According to phase-I/IIa findings from the ANCHOR (OP-104) trial that were introduced during the second EMN (European Myeloma Network) Meeting, ‘The triplet regimen of melphalan flufenamide (Pepaxto; melflufen) with dexamethasone and either daratumumab (Darzalex) or bortezomib (Velcade) shown the promising clinical activity and was well tolerated in patients with heavily pretreated RRMM (Relapsed or Refractory Multiple Myeloma).
The ORR with the triplet melphalan, dexamethasone, and daratumumab have been noted as 73%; with melphalan, dexamethasone, and bortezomib, the ORR have been noted as 62% in this patient population.
According to Enrique M. Ocio, MD, PhD, head of the Hematology Department, University Hospital Marqués de Valdecilla, University of Cantabria, in Santander, Spain, “Interestingly, the (median PFS) for melflufen, daratumumab, and dexamethasone have been noted as 12.9 months.”
Findings are not promising for patients with RRMM, who often develop resistance to the standard therapies. As a first-in-class peptide drug conjugate, melphalan flufenamide mainly leverages aminopeptidases as well as quickly delivers and releases alkylating agents inside the tumor cells.
In February 2021, Melphalan flufenamide got the approval by FDA for the treatment of relapsed/refractory myeloma together with dexamethasone, who have received at least 4 prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory drug (IMiD), and one CD38-directed monoclonal antibody.
This FDA approval took place on behalf of the findings from the phase-II HORIZON study, where the doublet elicited a 23.7% objective response rate in heavily pretreated patients with RRMM.
In the phase phase-I/IIa dose-escalation ANCHOR study, with 3+3 design, examiners evaluated melphalan flufenamide plus dexamethasone together with bortezomib or daratumumab in a RR (relapsed/refractory) population.
In order to be eligible for the enrollment, all patients had to be at aged at least 18 years, have measurable disease, an ECOG performance status of 0-2, have received 1-4 prior lines of therapy, and be refractory to or intolerant of an immunomodulatory drug or a proteasome inhibitor.
For such who were given the addition of the daratumumab, patients couldn’t have received prior treatment with an anti-CD38 antibody; in the arm of bortezomib, patients could not be refractory to a prior proteasome inhibitor in their last line of treatment prior to the study enrollment.
The medication melphalan flufenamide was administered intravenously, starting at 30 mg, and either increased to 40 mg or reduced to 20 mg on behalf of dose-limiting toxicities, on the day 1 of 28-day cycles. In the cohort of the bortezomib, the proteasome inhibitor was administered at 1.3 mg/m2 subcutaneously on the days 1, 4, 8, and 11.
Dexamethasone was administered at 20 mg on the days 1, 4, 8, & 11 of each cycle and 40 mg on the days 15 & 22 of each cycle. For patients aged 75 years and older, a 12mg dose was administered on the days 1, 4, 8, & 11, and at 20 mg on the days 15 and 22. Patients were given treatment until the disease progression or unacceptable toxicity.
In the daratumumab population, monoclonal antibody is administered at a 16mg/kg dose on the day 2 from prolonged infusion time of the initial dose. Daratumumab is administered on the days 2, 8, 15, & 22 for the first cycle; on days 1, 8, 15, & 22 for the second cycle; on the days 1 and 15 for the cycles 3’rd to 6’th; and on day 1 for the cycles 7+. Dexamethasone is administered at a 40mg weekly dose.
Researchers had different findings measures in each phase of the carried out trial. In phase-I portion, the primary end point is to establish the optimal melphalan flufenamide dose together with the dexamethasone and either bortezomib or daratumumab.
In phase-II portion, the primary end point is investigator-assessed objective response rate, according to IMWG response criteria.
The secondary endpoints are best response, time to response, progression free survival, overall survival, and safety.
Once the optimal dose is confirmed, examiners noted that an additional 20 patients per regimen will be recruited into the phase-II portion of the study.
As of the DCO date of October 19, 2020, 13 patients were given melphalan flufenamide (30 mg, n = 6; 40 mg, n = 7) together with the dexamethasone and bortezomib. The median age was noted as 72 years (range, 61 to 82) and the median number of prior therapies was noted as 3 (range, 1 to 4).
44% of patients with known status had the high-risk cytogenetics; 77% were refractory to their last line of therapy and 92% were given a prior proteasome inhibitor. 8 patients (62%) had remained on the treatment and 5 (38%) interrupted the therapy, reasons of which included disease progression (n = 2), lack of efficacy (n = 1), side effects (n = 1), and others (n = 1).
Efficacy was assessed in both the bortezomib and daratumumab populations. In the arm of bortezomib, the CBR (Clinical Benefit Rate) was noted as 62%. At a median follow-up of 12.0 months, PFS data were immature; the median treatment duration was noted as 8.7 months (range, 1.4 to 29.0).
When stratified by the melphalan flufenamide dose, the Objective Response Rate and Clinical Benefit Rate at the 30mg dose were both 50%; at the 40mg dose, these rates were both 71%.
In the arm of daratumumab, the median age was noted as 63 years (range, 35 to 78), and 67% of enrolled patients were the female. The median time since diagnosis was noted as 3.8 years (range, 0.7 to 15.6) and the number of lines of prior therapy was noted as 2 (range, 1 to 4).
Maximum patients (73%) were International Staging System (ISS) I at study entry, and over half (54%) had high-risk cytogenetics. About half (48%) had an ECOG performance status of 1; and 79% had undergone prior autologous stem cell transplant.
12% of patients were found refractory to an alkylating agent, 64% to an immunomodulatory drug, and 45% to a proteasome inhibitor.
61% of patients were refractory to their last line of therapy; 36% of patients were found refractory to an immunomodulatory drug as well as a proteasome inhibitor.
In the daratumumab cohort, 33 patients were given treatment (30 mg, n = 6; 40 mg, n = 27). As of October 19’th, 2020, a total of 5 patients remained on the therapy (30 mg, n = 2; 40 mg, n = 3), and 28 patients interrupted treatment (30 mg, n = 4; 40 mg, n = 24). Patients interrupted due to the disease progression (30 mg, n = 2; 40 mg, n = 12), side effects (30 mg, n = 1; 40 mg, n = 7), and others (30 mg, n = 1; 40 mg, n = 5).
In the arm of daratumumab, median follow-up was noted as 18.4 months; in the 30mg population, this was noted as 28.4 months vs 16.9 months in the 40mg population. The median time period of the treatment was noted as 21.7 months (range 1.0 to 30.2) and 6.2 months (range, 1.0 to 27.6) in the 30mg and 40mg populations, respectively. 2 patients on the 30mg dose and 7 patients on the 40mg dose interrupted melphalan flufenamide, but did continue with the daratumumab (Darzalex) and dexamethasone-a glucocorticoid drug.
Outcomes demonstrated that the objective response rate and clinical benefit rate were noted as 83% through 30mg dose; through 40mg dose, the objective response rate was noted as 70% and the clinical benefit rate was noted as 74%.
The median time period of response was noted as 12.6 months (95% CI, 7.6 to 24.2); 5 of 33 patients’ responses were ongoing at the time of DCO. In addition, at median follow-up of 18.9 months, the median progression free survival was noted 12.9 months (95% CI, 7.7 to 15.4), and the overall survival findings were noted as immature at a median 18.4 month median follow-up.
With regard to the safety in the bortezomib (Velcade) population, no DLTs (dose-limiting toxicities) were noted at any dose level. Grade 3 or higher treatment-related side effects included thrombocytopenia, neutropenia, and anemia.
Serious TRAEs, included in the 3 patients, were pneumonia, neutropenia, thrombocytopenia and neutropenia. 1 patient had a side effects related to death within 30 days following the last dose of the study treatment, which was noted as chronic cardiac failure and was considered unrelated to the therapy.
The safety data in the daratumumab population demonstrated that no dose limiting toxicities were noted at any dose levels in the phase-I portion. Overall, the rate of grade 3 or higher TRAEs was noted as 88%, comprising thrombocytopenia, neutropenia, anemia, lymphopenia, febrile neutropenia and pneumonia.
The rate of serious adverse reactions was noted as 45%; 67% of these through the 30mg dose and 41% were through the 40mg dose. The most common serious adverse reactions were pneumonia and influenza; parainfluenza virus infection, sepsis, urinary tract infection, and febrile neutropenia all developed at 6% each.
Reductions in dose due to treatment emergent adverse reactions developed in 50% (n=3) of patients in the 30mg population (thrombocytopenia, n=2; neutropenia, n=1) and in 67% (n=18) in the 40mg cohort (thrombocytopenia, n=15; neutropenia, n=7).
Fatal adverse reactions reported in 4 patients because of sepsis in the cohort of 30mg, which was not treatment related, and in the 40mg cohort; which was linked to the melphalan flufenamide.
Additionally, in a cohort of 40mg, the other fatal adverse reactions included chronic cardiac failure and physical health deterioration, and were not related to the treatment.
The author noted that, “For the arm of daratumumab, the safety as well as efficacy analysis has demonstrated that the melflufen at 30mg should be the recommended dose together with the daratumumab (Darzalex) in the future studies.”
The arm of bortezomib in this carried out study is still recruiting; the recommended phase-II dose has not yet been fixed on.