Jacob, A. L.

Abstract Abstract 4954 Background Multiple Myeloma (MM) remains incurable with current approaches and newer therapies targeting the abnormal disease biology need to be developed. The malignant plasma cell is highly dependent on the marrow microenvironment, which promotes tumor cell proliferation as well as survival. There is increased bone marrow vascular density in patients with MM and the degree of neo-angiogenesis appear to be prognostic in this disease. Studies have also shown that vascular endothelial growth factor (VEGF) is intricately involved in the interaction between the marrow microenvironment and the myeloma cell. These findings suggested that the VEGF pathway may be a valuable target for therapeutic approach in this disease. Patients and Methods We designed a phase 2 trial of Sunitinib in patients with relapsed multiple myeloma who had received less than three prior therapies. Sunitinib malate (SU11248; Sutent) is a novel, multi-targeted, small molecule inhibitor of the receptor tyrosine kinases (RTKs), including vascular endothelial growth factor receptor-1 (VEGFR-1), -2, and -3, and platelet-derived growth factor receptor (PDGFR) -α and -β. The treatment consisted of Sunitinib 37.5 mg given daily in a continuous fashion in six-week cycles. Toxicities were graded according to CTCAE response version 3.0 and responses were assessed according to the International Myeloma Working Group consensus criteria. Response rate of single agent Sunitinib was the primary endpoint of the study. Results 13 patients were accrued between July of 2007 and April 2009 before the study was closed. The median age of the study population was 61 years (range, 53 - 84), and included nine females (69%). The median time from diagnosis to registration was 39.2 months (range, 4.5 - 88) and 10 patients had received previous stem cell transplant. Previous therapy included lenalidomide in 7 patients, thalidomide in 5 patients and bortezomib in 2 patients. All 13 patients were alive at last follow up with a median follow-up of 11.2 months (range, 1.3 -21.2). All patients have gone off study, disease progression being the most common cause (9 patients), followed by adverse events (3 pts) and alternate treatment in the remaining patient. A hematological grade 3 or higher adverse event was documented in 6 patients and a grade 3 or higher non-hematological adverse event was seen in 8 patients. A grade 3 or higher neutropenia was observed in 5 pts and thrombocytopenia in 2 pts. Fatigue was common and was seen in 11 pts. The median number of cycles administered was one (range, 1-5) and the total number of cycles across 13 patients was 22. Treatment delays or interruptions were seen in five and six patients respectively. The most common reason for treatment delays was hematologic adverse events. No responses (PR or better) were seen, and stable disease was seen in eight of the 13 patients as the best response. The median time to progression was 2.9 months. Conclusions Single agent Sunitinib has no clinically relevant efficacy in this group of patients with relapsed myeloma with one or two previous therapies. Hematological toxicity was higher than anticipated. Whereas these results indicate that VEGFR TK inhibitors are not active in previously treated myeloma, it does not preclude the possibility that VEGF targeting strategies may enhance the efficacy of other therapies. Disclosures Kumar: CELGENE: Research Funding; MILLENNIUM: Research Funding; BAYER: Research Funding; GENZYME: Research Funding; NOVARTIS: Research Funding. Gertz:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dispenzieri:Celgene: Research Funding.

Abstract Lenalidomide is an orally active immunomodulatory drug effective in the treatment of multiple myeloma. We evaluated the toxicity and efficacy of MPR combination in a phase I/II study. Patients with newly diagnosed symptomatic multiple myeloma who were not candidates or refused stem cell transplantation were eligible. Treatment consisted of M and P on days 1 – 4 and R on days 1 – 21 in a 28 day cycle. All patients received aspirin 325 mg a day. Routine antibacterial prophylaxis was not used. Patients were accrued in cohorts of 3 at dose level 0 (M 5mg/m 2/d P 60 mg/m2/d R 10 mg/d) and level 1 (M 8mg/m2/d P 60 mg/m2/d R 10 mg/d). Patients were followed for at least 2 cycles to assess Dose Limiting Toxicity (DLT). G/GM-CSF use was not allowed in the first 2 cycles unless DLT had occurred. DLT was defined as occurrence of at least grade (G) 4 hematologic toxicity, G3 febrile neutropenia, or G 3 non-hematologic toxicity in the first two cycles. Failure to start the next cycle within 7 days of day 1 due to toxicity also constituted DLT. Results: 7 patients have been accrued (4 at dose level 0 {one patient had to be replaced} and 3 at dose level 1). 4 were males. ECOG performance status was 0 or1 (2 and 4 patients). Median age was 74 yrs, range 72 – 85. Between 3 and 10 cycles (median 4) have been administered at the time of this reporting. The following G3 or higher toxicities were encountered and considered at least possibly related to treatment: 2 patients at level 0 had G3 neutropenia. Of the three patients at dose level 1, there was 1 G4 neutropenia, 1 G4 thrombocytopenia, 1 G3 hyperglycemia and 1 G4 vascular access device related thrombosis. Responses were defined by EBMT/IBMTR criteria. 1 had a complete remission (after 3 cycles), 4 had partial remission (at least 50% reduction in monoclonal protein) and 1 had minimal response (after 3 cycles). Due to 3 DLT’s in dose level 1, dose level 0 was chosen for phase II of the study. Conclusion: M 5 mg/m2, P 60 mg/m2 and R 10 mg combination is well tolerated and appears effective in patients with multiple myeloma. These results are similar to the experience reported by Palumbo et al (Blood2005, 106(11):abst 785) although a stricter definition of DLT was used in our study. Escalation of R dose in combination with M 5 mg/m2, P 60 mg/m2 may be possible and improve responses. Updated data will be presented.