Background
Multiple myeloma (MM) is the second most common hematologic malignancy and is a disease of terminally differentiated plasma cells. As MM progresses, treatment becomes increasingly difficult, and the periods of remission after each relapse grow shorter. There is an urgent need for new therapeutic combinations that can provide deeper and more durable responses. Recently, Haematologica published the final results of the phase I/IIa ANCHOR study, which investigated the efficacy and safety of the novel alkylating peptide-drug conjugate melflufen flufenamide (melflufen) in combination with dexamethasone and either daratumumab or bortezomib for the treatment of relapsed/refractory MM.Introduction
Melflufen is a novel alkylating peptide-drug conjugate. Due to its high lipophilicity, melflufen is rapidly taken up by tumor cells. Once inside the cell, melflufen is quickly hydrolyzed by peptidases and esterases, resulting in the intracellular distribution and accumulation of cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen). Melflufen combined with dexamethasone has been approved in Europe for treating triple-class refractory relapsed/refractory MM patients who have received ≥3 lines of therapy, shown progression after the last therapy, and relapsed ≥3 years post-autologous stem cell transplantation (ASCT). Proteasome inhibitors (e.g., bortezomib), immunomodulatory drugs (e.g., lenalidomide), and anti-CD38 monoclonal antibodies (e.g., daratumumab) are standard treatments for MM, but resistance to these drugs is a significant clinical concern.
Methods
The ANCHOR study is an open-label, phase I/IIa, non-comparative study (OP-104; NCT03481556). Eligible patients were aged 18 years and older, previously diagnosed with MM, had disease progression after 1 to 4 lines of therapy, and were refractory or intolerant to immunomodulatory drugs and/or proteasome inhibitors, with measurable disease at screening. In the bortezomib group, prior proteasome inhibitor treatment was allowed, but patients could not be refractory to proteasome inhibitors in their last line of therapy. In the daratumumab group, prior anti-CD38 monoclonal antibody treatment was not allowed.
The phase I portion followed a standard 3+3 dose-escalation design. The starting dose of melflufen was 30 mg. If no dose-limiting toxicities were reported, the next cohort received 40 mg melflufen. Patients received melflufen intravenously on day 1 of each 28-day cycle. In the daratumumab group, patients received daratumumab 16 mg/kg intravenously on days 2, 8, 15, and 22 of cycle 1; days 1, 8, 15, and 22 of cycle 2; days 1 and 15 of cycles 3 to 6; and day 1 of cycle 7 and beyond, along with dexamethasone 40 mg on days 1, 8, 15, and 22 (reduced to 20 mg for patients aged 75 years and older). In the bortezomib group, patients received bortezomib 1.3 mg/m2 subcutaneously on days 1, 4, 8, and 11, along with dexamethasone 20 mg on days 1, 4, 8, 11, and 15, 22 (reduced to 12 mg for patients aged 75 years and older). Patients continued treatment until disease progression, intolerable toxicity, or a decision by the patient or physician to discontinue. In the phase IIa portion, 20 additional evaluable patients were treated at the recommended dose.
Results
In this study of relapsed/refractory MM, melflufen combined with dexamethasone, and either daratumumab or bortezomib, showed significant therapeutic effects. A total of 56 patients were enrolled: 33 in the daratumumab group (melflufen, daratumumab, and dexamethasone) and 23 in the bortezomib group (melflufen, bortezomib, and dexamethasone).
In the daratumumab group, patients treated with 30 mg melflufen had a longer treatment duration than those treated with 40 mg. The overall response rate (ORR) was 73%, including 3% achieving stringent complete response, 6% complete response, 24% very good partial response, and 39% partial response. Over 85% of patients had a ≥25% reduction in M protein. The median duration of response was 12.0 months, median progression-free survival (PFS) was 12.9 months, and median overall survival (OS) was 26.1 months.
In the bortezomib group, with median follow-up times of 9.0 and 22.9 months, the average treatment duration was 8.2 months in the 30 mg group and 11.8 months in the 40 mg group. The ORR increased to 78%, with one patient achieving stringent complete response, one complete response, five very good partial responses, and eleven partial responses. 87% of patients saw at least a 25% reduction in M protein. The median duration of response was 15.8 months, and median PFS extended to 14.7 months. Although the OS data for the bortezomib group was not fully mature due to early study termination, 74% of patients were alive at a median follow-up of 17.6 months.
No dose-limiting toxicities were observed, confirming the safety of melflufen in combination therapies. However, thrombocytopenia and neutropenia were common adverse events leading to treatment discontinuation. Notably, for patients with extramedullary disease, 100% in the daratumumab group and 50% in the bortezomib group achieved partial response or better. Based on these positive results, the study recommends melflufen 30 mg as the dose for future studies combining melflufen with dexamethasone and either daratumumab or bortezomib in relapsed/refractory MM.
In the treatment of MM, melflufen, a novel alkylating peptide-drug conjugate, has shown significant clinical efficacy when combined with dexamethasone. The phase I/IIa ANCHOR study evaluated the efficacy of melflufen combined with dexamethasone and either daratumumab or bortezomib in relapsed/refractory MM patients who were refractory to immunomodulatory drugs and/or proteasome inhibitors and had received 1 to 4 lines of prior therapy. Based on the study results, melflufen 30 mg is recommended as the standard dose for future studies of this combination therapy, balancing safety, tolerability, and efficacy. The findings from the ANCHOR study provide new treatment options for relapsed/refractory MM and offer important insights for future clinical research and practice.
