A Phase II Trial of Gleevec™ in Patients with Refractory/Relapsed Myeloma.
Authors: Dispenzieri Angela , Witzig Thomas E. , Lacy Martha Q. , Geyer Susan M. , Kimlinger Teresa , Rajkumar S. Vincent , Greipp Philip R. , Fonseca Rafael , Lust John A. , Zeldenrust Steven R. , Hayman Susazanne R. , Gertz Morie A. 
Published: October 2019

Abstract
Background: Though STI-571 (Gleevec™) was designed to specifically inhibit the bcr-abl gene product, it inhibits other receptor tyrosine kinases at physiologically attainable concentrations, including c-kit (steel factor receptor, stem cell factor receptor, SCF-R or CD 117). Studies have shown that about one-third of patients with multiple myeloma or monoclonal gammopathy of undetermined significance have plasma cells that display reactivity for c-kit. Others have shown that several myeloma cell lines and fresh myeloma bone marrow cells proliferate in response to stem cell factor. mRNA transcripts for c-kit ligand and, more commonly, its receptor have been detected in myeloma cell lines RPMI 8226, JJN3, U266 B1, NCI-H929, ARH77 and HS-Sultan by RT-PCR.
Methods: Patients were eligible for study if they presented with relapsed or refractory myeloma, an ECOG performance score < 3, ability to sign informed consent, serum creatinine <3.5 mg/dL, direct bilirubin <2 mg/dL, alkaline phosphatase <750 U/L, absolute neutrophil count > .5 x 10(9)/L and platelet count > 50 x 10(9)/L. Patients were treated with Gleevec™ 400 mg po qd. The purpose of the study was to assess the response rate of the drug Gleevec™ in patients with relapsed multiple myeloma. Secondary objectives included assessment of the tolerability of the regimen in this cohort of patients and to correlation between disease response and c-kit positivity (CD117) by flow cytometry.
Results: Overall, 23 patients were enrolled between 12/01 and 11/02, of which 16 were male and 12 had a prior PBSCT. Median age was 63 years (range: 49 – 82), and the baseline performance scores were 0 (8 patients), 1 (10), and 2 (4). Median time from MM diagnosis to enrollment was 57 months (range: 11 – 133). Patients were high risk with a median PCLI of 1.3 (range: 0 – 23%) and a median beta-2 microglobulin of 4.6 (range: 1.4 – 10.1). Eleven of 21 tested patients had positive CD117 (≥20%) staining of their bone marrow plasma cells by flow cytometry. None were PDGF positive. The treatment was well tolerated. After treatment with Gleevec™, there were only 3 non-hematologic grade 3 or 4 toxicities, and they occurred in 1 patient: he developed a capillary leak type syndrome, ascites, and dyspnea as part of his terminal phase of myeloma which included evolution into plasma cell leukemia. Grade 3 myelosuppression was observed in a minority of patients: thrombocytopenia (3), neutropenia (1), and anemia (3). There were no responses, and no patients are currently receiving treatment. Patients ended treatment due to progressive disease (18 patients), death on study (3), adverse reactions (1), and other reasons (1). The median duration of treatment was 48 days (range: 12 to 349). Of the 7 patients who remained on study for more than 60 days, CD117 status was as follows: positive (4); negative (3); not ascertained (1). As of August 2004, 12 patients have died.
Conclusions: Though forty-eight percent of the enrolled myeloma patients were CD117 positive, providing a putative target for the Gleevec™, no responses were seen in this high risk population of relapsed patients. Further study will be necessary to determine the significance of the observed stabilization of disease in 36% of the CD117 positive patients.