Melphalan Triplets Elicit Responses, Are Safe in Relapsed/Refractory Multiple Myeloma

Enrique M. Ocio, MD

The triplet regimen of melphalan flufenamide (Pepaxto; melflufen) with dexamethasone and either daratumumab (Darzalex) or bortezomib (Velcade) demonstrated encouraging clinical activity and was well tolerated in patients with heavily pretreated relapsed/refractory multiple myeloma, according to phase 1/2a results of the ANCHOR (OP-104) trial that were presented during the 2nd European Myeloma Network Meeting.¹

The objective response rate (ORR) with the 3-drug combination of melphalan, dexamethasone, and daratumumab was 73%; with melphalan, dexamethasone, and bortezomib, the ORR was 62% in this patient population.

“Interestingly, the [median progression-free survival] for melflufen, daratumumab, and dexamethasone was 12.9 months,” said lead study author Enrique M. Ocio, MD, PhD, head of the Hematology Department, University Hospital Marqués de Valdecilla, University of Cantabria, in Santander, Spain, in a virtual presentation of the data.

Outcomes are poor for patients with relapsed/refractory multiple myeloma, who often develop resistance to standard therapies. Melphalan flufenamide is a first-in-class peptide-drug conjugate that leverages aminopeptidases and quickly delivers and releases alkylating agents inside tumor cells.

In February 2021, the FDA approved melphalan flufenamide for use in combination with dexamethasone in adult patients with relapsed/refractory myeloma, who have received at least 4 prior lines of therapy and whose disease is refractory to at least 1 proteasome inhibitor, 1 immunomodulatory drug (IMiD), and 1 CD38-directed monoclonal antibody.

The approval was based on data from the phase 2 HORIZON study (NCT02963493), where the doublet was elicited a 23.7% ORR in heavily pretreated patients with relapsed/refractory multiple myeloma.²

In the phase 1/2a dose-escalation ANCHOR (NCT03481556) study, which had a 3+3 design, investigators tested melphalan flufenamide plus dexamethasone in combination with bortezomib or daratumumab in a relapsed/refractory population.

To be eligible for enrollment, all patients had to be at least 18 years old, have measurable disease, an ECOG performance status of 0 to 2, have received 1 to 4 prior lines of therapy, and be refractory to or intolerant of an IMiD and/or a proteasome inhibitor. For those who received the addition of daratumumab, patients could not have received prior treatment with an anti-CD38 antibody; in the bortezomib arm, patients could not be refractory to a prior proteasome inhibitor in their last line of treatment before study enrollment.

Melphalan flufenamide was given intravenously, starting at 30 mg, and either increased to 40 mg or reduced to 20 mg based on dose-limiting toxicities, on day 1 of 28-day cycles. In the bortezomib cohort, the proteasome inhibitor was given at 1.3 mg/m² subcutaneously on days 1, 4, 8, and 11. Dexamethasone was given at 20 mg on days 1, 4, 8, and 11 of each cycle and 40 mg on days 15 and 22 of each cycle. For patients aged 75 years and older, a 12‑mg dose was administered on days 1, 4, 8, and 11, and at 20 mg on days 15 and 22. Patients received treatment until disease progression or unacceptable toxicity.

In the daratumumab group, the monoclonal antibody is administered at a 16-mg/kg dose on day 2 from prolonged infusion time of the first dose. Daratumumab is given on days 2, 8, 15, and 22 for cycle 1; on days 1, 8, 15, and 22 for cycle 2; on days 1 and 15 for cycles 3 to 6; and day 1 for cycles 7+. Dexamethasone is given at a 40-mg weekly dose.

Investigators had different outcome measures in each phase of the trial. In the phase 1 portion, the primary end point is to determine the optimal dose of melphalan flufenamide in combination with dexamethasone and either bortezomib or daratumumab. In the phase 2 portion, the primary end point is investigator-assessed ORR, according to International Myeloma Working Group response criteria.

Secondary end points are best response, time to response, PFS, overall survival (OS), and safety.

Once the optimal dose is established, investigators noted that an additional 20 patients per regimen will be recruited into the phase 2 portion of the study.

As of the data cutoff date of October 19, 2020, 13 patients received melphalan flufenamide (30 mg, n = 6; 40 mg, n = 7) combined with dexamethasone and bortezomib. The median age was 72 years (range, 61-82) and the median number of prior therapies was 3 (range, 1-4). Forty-four percent of patients with known status had high-risk cytogenetics; 77% were refractory to their last line of therapy and 92% had received a prior proteasome inhibitor. Eight patients (62%) had remained on treatment and 5 (38%) discontinued therapy, reasons of which included disease progression (n = 2), lack of efficacy (n = 1), adverse effects (AEs; n = 1), and other (n = 1).

Efficacy was evaluated in both the bortezomib and daratumumab groups. In the bortezomib arm, the clinical benefit rate (CBR) were 62%. At a median follow-up of 12.0 months, progression-free survival data were immature; the median treatment duration was 8.7 months (range, 1.4-29.0).

When stratified by melphalan flufenamide dose, the ORR and CBR at the 30-mg dose were both 50%; at the 40-mg dose, these rates were both 71%.

In the daratumumab arm, the median age was 63 years (range, 35-78), and 67% of patients were female. The median time since diagnosis was 3.8 years (range, 0.7-15.6) and the number of lines of prior therapy was 2 (range, 1-4). Most patients (73%) were International Staging System (ISS) I at study entry, and more than half (54%) had high-risk cytogenetics. Nearly half (48%) had an ECOG performance status of 1; and 79% had underwent prior autologous stem cell transplant. Twelve percent of patients were refractory to an alkylating agent, 64% to an IMiD, and 45% to a proteasome inhibitor. Sixty-one percent of patients were refractory to their last line of therapy; 36% of patients were refractory to both an IMiD and a proteasome inhibitor.

In the cohort with daratumumab, 33 patients received treatment (30 mg, n = 6; 40 mg, n = 27). As of October 19, 2020, 5 patients remained on therapy (30 mg, n = 2; 40 mg, n = 3), and 28 patients discontinued treatment (30 mg, n = 4; 40 mg, n = 24). Patients discontinued due to disease progression (30 mg, n = 2; 40 mg, n = 12), AEs (30 mg, n = 1; 40 mg, n = 7), and other (30 mg, n = 1; 40 mg, n = 5).

In the daratumumab arm, the median follow-up was 18.4 months; in the 30-mg group, this was 28.4 months vs 16.9 months in the 40-mg group. The median duration of treatment was 21.7 months (range 1.0-30.2) and 6.2 months (range, 1.0-27.6) in the 30-mg and 40-mg groups, respectively. Two patients on the 30-mg dose and 7 on the 40-mg dose discontinued melphalan flufenamide, but did continue with daratumumab and dexamethasone.

Results showed that the ORR and CBR were 83% at the 30-mg dose; at the 40-mg dose, the ORR was 70% and the CBR was 74%. The median duration of response was 12.6 months (95% CI, 7.6-24.2); 5 of 33 patients’ responses were ongoing at the time of data cutoff. Additionally, at a median follow-up of 18.9 months, the median PFS was 12.9 months (95% CI, 7.7-15.4), and the OS data were immature at a median 18.4-month median follow-up.

Regarding safety in the bortezomib group, no dose-limiting toxicities (DLTs) were observed at any dose level. Grade 3 or higher treatment-related AEs (TRAEs; 92%) included thrombocytopenia (77%), neutropenia (54%), and anemia (46%).

Serious TRAEs, which included in 3 patients (23%), were comprised of pneumonia and neutropenia, thrombocytopenia and neutropenia, and syncope (n = 1 each). One patient had an AE related to death within 30 days after the last dose of study treatment, which was chronic cardiac failure that was considered unrelated to therapy.

Safety data in the daratumumab group showed that no DLTs were reported at any dose levels in the phase 1 portion. Overall, the rate of grade 3 or higher TRAEs was 88%, which comprised thrombocytopenia (73%), neutropenia (67%), anemia (24%), lymphopenia (6%), febrile neutropenia (6%), and pneumonia (6%).

The rate of serious AEs was 45%; 67% of these were at the 30-mg dose and 41% were at the 40-mg dose. The most common serious AEs were pneumonia (12%) and influenza (9%); parainfluenza virus infection, sepsis, urinary tract infection, and febrile neutropenia all occurred at 6% each.

Dose reductions due to treatment-emergent AEs occurred in 50% (n = 3) of patients in the 30-mg group (thrombocytopenia, n = 2; neutropenia, n = 1) and in 67% (n = 18) in the 40-mg cohort (thrombocytopenia, n = 15; neutropenia, n = 7).

Fatal AEs reported in 4 patients due to sepsis in the 30-mg cohort, which was not treatment related, and in 40-mg cohort; which was possibly linked to melphalan flufenamide. Additionally, in the 40-mg cohort, the other fatal AEs included chronic cardiac failure and physical health deterioration, which were unrelated to treatment.

“For the daratumumab arm, the safety and efficacy analysis has determined that melflufen at 30 mg should be the recommended dose with daratumumab in future studies,” the authors noted.

The bortezomib arm in this study is still recruiting; the recommended phase 2 dose has not yet been determined.

References

1. Ocio EM, Efebera YA, Hájek R, et al. ANCHOR (OP-104): melflufen plus dexamethasone and daratumumab or bortezomib in relapsed/refractory multiple myeloma refractory to an IMiD and/or a proteasome inhibitor — updated efficacy and safety. Presented at: 2nd European Myeloma Network Meeting; March 3-6, 2020; virtual. Abstract P42.
2. Richardson PG, Oriol A, Larocca A, et al. HORIZON (OP-106): Melflufen plus dexamethasone in relapsed/refractory multiple myeloma refractory to pomalidomide and/or an anti-CD39 monoclonal antibody – primary and subgroup analysis. Presented at: 2020 European Hematology Association Annual Congress; June 11-21, 2020; Virtual. https://bit.ly/3dTqayA.