Abstract
Abstract 1876
Poster Board I-901
Multiple Myeloma (MM) remains incurable in spite of new effective agents and combination regimens. SRC family kinases (SFK) are potential targets for therapy in MM: Hck, Fyn and Lyn are implicated in IL6-induced proliferation. Dasatinib is a potent inhibitor of not only BCR-ABL, but also SFK, c-KIT, PDGFRb, and EPHA. In myeloma and endothelial cells (ECs) isolated from MM patients (pts), dasatinib blocked proliferation, survival, adhesion, migration, and angiogenic potential, through a combined targeting of PDGFRβ as well as VEGF-triggered phosphorylation of SRC. Lenalidomide has clinical efficacy in the treatment of multiple myeloma (MM) as a single agent and in combination with dexamethasone. The combination of dasatinib, lenalidomide and dexamethasone exhibits synergistic inhibition of MMIS cells.
The primary objective of this Phase I, multicenter, open-label, non-randomized study was to determine the maximum tolerated dose (MTD) of the combination of dasatinib, with lenalidomide and dexamethasone in pts with relapsed or refractory (RR) MM. Secondary objectives were to assess the tolerability of the combination, to establish the dose for future clinical investigations, and to assess the efficacy by International Uniform Response and EBMT Criteria.
Pts ≥18 years with confirmed RR MM, measurable disease (at least 1 g/dL for IgG or 0.5 g/dL for IgA in serum or urinary excretion of 200 mg monoclonal light chain/24 hours), and at least one prior treatment were enrolled sequentially into increasing dose cohorts (using a 3+3 design). Pts received oral dasatinib daily on a continuous schedule, oral lenalidomide daily for 21 days, and oral dexamethasone 40 mg/day (Days 1, 8, 15, and 22). Cycles were repeated every 28 days. Dose-limiting toxicities (DLTs) were assessed in the first cycle. If there was no DLT, dose escalation continued to MTD, followed by an expansion phase of the established dose.
Cohort . | Dasatinib/mg . | Lenalidomide/mg . | Accrual . |
---|---|---|---|
1 | 70 | 15 | 6 |
2 | 70 | 20 | 3 |
3 | 100 | 20 | 3 |
4 | 100 | 25 | 4 |
5 | 140 | 25 |
Cohort . | Dasatinib/mg . | Lenalidomide/mg . | Accrual . |
---|---|---|---|
1 | 70 | 15 | 6 |
2 | 70 | 20 | 3 |
3 | 100 | 20 | 3 |
4 | 100 | 25 | 4 |
5 | 140 | 25 |
Enrollment is ongoing. 16 pts (6 M, 10 F; median age 70.5 years, range 51–80) were treated in cohorts 1, 2, 3 and 4; MTD has not been established (as by July 2009). The median number of prior lines of therapy was 3 (range 1–6). Seven pts had prior autologous stem cell transplantation; 8 pts had prior thalidomide, 4 prior lenalidomide and 3 pts both. Baseline β2 microglobulin levels of >3.5mg/L were reported in 4 pts. The most common (310%) treatment related adverse events (AEs) diarrhea 6 (38%); nausea 4 (25%); constipation 2 (13%); stomatitis 2 (13%); asthenia 3 (19%); weight decrease 5 (31%); dyspnea 2 (13%); rash 2 (13%); vertigo 2 (13%); insomnia 2 (13%). The most common grade 3 / 4 hematologic AEs included neutropenia 6 (38%), anemia 4 (25%) and thrombocytopenia 3 (19%). Two DLTs were identified in cohorts 1 and 4: 1 pt had 2 point decline in ECOG Performance Status and other pt had a drug interruption > 15 days due to nausea and vomiting, respectively. Six out of 16 pts discontinued treatment: 1 due to death in first cycle (D19); 3 for AEs (2 study drug related and 1 unrelated), 1 withdrawal of consent, 1 following maximal clinical benefit (minor response) after 12+ cycles. As of July 2009, 10 pts remain on treatment, with a median duration of treatment of 4.2 months (range 0.6–12). Responses were observed in 13 pts: 8 partial responses (PR), and 5 minor responses (MR). 1 pt had stable disease (SD) and 2 pts were not evaluable (1 pts died before completion of cycle 1 and other pt was too early for assessment).
Dasatinib in combination with lenalidomide and dexamethasone is well tolerated and preliminary activity has been observed.
Facon:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Stewart:Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy; Takeda, Millenium: Research Funding; Genzyme, Celgene, Millenium, Proteolix: Honoraria. Garzon:BMS: Employment. Bleickardt:BMS: Employment. Gialelis:BMS: Employment. Tuozzoli:BMS: Employment. Derreumaux:BMS: Employment. Sonneveld:Janssen-Cilag: Honoraria.
Author notes
Asterisk with author names denotes non-ASH members.