Contributions
Abstract: EP970
Type: E-Poster Presentation
Session title: Myeloma and other monoclonal gammopathies - Clinical
Background
The development of resistance to standard treatments for relapsed/refractory multiple myeloma (RRMM) highlights the need for novel therapies. 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. Melflufen plus dexamethasone showed clinical activity and an acceptable safety profile in RRMM in the phase 2 HORIZON study (Richardson PG, et al. J Clin Oncol. 2020 Dec 9 [Epub]).
Aims
To provide an update of the phase 1 dose-finding part of the bortezomib arm of the phase 1/2a ANCHOR study of melflufen plus dexamethasone in combination with bortezomib or daratumumab in patients with RRMM (NCT03481556).
Methods
Eligible patients with RRMM were refractory to (or intolerant of) a prior IMiD, with 1-4 prior lines of therapy. Prior treatment with a proteasome inhibitor (PI) was allowed, but patients could not be refractory to PIs in the last line of therapy. Melflufen (30, 40, or 20 mg intravenously; day 1 of each 28‑day cycle) was administered with bortezomib (1.3 mg/m2 subcutaneous; days 1, 4, 8, and 11) plus oral dexamethasone (20 mg on days 1, 4, 8, and 11 and 40 mg on days 15 and 22; dexamethasone dose reduced for patients aged ≥ 75 years). The primary objective in phase 1 was to determine the optimal phase 2 dose of melflufen for this combination.
Results
As of the data cutoff date (October 19, 2020), 13 patients received melflufen (30 mg, n = 6; 40 mg, n = 7) plus dexamethasone and bortezomib. In the 30-mg and 40-mg cohorts, respectively, the median age was 78.5 years (range, 70-82) and 70.0 years (range, 61-76); the median prior lines of therapy was 3.5 (range, 2-4) and 2.0 (range, 1-4); 33% and 50% of evaluable patients had high-risk cytogenetics; 83% and 71% were refractory to the last line of therapy; 100% and 86% received a prior PI; and 33% and 14% were refractory to PIs. In the 30-mg and 40-mg cohorts, respectively, the median treatment duration was 6.5 months (range, 1.4-29.0) and 8.7 months (range, 2.1-19.6); 4 patients (67%) and 4 patients (57%) were still on treatment; and 2 patients and 3 patients discontinued study treatment. Reasons for discontinuation included progressive disease (PD; n=1) and other (n=1) in the 30-mg cohort and adverse event (AE; n=1), lack of efficacy (n=1), and PD (n=1) in the 40-mg cohort. The confirmed overall response rate in the 30-mg and 40-mg cohorts, respectively, was 50% (1 very good partial response [VGPR] and 2 partial response [PR]) and 71% (1 complete response, 3 VGPR, and 1 PR). The most common grade 3/4 treatment-related AEs (TRAEs) were thrombocytopenia (30 mg, 50%; 40 mg, 100%) and neutropenia (30 mg, 33%; 40 mg, 71%); grade 3/4 nonhematologic TRAEs were infrequent. Three patients discontinued study treatment due to treatment-emergent AEs (30 mg, cardiac failure chronic [n=1] and osteolysis [n=1]; 40 mg, thrombocytopenia [n=1]). Serious TRAEs occurred in 2 patients (33%) in the 30-mg cohort (neutropenia and pneumonia [n=1], syncope [n=1]) and 1 patient (14%) in the 40-mg cohort (thrombocytopenia and neutropenia). No dose-limiting toxicities occurred at either dose level. A fatal AE occurred in 1 patient in the 30-mg cohort (cardiac failure chronic; considered unrelated to study treatment).
Conclusion
ANCHOR determined that the optimal dose of melflufen is 30 mg and results showed clinical activity in heavily pretreated patients with RRMM and poor prognostic factors. Recruitment in phase 2 is ongoing; updated data will be presented.
Keyword(s): Bortezomib, Dexamethasone, Melphalan, Multiple myeloma
Abstract: EP970
Type: E-Poster Presentation
Session title: Myeloma and other monoclonal gammopathies - Clinical
Background
The development of resistance to standard treatments for relapsed/refractory multiple myeloma (RRMM) highlights the need for novel therapies. 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. Melflufen plus dexamethasone showed clinical activity and an acceptable safety profile in RRMM in the phase 2 HORIZON study (Richardson PG, et al. J Clin Oncol. 2020 Dec 9 [Epub]).
Aims
To provide an update of the phase 1 dose-finding part of the bortezomib arm of the phase 1/2a ANCHOR study of melflufen plus dexamethasone in combination with bortezomib or daratumumab in patients with RRMM (NCT03481556).
Methods
Eligible patients with RRMM were refractory to (or intolerant of) a prior IMiD, with 1-4 prior lines of therapy. Prior treatment with a proteasome inhibitor (PI) was allowed, but patients could not be refractory to PIs in the last line of therapy. Melflufen (30, 40, or 20 mg intravenously; day 1 of each 28‑day cycle) was administered with bortezomib (1.3 mg/m2 subcutaneous; days 1, 4, 8, and 11) plus oral dexamethasone (20 mg on days 1, 4, 8, and 11 and 40 mg on days 15 and 22; dexamethasone dose reduced for patients aged ≥ 75 years). The primary objective in phase 1 was to determine the optimal phase 2 dose of melflufen for this combination.
Results
As of the data cutoff date (October 19, 2020), 13 patients received melflufen (30 mg, n = 6; 40 mg, n = 7) plus dexamethasone and bortezomib. In the 30-mg and 40-mg cohorts, respectively, the median age was 78.5 years (range, 70-82) and 70.0 years (range, 61-76); the median prior lines of therapy was 3.5 (range, 2-4) and 2.0 (range, 1-4); 33% and 50% of evaluable patients had high-risk cytogenetics; 83% and 71% were refractory to the last line of therapy; 100% and 86% received a prior PI; and 33% and 14% were refractory to PIs. In the 30-mg and 40-mg cohorts, respectively, the median treatment duration was 6.5 months (range, 1.4-29.0) and 8.7 months (range, 2.1-19.6); 4 patients (67%) and 4 patients (57%) were still on treatment; and 2 patients and 3 patients discontinued study treatment. Reasons for discontinuation included progressive disease (PD; n=1) and other (n=1) in the 30-mg cohort and adverse event (AE; n=1), lack of efficacy (n=1), and PD (n=1) in the 40-mg cohort. The confirmed overall response rate in the 30-mg and 40-mg cohorts, respectively, was 50% (1 very good partial response [VGPR] and 2 partial response [PR]) and 71% (1 complete response, 3 VGPR, and 1 PR). The most common grade 3/4 treatment-related AEs (TRAEs) were thrombocytopenia (30 mg, 50%; 40 mg, 100%) and neutropenia (30 mg, 33%; 40 mg, 71%); grade 3/4 nonhematologic TRAEs were infrequent. Three patients discontinued study treatment due to treatment-emergent AEs (30 mg, cardiac failure chronic [n=1] and osteolysis [n=1]; 40 mg, thrombocytopenia [n=1]). Serious TRAEs occurred in 2 patients (33%) in the 30-mg cohort (neutropenia and pneumonia [n=1], syncope [n=1]) and 1 patient (14%) in the 40-mg cohort (thrombocytopenia and neutropenia). No dose-limiting toxicities occurred at either dose level. A fatal AE occurred in 1 patient in the 30-mg cohort (cardiac failure chronic; considered unrelated to study treatment).
Conclusion
ANCHOR determined that the optimal dose of melflufen is 30 mg and results showed clinical activity in heavily pretreated patients with RRMM and poor prognostic factors. Recruitment in phase 2 is ongoing; updated data will be presented.
Keyword(s): Bortezomib, Dexamethasone, Melphalan, Multiple myeloma