FINAL PHASE 2 STUDY DATA OF MELFLUFEN AND DEXAMETHASONE FOR PATIENTS WITH RELAPSED-REFRACTORY MULTIPLE MYELOMA (RRMM)
Author(s): ,
Antonio Palumbo
Affiliations:
University of Torino Oncology Department,Myeloma Unit Division of Hematology,Torino,Italy
,
Valeria Magarotto
Affiliations:
University of Torino Oncology Department,Myeloma Unit Division of Hematology,Torino,Italy
,
Pieter Sonneveld
Affiliations:
Erasmus MC,Rotterdam,Netherlands
,
Torben Plesner
Affiliations:
Hematology,Vejle Hospital,Vejle,Denmark
,
Claudia Paba-Prada
Affiliations:
Dana Farber Cancer Institute,Boston MA,United States
,
Peter Voorhees
Affiliations:
University of North Carolina,Chapel Hill, NC,United States
,
Ulf-Henrik Mellqvist
Affiliations:
Södra Älvsborgs Sjukhus,Borås,Sweden
,
Catriona Byrne
Affiliations:
Oncopeptides AB,Miami FL,United States
,
Johan Harmenberg
Affiliations:
Oncopeptides AB,Stockholm,Sweden
,
Eva Nordström
Affiliations:
Oncopeptides AB,Clinical,Stockholm,Sweden
,
Hanan Zubair
Affiliations:
Oncopeptides AB,Stockholm,Sweden
Paul G Richardson
Affiliations:
Dana Farber Cancer Institute,Boston MA,United States
EHA Library. Palumbo A. 06/10/16; 133268; P281
Prof. Antonio Palumbo
Prof. Antonio Palumbo
Contributions
Abstract
Abstract: P281

Type: Poster Presentation

Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45

Location: Poster area (Hall H)

Background
Melflufen is a peptidase potentiated therapy with an alkylating payload, designed for efficient targeting of tumor cells with a unique mechanism of action. As a highly potent anti-angiogenic compound, melflufen triggers rapid, robust and irreversible DNA damage and exerts its cytotoxicity through alkylation of DNA. The lipophilicity of melflufen leads to rapid and extensive distribution into cells where it is readily metabolized by intracellular peptidases (often over-expressed in malignant cells) into hydrophilic alkylating metabolites leading to 50-fold enrichment in MM cells of these metabolites.

Aims
To study the efficacy and safety of melflufen in combination with dexamethasone (dex) in patients (pts) with RRMM.

Methods
40 mg melflufen was given in 28-day cycles in combination with 40 mg weekly dex in RRMM pts with ≥2 prior lines of therapy, including lenalidomide and bortezomib, and who progressed on or within 60 days of last therapy.

Results
As of 11 Feb 2016, recruitment was complete (N=40). Median time from initial diagnosis to first dose of melflufen was 5.0 years (range 1-20) and the median number of prior therapies was 4 (range 2-9). 12 patients had ISS stage I, 16 stage II, 10 stage III and 2 unknown. 12 pts (30%) had high cytogenetic risk (del17p, t(4;14) or t(14;16)).  62% were double-refractory and 56% alkylator-refractory. Median duration of treatment was 4.0 months (m), (range 0.7-15) with 4 pts still ongoing.The best response achieved in the 30 efficacy evaluable pts (defined as received ≥2 cycles with appropriate assessments) was VGPR in 3 and PR in 9 for an overall response rate (ORR, ≥PR) of 40%. An additional 7 pts achieved MR for a clinical benefit rate (≥MR) of 63%. 10 pts achieved SD and 1 PD. Similar results were seen regardless of refractory status with an ORR of 35% in double-refractory pts and 53% in alkylator-refractory pts. The ORR was 33% in pts with high-risk cytogenetics. Time to first response (≥MR) was rapid with a median of 1.0 m (range 0.6-5.5). ORR in all 40 treated pts was 30%.The median Progression-Free Survival (PFS) was 8.0 m (95% conf. int. [CI] 4.1-13.6) based on 21 events in 30 pts in the efficacy evaluable population. Median PFS was 4.5 m (95% CI 3.7-11.0) based on 30 events in all 40 treated pts. Median duration of response was 8.8 m and overall survival was not yet measurable.Hematologic toxicity was common but manageable with cycle prolongations, dose modifications and supportive therapy. Melflufen treatment-related Grade 3/4 adverse events (AE) were reported in 85% of patients; thrombocytopenia 63%, neutropenia 58%, anemia 43% and neutrophil count decreased 10% followed by febrile neutropenia, asthenia, pyrexia, fatigue and pneumonia that each occurred in 5% of patients. 16 patients (40%) experienced serious AEs and 12 patients (30%) had melflufen treatment-related serious AEs. 58% of the pts required RBC transfusions, 43% platelet transfusions and 53% G-CSF.

Conclusion
Melflufen produces rapid and durable responses in MM pts refractory to the major classes of therapy and with high-risk cytogenetics. Clinical benefit (≥MR) was achieved among 63% of these advanced and heavily pretreated pts. Median PFS was 8.0 m in efficacy evaluable pts. Hematological AEs were common but manageable and non-hematological AEs were infrequent. Results support continued development of melflufen with its unique mechanism of action. Recruitment continues to a cohort of single-agent melflufen. Updated information will be presented at the time of the conference.

Session topic: Innovative therapies for MM 2

Keyword(s): Multiple myeloma, Phase II
Abstract: P281

Type: Poster Presentation

Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45

Location: Poster area (Hall H)

Background
Melflufen is a peptidase potentiated therapy with an alkylating payload, designed for efficient targeting of tumor cells with a unique mechanism of action. As a highly potent anti-angiogenic compound, melflufen triggers rapid, robust and irreversible DNA damage and exerts its cytotoxicity through alkylation of DNA. The lipophilicity of melflufen leads to rapid and extensive distribution into cells where it is readily metabolized by intracellular peptidases (often over-expressed in malignant cells) into hydrophilic alkylating metabolites leading to 50-fold enrichment in MM cells of these metabolites.

Aims
To study the efficacy and safety of melflufen in combination with dexamethasone (dex) in patients (pts) with RRMM.

Methods
40 mg melflufen was given in 28-day cycles in combination with 40 mg weekly dex in RRMM pts with ≥2 prior lines of therapy, including lenalidomide and bortezomib, and who progressed on or within 60 days of last therapy.

Results
As of 11 Feb 2016, recruitment was complete (N=40). Median time from initial diagnosis to first dose of melflufen was 5.0 years (range 1-20) and the median number of prior therapies was 4 (range 2-9). 12 patients had ISS stage I, 16 stage II, 10 stage III and 2 unknown. 12 pts (30%) had high cytogenetic risk (del17p, t(4;14) or t(14;16)).  62% were double-refractory and 56% alkylator-refractory. Median duration of treatment was 4.0 months (m), (range 0.7-15) with 4 pts still ongoing.The best response achieved in the 30 efficacy evaluable pts (defined as received ≥2 cycles with appropriate assessments) was VGPR in 3 and PR in 9 for an overall response rate (ORR, ≥PR) of 40%. An additional 7 pts achieved MR for a clinical benefit rate (≥MR) of 63%. 10 pts achieved SD and 1 PD. Similar results were seen regardless of refractory status with an ORR of 35% in double-refractory pts and 53% in alkylator-refractory pts. The ORR was 33% in pts with high-risk cytogenetics. Time to first response (≥MR) was rapid with a median of 1.0 m (range 0.6-5.5). ORR in all 40 treated pts was 30%.The median Progression-Free Survival (PFS) was 8.0 m (95% conf. int. [CI] 4.1-13.6) based on 21 events in 30 pts in the efficacy evaluable population. Median PFS was 4.5 m (95% CI 3.7-11.0) based on 30 events in all 40 treated pts. Median duration of response was 8.8 m and overall survival was not yet measurable.Hematologic toxicity was common but manageable with cycle prolongations, dose modifications and supportive therapy. Melflufen treatment-related Grade 3/4 adverse events (AE) were reported in 85% of patients; thrombocytopenia 63%, neutropenia 58%, anemia 43% and neutrophil count decreased 10% followed by febrile neutropenia, asthenia, pyrexia, fatigue and pneumonia that each occurred in 5% of patients. 16 patients (40%) experienced serious AEs and 12 patients (30%) had melflufen treatment-related serious AEs. 58% of the pts required RBC transfusions, 43% platelet transfusions and 53% G-CSF.

Conclusion
Melflufen produces rapid and durable responses in MM pts refractory to the major classes of therapy and with high-risk cytogenetics. Clinical benefit (≥MR) was achieved among 63% of these advanced and heavily pretreated pts. Median PFS was 8.0 m in efficacy evaluable pts. Hematological AEs were common but manageable and non-hematological AEs were infrequent. Results support continued development of melflufen with its unique mechanism of action. Recruitment continues to a cohort of single-agent melflufen. Updated information will be presented at the time of the conference.

Session topic: Innovative therapies for MM 2

Keyword(s): Multiple myeloma, Phase II

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