Оптимизация использования мелфлюфена (melphalan flufenamide) в реанимированных или рефрактных миеломах: рекомендации для клинической практики.

Introduction

Melphalan flufenamide, also called melflufen, is approved in combination with dexamethasone for the treatment of adult patients with MM who have received at least three prior lines of therapies, whose disease is refractory to at least one proteasome inhibitor (PI), one immunomodulatory agent (IMiD), and one anti-CD38 monoclonal antibody (anti-CD38 mAb), and who have demonstrated disease progression on or after the last therapy. For patients with a prior autologous stem cell transplantation (ASCT), the time to progression (TTP) should be at least three years from transplantation [ 1 ].

The Food and Drug Administration (FDA) granted accelerated approval for melflufen in February 2021 for RRMM but requested a partial clinical hold in July 2021. In February 2024, the FDA withdrew the accelerated approval because it did not recognize clinically relevant differences among patient subgroups in the randomized, phase 3 OCEAN trial (melflufen/dexamethasone versus pomalidomide/dexamethasone) [ 2 ]. In contrast, the European Medicine Agency (EMA) determined that the confirmatory OCEAN trial met its primary endpoint by demonstrating superior PFS and concluded that the potential negative impact on OS was limited to patients progressing within less than 36 months after ASCT. Consequently, the European Commission granted melflufen full marketing authorization in August 2022.

The early availability of melflufen in Germany and Austria, outside of clinical trials, has allowed experts in these countries to gain practical experience. For this reason, in May 2024 a group of myeloma specialists and clinicians with experience in the use of melflufen met to discuss the practical management of melflufen in patients with MM. The recommendations presented here are based on the clinical data derived from the current literature, the European public assessment report (EPAR) published by the EMA and the clinical experience of the panel members in the practical use of melflufen. The recommendations focus on the current approved EMA label of the drug.

Mechanism of action

Melflufen is a first-in-class peptide-drug conjugate approved for the therapy of MM [ 1 , 3 ]. It consists of a melphalan molecule conjugated to p-L fluoro-phenylalanin ethylester by a peptide bond, making it highly lipophilic and enabling it to passively cross cell membranes (Fig. 1 ) [ 4 ]. Inside the cell, melflufen is rapidly hydrolysed by peptidases and esterases, which are overexpressed in tumour cells. This releases the hydrophilic alkylators melphalan and desethyl-melflufen and creates a concentration gradient that further drives melflufen into the cells [ 4 – 9 ]. The hydrophilic nature of these metabolites diminishes their diffusion out of the cells, resulting in accumulation of cytotoxic agents and ultimately causes DNA damage and apoptosis [ 7 , 10 , 11 ]. Melflufen has shown higher cytotoxic activity against tumour cells than other alkylators and overcomes p53 deficiency-mediated resistance in myeloma cell lines [ 12 ].

Melflufen in clinical trials

Melflufen has been evaluated in seven clinical trials for multiple myeloma and is currently being studied in two ongoing non-interventional studies (overview in Fig. 4 APPENDIX). In the phase 1/2 trial O-12-M1, the recommended starting dose of 40 mg melflufen in combination with weekly dexamethasone (40 mg or 20 mg if ≥ 75 years) and optimal dosing schedule of a 28-day cycle for melflufen were established [ 13 ].

The pivotal single-arm phase 2 HORIZON trial (OP-106) [ 14 ] and the confirmatory phase 3 OCEAN trial (OP-103) [ 15 ], a head-to-head study of melflufen plus dexamethasone versus pomalidomide plus dexamethasone, evaluated the efficacy and safety of melflufen in patients with RRMM.

The HORIZON trial included 157 patients who had received at least two prior lines of therapy, including an IMiD and a PI, and were refractory to pomalidomide and/or an anti-CD38 mAb. At baseline, patients had a median age of 65 years (range, 35–86) and had received a median of five prior lines of therapy (range, 2–12); 25% had ISS stage III disease, 38% had high-risk cytogenetics, 35% had extramedullary disease (EMD), and 76% had triple-class–refractory disease.

The overall response rate (ORR) was 29% (95% CI, 22–37), with a median duration of response (DOR) of 5.5 months (95% CI, 3.9–7.6), a median progression-free survival (PFS) of 4.2 months (95% CI, 3.4–4.9) and a median overall survival (OS) was 11.6 months (95% CI, 9.3–15.4) [ 14 ]. For the triple-class refractory patients ( n = 119), ORR was 26% (95% CI, 18–35), DOR was 4.4 months (95% CI, 3.4–7.6) and PFS 3.9 months (95% CI, 3.0–4.6.0.6). OS in this difficult to treat population was 11.2 months (95% CI, 7.7–13.2) [ 16 ].

The OCEAN trial included 495 patients with MM who had progressed after 2–4 previous treatment lines and who were refractory to both lenalidomide and their last treatment line. The median age was 68 years in both treatment arms. Patients had received a median of three prior lines of therapy. 51% of patients in the melflufen arm and 48% in the pomalidomide arm had undergone a previous ASCT [ 15 ].

The primary endpoint of superior PFS for the melflufen arm over the pomalidomide arm was met; median PFS of 6.8 months in the melflufen arm compared to 4.9 months in the pomalidomide arm (HR 0.79; [95% CI: 0.64–0.98] p = 0.032). The ORR was 33% (95% CI: 27–39) in the melflufen arm compared to 27% (95% CI: 22–33) in the pomalidomide arm. The median OS, although not statistically significant, was longer in the pomalidomide arm (25.0 months) compared to melflufen arm (19.8 months) (HR: 1.10; [95% CI: 0.85–1.44] p = 0.47) [ 15 , 17 ].

The discrepancy between the PFS and OS results prompted further exploratory analyses to explore any signals for pre-specified subgroups (e.g. by age, ASCT, gender, creatinine clearance) [ 15 , 18 ]. PFS data favoured melflufen in most subgroups, including patients aged ≥ 75 years (HR: 0.43; [95% CI: 0.24–0.76]; p = 0.0031) and patients without prior ASCT (HR: 0.59 [0.44–0.79]; p = 0.0004) whereas OS data favoured pomalidomide in patients younger than 65 years (HR: 1.68; [95% CI: 1.13–2.49]; p = 0.01) and patients with a previous ASCT (HR 1.53; [95% CI: 1.11–2.11]; p = 0.0088). A post-hoc analyses showed that patients in the melflufen arm who had not received a previous ASCT or have had a TTP of at least 36 months after an ASCT, had a significantly increased PFS of 9.3 months compared to 4.6 months in the pomalidomide arm (HR: 0.58; [95% CI: 0.44–0.76]; p = 0.0001, Fig. 2 A) and numerically higher OS of 23.6 months compared to 19.8 months (HR: 0.83; [95% CI: 0.62–1.12]; p = 0.22, Fig. 2 B) [ 19 ].

Two trials have investigated melflufen in triplet combinations. The ANCHOR phase 1/2 trial evaluated melflufen and dexamethasone with either daratumumab or bortezomib [ 21 ]. The LIGHTHOUSE phase 3 trial compared melflufen-daratumumab-dexamethasone to single-agent daratumumab in patients with RRMM who were double refractory to an IMiD and a PI [ 22 ]. Both trials were prematurely terminated due to financial reasons.

The safety profile of melflufen plus dexamethasone has been consistent and manageable across all clinical trials, with haematological adverse events being the most frequent [ 1 , 23 ].

Administration of melflufen

Dosing and administration

The recommended starting dose of melflufen is 40 mg intravenously on day 1 of each 28-day treatment cycle in combination with dexamethasone. For patients with a body weight of 60 kg or less the recommended starting dose is 30 mg on day 1 of each 28-day cycle. The recommended dose of dexamethasone is 40 mg orally on days 1, 8, 15 and 22 of each 28-day treatment cycle; for patients 75 years of age and older the recommended dose of dexamethasone is 20 mg [ 1 ].

Melflufen is administered as a 30-minute infusion via peripheral or central venous route. The peripheral route was investigated in PORT (OP-109), a cross-over study of peripheral and central venous catheter administration. No phlebitis or local infusion-related reactions or extravasations were observed [ 24 ]. If melflufen is administered peripherally, it is recommended to alternate veins for infusion [ 1 ].

In patients with an estimated glomerular filtration rate (eGFR) greater than 45 mL/min/1.73 m 2 no dose adjustment is required. A dose reduction to 30 mg is recommended in patients with eGFR between 30 and 45 mL/min/1.73 m 2 . There is not sufficient data available to make a dose recommendation for patients with an eGFR below 30 mL/min/1.73 m 2 [ 1 ].

No dose adjustment of melflufen is required for patients with mild hepatic impairment. There is insufficient data in patients with moderate or severe hepatic impairment to support a dose recommendation [ 1 ].

Authors’ perspective

The optimal starting dose for most patients is 40 mg intravenously every 28 days in combination with dexamethasone.

The administration via a peripheral venous route has become a routine procedure.

It is recommended that treatment should be continued until disease progression or unacceptable toxicity.

Cautioun is recommended when using melflufen in patients with severely impaired haematopoietic capacity due to previous therapy or comorbidity but not due to MM, as well as in patients with severe renal or hepatic insufficiency.

In patients with CNS involvement, data from clinical trials is not available.

Combination with other drugs

Drug interaction studies have not been conducted with melflufen. Based on available in vitro and clinical data there is a low risk of pharmacokinetic or pharmacodynamic drug interactions [ 1 ].

Treatment duration

Treatment with melflufen should be continued until disease progression or unacceptable toxicity. In the targeted safety population of 422 patients who received 40 mg of melflufen every 28 days across different studies (O-12-M1, HORIZON, OCEAN, ANCHOR, BRIDGE), the median duration of treatment was 17.9 weeks (range: 4–117) and the median number of completed treatment cycles was 3.0 (range: 0–28). Overall, 144/422 (34.1%) of patients stayed on melflufen for at least 6 months and 46/422 (10.9%) for at least 12 months [ 18 ].

Authors’ perspective

In their practice the experts see that about 30–40% of patients achieve clinical benefit from melflufen treatment and often tolerate longer treatment durations.

Clinical experience shows that responders and non-responders can be differentiated within a short period of time by IMWG response criteria.

It is recommended that treatment should be continued until disease progression or unacceptable toxicity.

Management of Adverse Events

Overview

Melflufen is associated with a safety profile that is characterized by hematologic toxicity, particularly thrombocytopenia, neutropenia, and anaemia. In a safety population of 491 patients who received melflufen and dexamethasone ( n = 478) or melflufen as a monotherapy ( n = 13), thrombocytopenia was reported in 83% of the patients, neutropenia in 72% and anaemia in 66%. Dose modification should be implemented in the event of adverse reactions [ 1 ]. In the HORIZON trial, 21.7% of the patients had a TEAE that led to the discontinuation of melflufen and for 26.8% of the patients, the TEAE led to a dose reduction. In 23 patients (5.4%), the recorded cause of death was an adverse event [ 18 ].

Overall, the safety profile of melflufen is well characterized and has been consistent throughout clinical studies.

Thrombocytopenia

In the safety population ( N = 491), 74% experienced at least one Grade 3/4 thrombocytopenia. These events led to dose delay in 41% and dose reduction in 23% of patients.12% of the patients discontinued the treatment due to thrombocytopenia [ 1 ]. In HORIZON and OCEAN, thrombocytopenia of any grade was reported by 82% and 86.8% of the patients respectively, whereas a Grade 3/4 was seen in 76.6% of the patients in HORIZON and 76.3% in OCEAN [ 18 ]. In HORIZON, 43% of the patients received platelet transfusions [ 14 ].

Bleeding events

Bleeding events of any grade occurred in 21% of patients in the safety population, whereas a Grade 3 bleeding was reported in 2% [ 1 ]. In the HORIZON study, Grade 3/4 thrombocytopenia and concomitant Grade 3/4 bleeding occurred in 2.5% of patients [ 14 , 18 ].

Authors’ perspective

The melflufen Summary of Product Characteristics recommends that treatment should be withheld until platelet count is ≥ 50 × 10 9 /L (without recent transfusions). Expert consensus would accept lower platelet counts for the first few cycles if due to MM (e.g. high bone marrow infiltration). Re-evaluation of bone marrow after two courses is recommended to differentiate disease persistence from toxicity.

Treating thrombocytopenia with transfusions and/or thrombopoietin receptor agonists is recommended as clinically indicated.

The threshold for platelet transfusions depends on clinical signs, co-morbidity and, if present, anti-coagulant co-medication.

Expert consensus suggests weekly monitoring in the first cycle, then adaption, depending on cytopenia, to biweekly or four-weekly controls.

The melflufen dose or schedule should be adjusted based on signs and symptoms of bleeding.

Neutropenia

Grade 3/4 neutropenia was reported in 66% of the safety population ( N = 491). In the HORIZON trial, 124 of 157 patients (79%) had at least one TEAE of Grade 3/4 neutropenia, whereof 47% had Grade 4 neutropenia [ 14 , 18 ]. Dose modifications due to neutropenia occurred in 22% of patients (dose delays in 19%, discontinuation in 3%) [ 18 ]. The rate of Grade 4 neutropenia in the OCEAN trial was 26% in the melflufen arm and 15% in the pomalidomide arm [ 15 ].

In HORIZON, neutropenia was managed with G-CSF in 68% of patients [ 18 ].

Authors’ perspective

Secondary prophylaxis with haematopoietic growth factors like G-CSF after Grade 3/4 neutropenia is recommended as a supportive option.

G-CSF can either be used in addition to dose reduction or dose delay, or as an alternative to dose reduction/dose delay, especially in the early phase of treatment when control of myeloma is not yet achieved.

In patients responding to melflufen therapy it is recommended to reduce or delay the dose rather than using growth factors with an unchanged dose.

In patients with thrombocytopenia Grade 3/4, dose reductions should be preferred to dose delays especially in combination with anticoagulative agents.

In patients with a stable response, a delay of the next dose is an alternative to a dose reduction with respect to patient’s quality of life.

Infections

Infections were reported in 52% of the safety population ( N = 491) [ 1 ]. In the HORIZON trial, 58% patients had at least one infectious TEAE, one of these patients died (Grade 5), 22% had a Grade 3/4 infection and 31% reported an infective pneumonia [ 18 ]. Febrile neutropenia occurred in 6.4% of patients. Severe infections (Grade 3/4) were related to Grade 3/4 neutropenia and occurred concomitantly in 18 (11%) patients; 11 patients had Grade 3/4 neutropenia and concurrent Grade 3/4 pneumonia [ 14 ].

Authors’ perspective

Anti-infective prophylaxis

Anti-bacterial or anti-fungal prophylaxis is not generally recommended unless the patient has relevant risk factors, e.g. previous episodes of infection or relevant comorbidity like chronic pulmonary diseases.

There were differing views withing the expert group regarding the routine use of prophylaxis against varicella-zoster virus (VZV) infections or Pneumocystis jirovecii pneumonia (PJP). The use of dexamethasone in standard doses in RRMM patients was seen by some experts as a relevant risk factor for VZV reactivation; PJP prophylaxis should be considered in patients with prolonged neutro- or lymphopenia (> 4 weeks).

Substitution with iv or sc immunoglobin (IgG) should be considered according to the established guidelines.

Antibiotic therapy

As per guidelines antibiotic therapy should be instituted without delay (within three hours) in neutropenic patients with fever or other signs of generalised infections.

Outpatients should be provided with the necessary instructions to seek medical care immediately if febrile.

Thromboembolism

Venous thrombo-embolic events have been observed in patients treated with melflufen in combination with dexamethasone [ 18 ]. In the OCEAN trial, 8.3% patients had ≥ 1 TEAE of thromboembolism and 1.3% experienced a pulmonary embolism in the melflufen arm while 8.9% of patients had ≥ 1 TEAE of thromboembolism and 2.4% experienced a pulmonary embolism in the pomalidomide arm. It should be noted that all patients in the pomalidomide arm were to receive prophylactic anti-thrombotic treatment, unless contraindicated [ 15 ]. Malignancies, including MM, are associated with an increased risk of thrombosis [ 25 , 26 ]. Dexamethasone, especially in high doses, is a known risk factor for venous thrombosis in MM [ 27 , 28 ].

Authors’ perspective

Routine anticoagulation during melflufen treatment is not recommended but should be considered for patients with risk factors for thrombo-embolic events (including prior thrombosis).

An increased bleeding risk may result from anticoagulation.

Close monitoring is recommended in patients with known risk factors.

Gastrointestinal adverse events

Gastrointestinal adverse events do occur with melflufen treatment but are not severe. Like low dose melphalan, melflufen is seen as a substance of low emetogenic potential. In the safety population ( N = 491), 21% of patients reported nausea and19% reported diarrhoea [ 18 ]. In HORIZON ( N = 157), 32% of patients reported at least one episode of TEAE nausea (1 patient with Grade 3, none with Grade 4), 13% vomiting and 27% diarrhoea. No Grade 3/4 vomiting or diarrhoea were reported [ 14 ].

Authors’ perspective

Limited nausea and vomiting may occur after melflufen treatment and prophylaxis with anti-emetic agents should be considered prior to and during infusion.

Typically, granisetron is administered prophylactically on the day of melflufen infusion and the patient should be provided with additional on-demand anti-emetic medication (e.g. metoclopramide and ondansetron).

Second primary malignancies

At the time of EMA approval, SPMs were reported in 13 out of 495 patients (2.6%) within the cohort of all patients treated with melflufen. Acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) were observed in six patients (1.2%), non-invasive cutaneous malignancies in five patients, while one patient developed malignant melanoma. Solid tumours were observed in two patients including one case of colon adenocarcinoma and one oesophageal carcinoma [ 18 ].

Authors’ perspective

The available data on the incidence of SPM is within the expected range of heavily pretreated patients.

The experts do not recommend melflufen in combination with lenalidomide due to the potentially increased risk of SPM [ 29 , 30 ]. Also, there is no clinical data available for this combination.

Other adverse events

Fatigue (29%) and asthenia (27%) were common amongst other non-haematological adverse events reported in the HORIZON trial [ 23 ]. Alopecia of any Grade has not been reported in clinical trials with melflufen [ 13 – 15 , 31 ]. In OCEAN, peripheral neuropathy was reported in 7 patients (3%) in the melflufen arm and in 8 patients (3%) in the pomalidomide arm [ 15 ].

Authors’ perspective

The expert panel notes that fatigue can be a symptom of progressive disease, of anti-myeloma therapies, and/or ongoing infections.

Extravasation

Melflufen can cause local tissue damage. Among all 495 MM patients treated with melflufen, which mostly received the infusion by a central venous catheter, one serious Grade 2 extravasation and one non-serious Grade 1 catheter site extravasation was reported. Overall, there were four TEAEs of peripheral swelling, three events of localized oedema, one serious event of extravasation and one event of infusion site irritation [ 18 ].

Authors’ perspective

In case of extravasation at a peripheral or central site, the administration at this site should be interrupted immediately.

The same care as for melphalan extravasation should be applied.

Recommendations for patient selection

The available evidence for the selection of patients for melflufen treatment is based on patient-related (e.g. age and renal function), myeloma-related (e.g. EMD and cytogenetics) and treatment-related factors (e.g. alkylator refractoriness).

Patient-related factors

Subgroup analyses by age in the HORIZON trial demonstrated comparable ORR for patients in the age group 65–74 years and over 74 years (35% and 32%, respectively), while the ORR for patients under 65 years was lower (24%) but with an overlapping 95% confidence interval (95% CI 15–35%) [ 14 ]. Similarly, in the comparison of age cohorts in the OCEAN trial, the hazard ratios for PFS for the comparison of the melflufen arm with the pomalidomide arm decreased with increasing age: 1.04 (95% CI, 0.74–1.47; p = 0.83) for those below 65 years, 0.71 (0.52–0.96; p = 0.026) for those 65–74 years and 0.43 (0.24–0.76; p = 0.0031) for those above 74 years [ 15 , 19 ] indicating high activity in elderly patients.

The OCEAN trial reported a subgroup analysis according to renal function: Patients with a creatinine clearance between ≥ 45-<60 mL/min and ≥ 60-<90 mL/min had a median PFS of 6.7 (95% CI, 4.5–10.0) and 7.5 months (95% CI, 5.5–9.4), respectively, in favour of melflufen when compared to pomalidomide, whereas the median PFS was 5.1 months (95% CI, 4.1–8.5) for patients with a clearance of at least 90 mL/min [ 32 ].

It should be noted that age and renal function are likely related to previous treatment with ASCT (Fig. 3 ). A multivariate analysis of the OCEAN data that explored signals for effect modification (age, ASCT, gender, renal function) observed a strong signal for the post-hoc defined subgroup of TTP post-ASCT < 36 months versus no ASCT or TTP post-ASCT ≥ 36 months (HR = 2.02; 95%CI: 1.26–3.25) [ 18 ].

Health-related quality of life (HRQoL) was studied in 64 patients of the HORIZON trial and in 158 patients in the randomized OCEAN trial [ 33 , 34 ]. In HORIZON, a maintained HRQoL from baseline for up to eight treatment cycles was demonstrated. The median time until definitive deterioration for the pain scale was 13.8 months in patients with at least a minor response (≥ MR) versus 3.1 months in those who did not achieve an MR [ 33 ]. Similar results have been obtained in the OCEAN trial where patient-reported outcome scores remained stable during treatment with melflufen. There was no difference in HRQoL throughout the study between the melflufen and pomalidomide arms [ 34 ].

Authors’ perspective

Subgroup analyses of the HORIZON and OCEAN studies demonstrate a trend to better response in elderly patients. This may be due to the lower rate of ASCTs with high-dose melphalan in this age group (Fig. 3 ).

Patients with moderate renal insufficiency (creatinine clearance 30-<90 mL/min/1.73 m 2 ) responded similarly well as patients with normal renal function and should be treated with similar selection criteria. Patients with a creatinine clearance of 30–45 mL/min/1.73 m 2 should receive a reduced dose of 30 mg melflufen.

Patients with severely decreased bone marrow capacity or severe renal (creatinine clearance < 30 ml/min) or severe hepatic impairment are not eligible for melflufen therapy as there is no data available for these populations.

Patient-related aspects of melflufen treatment also include the avoidance of alopecia, as well as the lower number of office visits (once monthly infusion plus weekly to biweekly laboratory controls in the first treatment cycle).

The low frequency of peripheral neuropathy warrants the experts to consider melflufen for patients who must avoid further neuropathy-causing agents.

Myeloma-related factors

The available data on the efficacy of melflufen in patients with extramedullary myeloma lesions may suggest a therapeutic effect in this group of patients [ 14 – 16 , 19 ]. The HORIZON trial evaluated a large cohort of patients with EMD ( n = 55). The ORR was 24% in EMD patients and 32% in patients without EMD. The median DOR was similar between the EMD (5.5 months) and the non-EMD (5.1 months) patient group, while PFS was 2.9 and 4.9 months, respectively [ 16 ].

Between 30 and 40% of patients in the HORIZON and the OCEAN trials had high-risk cytogenetics. The ORR for these patients in the HORIZON study was 20% (95% CI, 11–33) (high-risk category defined as t(4;14), del(17/17p) or t(14;16) [ 14 ]. In the OCEAN trial the hazard ratio for PFS was 0.71 (95% CI, 0.50–1.02; p = 0.064) in favour of melflufen over pomalidomide for patients with high-risk cytogenetics (defined as t(4;14), t(14;16), t(14;20), del(17p), gain(1q21) or gain 1q(+ 1q) [ 15 ].

A recent post-hoc analysis by Acs et al. focused on the high-risk cytogenetic subpopulation with del(17p) in the OCEAN trial. Patients with del(17p) ( n = 70) demonstrated a 33% ORR in the melflufen arm versus 11% in the pomalidomide arm ( p = 0.028). A similar difference could be seen in the smaller group ( n = 33) of patients with del(17p) and TP53 gene mutations ( p = 0.14) [ 12 ].

Authors’ perspective

Available data suggests that melflufen has an effect in patients with extramedullary myeloma.

Based on its efficacy, melflufen may be considered as a treatment option in high-risk patients, including patients with del(17p) and TP53 gene mutations, especially if they had not been previously treated with high dose melphalan.

Treatment-related factors

Patients in the HORIZON trial who were refractory to prior alkylator therapy demonstrated an ORR of 21% (95% CI, 13–30) compared to 42% (95% CI, 29–54) in patients who were not refractory [ 14 ]. In a post hoc exploratory analysis of the OCEAN trial in patients who were refractory to prior alkylators, the melflufen and pomalidomide arms had similar median PFS of 5.6 months (95% CI, 4.2–8.3) versus 4.7 months (95% CI, 3.1–7.3) respectively, with a hazard ratio of 0.92 (95% CI, 0.63–1.33). In a comparison of alkylator-refractory patients with no prior ASCT or a TTP of at least 36 months after ASCT versus patients with a TTP of less than 36 months after ASCT, the median PFS was 8.0 months (95% CI, 4.2–10.8) versus 4.2 months (95% CI, 2.7–6.8) respectively, with a hazard ratio of 0.67 (95% CI, 0.43–1.04) [ 36 ].

Authors’ perspective

The experts expect greater treatment effect of melflufen in patients with a longer TTP after ASCT.

Patients who progressed within 36 months after ASCT with high-dose melphalan should not be selected for melflufen therapy.

Integration of melflufen into the myeloma treatment landscape

Updated guidelines from EHA-EMN for the treatment of MM were recently published [ 37 ]. Melflufen is mentioned as an option in third line and beyond for patients who have been treated with or are refractory to a PI, an IMiD and an anti-CD38 antibody. Furthermore, if a triple-class refractory patient has progressed after treatment with belantamab or a CAR T-cell therapy, either a bispecific antibody, selinexor or melflufen can be an alternative next treatment.

Authors’ perspective

Fit patients who have achieved a progression-free interval of at least 36 months after receiving high-dose melphalan and an ASCT may benefit from melflufen. Treatment with melflufen can follow after other novel treatment options such as immune therapies or CAR-T cell therapy.

Patients with intermediate or severe frailty who cannot receive high-dose melphalan or CAR-T cell therapy may benefit from earlier use of melflufen.

There is a need to consider the next therapy in line (e.g. planning for T-cell apheresis for CAR-T cells). Melflufen should not be administered before T-cell apheresis for CAR-T cell treatment.

Acknowledgements

We thank Axel Glasmacher, MD, and Christoph Weiligmann, PhD, for their assistance in the preparation of the manuscript. Their editorial support was funded by Oncopeptides.

Appendix

Author contributions

H.L. moderated the discussions, driving the concept of the manuscript. All authors contributed to the concept of the manuscript and are fully responsible for content and editorial decisions. All authors reviewed the manuscript.

Funding

The authors have no funding to declare.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

H.L: Research Support: Sanofi, Amgen. Speakers Bureau/Advisory Boards: Janssen, Sanofi, Pfizer, GSK, Pfizer, OncopeptidesE.K.M: Advisory Board: Amgen, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen-Cilag, Menarini Stemline, Oncopeptides, Sanofi und Takeda. Honoraria: Amgen, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen-Cilag, Menarini Stemline, Oncopeptides, Sanofi und Takeda. Research Funding: Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen-Cilag, Sanofi und Takeda. Travel expanses: Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen-Cilag, Menarini Stemline, Pfizer, Sanofi und TakedaM.H. received payments for Advisory boards or travel grants from Jansen Cilag, Sanofi Aventis, Oncopeptides, Takeda Oncology, Pfizer OncologyM.W.: Advisory board: Amgen, Bristol-Myers Squibb, Celgene, Gilead, Hexal, Janssen, Lilly, Medac, Novartis, Roche, Sanofi, Astra Zeneca, Oncopeptids. Honoraria: Amgen, Astellas, AstraZeneca, Celgene, Gilead, Hexal, Janssen, Lilly, Novartis, Roche, Sanofi, Daichii-Sankyo, OncopeptidsJ.M.W. has consulted for Johnson&Johnson, BMS, Sanofi, Take¬da, Pfizer, Oncopeptides and Skyline Dx; received honoraria from Takeda, GSK, Pharmamar and Beigene; and received research support from BMS.

Footnotes

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Associated Data

Data Availability Statement

No datasets were generated or analysed during the current study.