (55% of those evaluable; 50% intent‐to‐treat [ITT]) achieved PR or better, including three (27% evaluable; 25% ITT) with CR. In the HORIZON triple‐class refractory ITT population ( N = 119) there were no CRs, and the ORR was 26% [ 20 ].

Hematologic toxicities are common in patients with RRMM due to disease‐induced reduced marrow reserve as well as side effects of prior and current therapies [ 27 ]. Anemia, thrombocytopenia, and neutropenia are the principal AEs associated with melflufen [ 23 ]. In the overall HORIZON population ( N = 157), approximately 65% of patients received concomitant RBC or platelet transfusions, and 68% received concomitant growth factor support [ 20 ].

In our experience with real‐world administration of melflufen and dexamethasone, patients received intermittent transfusion support. Seven patients received blood transfusions throughout their treatment, and three of these patients received platelet transfusions. Eight patients (67%) received colony‐stimulating factors, with three patients on them prior to melflufen initiation. In addition, three patients received an erythropoiesis‐stimulating agent, and two patients received romiplostim. Consistent with clinical trials, the safety profile in our analysis was primarily characterized by hematologic toxicities that were effectively monitored and managed accordingly. Monitoring for cytopenias and providing appropriate management and supportive care, including growth factor support, platelet transfusions, and the use of romiplostim, may mitigate safety concerns with melflufen. Dose modifications of melflufen may be needed in case of sustained hematologic toxicities despite supportive care.

Notably, our patients treated in the real‐world setting and in the HORIZON trial were heavily pretreated (5.5 and 5.0 prior therapies, respectively); however, a larger proportion of patients treated in HORIZON had undergone prior ASCT (68% vs. 42%). Furthermore, because this analysis was conducted in a real‐world setting, we had the option of increasing the treatment interval between doses as opposed to dose reduction, with some patients initiating therapy with reduced doses on Cycle 1, Day 1, recognizing that both doses used (30 and 40 mg) were proven to be active as described in the European label for melflufen [ 23 ]. Another confounding factor in our series may be that patients were co‐managed with collaborative sites and received supportive care in accordance with institutional standards, with some variances in standards of care.

Current guidance for patients with a previous ASCT is that the time to progression should be > 36 months from transplantation before initiating melflufen treatment. Specifically, the OCEAN study demonstrated that the combination of melflufen and dexamethasone resulted in superior PFS (HR 0.79, 95% confidence interval [CI]: 0.64–0.98; log‐rank p = 0.032), but not OS (HR 1.10, 95% CI: 0.85–1.44; log‐rank p = 0.47) compared with pomalidomide and dexamethasone in lenalidomide‐refractory RRMM patients with 2–4 lines of previous therapy [ 21 ]. Post hoc analyses of OCEAN and HORIZON demonstrated that a time to progression < 36 months after prior ASCT was a negative prognostic factor for OS for the combination of melflufen and dexamethasone, likely due to both resistance to high‐dose alkylation as well as increased vulnerability to myelosuppression [ 28 ]. Interestingly, 50% of the patients in this real‐world study had received prior cyclophosphamide, and the overall responses seen are consistent with the results of the subgroup analysis of the O‐12‐M1 study, where similar activity was seen in such patients [ 29 , 30 ].

In conclusion, this experience with real‐world use of melflufen and dexamethasone as a standard therapy confirmed a significant level of antitumor activity based on ORR, depth of response, and duration of response. Within the limitation of the small sample size and retrospective nature of the current study, melflufen had an expected and manageable safety profile and was otherwise generally well tolerated, with the primary toxicities being hematologic in nature, requiring supportive care with growth factor and transfusion support. Of note, there were no instances of mucositis, alopecia, or secondary malignancies. These are consistent with observations first made in the early phase studies of melflufen in RRMM and supported thereafter in several subsequent trials [ 20 , 21 , 29 , 30 ]. In aggregate, the data provide additional support for the use of this novel, first‐in‐class, peptide‐drug conjugate in the management of RRMM, including high‐risk cytogenetics, and also support the rationale for additional combination approaches; for example, in the recently reported ANCHOR and LIGHTHOUSE studies, promising results were seen using either bortezomib or daratumumab in combination with melflufen and dexamethasone for the treatment of relapsed and refractory disease [ 31 , 32 ].

Author Contributions

S.H., P.G.R., and J.P.L. contributed to study conception and design. S.H. contributed to data collection. S.H., P.G.R., and J.P.L. contributed to data analysis and interpretation. All authors were involved in the drafting of the manuscript and approved the final article.

Ethics Statement

The study was approved by the Dana‐Farber Institutional Review Board.

Consent

The authors have nothing to report.

Conflicts of Interest

S.H. reports participation on an advisory board for Janssen, Sanofi, and Pfizer. C.M. reports participation on advisory boards for AbbVie, BMS, GSK, Janssen, Karyopharm, Sanofi, and Takeda, and consulting for AbbVie, Janssen, Karyopharm, and Sanofi. P.G.R. reports participation on advisory boards and/or consulting for Astra Zeneca, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Karyopharm, Oncopeptides, Regeneron, and Sanofi, and receiving research grants from Bristol Myers Squibb/Celgene, and Oncopeptides. S.P., H.L., K.G., E.R., K.O., K.N., and J.L. have nothing to disclose.

Acknowledgements

We thank Jayasri Srinivasan, MD, MBA, and Ashly Pavlovsky, PhD, of Team 9 Science for providing medical writing assistance under the guidance of the authors, which was funded by Dana Farber Cancer Institute, in part supported by the RJ Corman Multiple Myeloma Research Fund and an unrestricted grant from Oncopeptides AB.

Funding: This work was supported by the Dana‐Farber Cancer Institute, in part supported by the RJ Corman Multiple Myeloma Research Fund and an unrestricted grant from Oncopeptides AB.

Paul G. Richardson and Jacob Laubach are co‐senior authors.

Data Availability Statement

The data generated in this study are not publicly available because they could compromise patient privacy, but they are available upon reasonable request from the corresponding author.

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Associated Data

Data Availability Statement

The data generated in this study are not publicly available because they could compromise patient privacy, but they are available upon reasonable request from the corresponding author.