Contributions
Abstract: PB1655
Type: Publication Only
Session title: Myeloma and other monoclonal gammopathies - Clinical
Background
Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that leverages aminopeptidases and thereby delivers and rapidly releases alkylating agents inside tumor cells. In the phase 2 HORIZON study, melflufen plus dexamethasone showed clinical efficacy and was well tolerated in patients with heavily pretreated relapsed/refractory multiple myeloma (RRMM; Richardson et al. J Clin Oncol. 2020 Dec 9 [Epub]). The ongoing phase 1/2 ANCHOR study (OP-104) established the optimal dose for melflufen plus dexamethasone and daratumumab, showing meaningful clinical activity and manageable safety at both melflufen doses tested in patients with RRMM (Ocio et al. ASH 2020. Oral 417).
Aims
LIGHTHOUSE (OP-108; NCT04649060) is a randomized, open-label, multicenter, phase 3 study designed to evaluate the efficacy and safety of melflufen plus dexamethasone and daratumumab vs daratumumab alone in patients with RRMM previously treated with an IMiD and a proteasome inhibitor (PI).
Methods
Patient enrollment has begun, with N=240 patients planned for enrollment. The patient population is similar to that of the indication for daratumumab monotherapy. Key inclusion criteria are age ≥18 years, double refractory to (or intolerant of) an IMiD and a PI or having had ≥3 prior lines of therapy including an IMiD and a PI, have measurable disease, and Eastern Cooperative Oncology Group performance status ≤2. Patients with primary refractory disease and refractoriness to an anti-CD38 antibody are excluded. Patients will be randomized 1:1 to open-label melflufen plus dexamethasone and daratumumab (Arm A) or single-agent daratumumab (Arm B) and stratified by number of prior lines of therapy. Patients will receive therapy until progressive disease (PD) or unacceptable toxicity. In Arm A, patients will receive melflufen 30 mg intravenously on day 1 of each 28-day cycle; dexamethasone 40 mg weekly orally (20 mg if aged ≥ 75 years); daratumumab 1800 mg subcutaneously on days 1, 8, 15, and 22 of cycles 1 and 2, days 1 and 15 of cycles 3-6, and day 1 of cycles 7+. In Arm B, patients will receive daratumumab at the same dosage as in Arm A. Patients in Arm B with PD can opt to receive triplet therapy as in Arm A.
The primary objective of the study is to show superiority of progression-free survival (PFS) in patients treated with triplet therapy vs daratumumab alone (P value from the 2-sided statistical test <0.05; upper limit of the 2-sided 95% CI for the hazard ratio <1). An estimated sample of 240 patients with 160 expected events (PD or death) and 15% assumed dropout rate would provide 90% power at a 2-sided log rank test at 5% significance level to detect a hazard ratio for death of 0.6. Key secondary endpoints are overall response rate (ORR; ≥ partial response [PR]), duration of response, and safety. Response will be assessed by a blinded independent review committee based on International Myeloma Working Group response criteria. Other secondary endpoints include clinical benefit rate (≥ minimal response), time to response, time to progression, time to next treatment, and overall survival. Exploratory endpoints include minimal residual disease in patients achieving ≥ very good PR, PFS following next line of treatment (PFS-2), patient-reported outcomes, pharmacokinetics, translational biomarkers, response rate in patients with extramedullary disease, and efficacy (including ORR) in patients in Arm B who receive triplet therapy as in Arm A after PD.
Results
.
Conclusion
.
Keyword(s): Melphalan, Multiple myeloma, Phase III
Abstract: PB1655
Type: Publication Only
Session title: Myeloma and other monoclonal gammopathies - Clinical
Background
Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that leverages aminopeptidases and thereby delivers and rapidly releases alkylating agents inside tumor cells. In the phase 2 HORIZON study, melflufen plus dexamethasone showed clinical efficacy and was well tolerated in patients with heavily pretreated relapsed/refractory multiple myeloma (RRMM; Richardson et al. J Clin Oncol. 2020 Dec 9 [Epub]). The ongoing phase 1/2 ANCHOR study (OP-104) established the optimal dose for melflufen plus dexamethasone and daratumumab, showing meaningful clinical activity and manageable safety at both melflufen doses tested in patients with RRMM (Ocio et al. ASH 2020. Oral 417).
Aims
LIGHTHOUSE (OP-108; NCT04649060) is a randomized, open-label, multicenter, phase 3 study designed to evaluate the efficacy and safety of melflufen plus dexamethasone and daratumumab vs daratumumab alone in patients with RRMM previously treated with an IMiD and a proteasome inhibitor (PI).
Methods
Patient enrollment has begun, with N=240 patients planned for enrollment. The patient population is similar to that of the indication for daratumumab monotherapy. Key inclusion criteria are age ≥18 years, double refractory to (or intolerant of) an IMiD and a PI or having had ≥3 prior lines of therapy including an IMiD and a PI, have measurable disease, and Eastern Cooperative Oncology Group performance status ≤2. Patients with primary refractory disease and refractoriness to an anti-CD38 antibody are excluded. Patients will be randomized 1:1 to open-label melflufen plus dexamethasone and daratumumab (Arm A) or single-agent daratumumab (Arm B) and stratified by number of prior lines of therapy. Patients will receive therapy until progressive disease (PD) or unacceptable toxicity. In Arm A, patients will receive melflufen 30 mg intravenously on day 1 of each 28-day cycle; dexamethasone 40 mg weekly orally (20 mg if aged ≥ 75 years); daratumumab 1800 mg subcutaneously on days 1, 8, 15, and 22 of cycles 1 and 2, days 1 and 15 of cycles 3-6, and day 1 of cycles 7+. In Arm B, patients will receive daratumumab at the same dosage as in Arm A. Patients in Arm B with PD can opt to receive triplet therapy as in Arm A.
The primary objective of the study is to show superiority of progression-free survival (PFS) in patients treated with triplet therapy vs daratumumab alone (P value from the 2-sided statistical test <0.05; upper limit of the 2-sided 95% CI for the hazard ratio <1). An estimated sample of 240 patients with 160 expected events (PD or death) and 15% assumed dropout rate would provide 90% power at a 2-sided log rank test at 5% significance level to detect a hazard ratio for death of 0.6. Key secondary endpoints are overall response rate (ORR; ≥ partial response [PR]), duration of response, and safety. Response will be assessed by a blinded independent review committee based on International Myeloma Working Group response criteria. Other secondary endpoints include clinical benefit rate (≥ minimal response), time to response, time to progression, time to next treatment, and overall survival. Exploratory endpoints include minimal residual disease in patients achieving ≥ very good PR, PFS following next line of treatment (PFS-2), patient-reported outcomes, pharmacokinetics, translational biomarkers, response rate in patients with extramedullary disease, and efficacy (including ORR) in patients in Arm B who receive triplet therapy as in Arm A after PD.
Results
.
Conclusion
.
Keyword(s): Melphalan, Multiple myeloma, Phase III