Abstract
The hepatocyte growth factor/c-MET pathway has been implicated in the pathobiology of multiple myeloma, and c-MET inhibitors induce myeloma cell apoptosis, suggesting that they could be useful clinically. We conducted a phase II study with the c-MET inhibitor tivantinib in patients with relapsed, or relapsed and refractory myeloma whose disease had progressed after one to four prior therapies. Tivantinib, 360 mg orally per dose, was administered twice daily continuously over a 4-week treatment cycle without a cap on the number of allowed cycles, barring undue toxicities or disease progression. Primary objectives were to determine the overall response rate and the toxicities of tivantinib in this patient population. Sixteen patients were enrolled in a two-stage design. Notable grade 3 and 4 hematological adverse events were limited to neutropenia in five and four patients, respectively. Nonhematological adverse events of grade 3 or higher included hypertension (in four patients); syncope, infection, and pain (two each); and fatigue, cough, and pulmonary embolism (one each). Four of 11 evaluable patients (36%) had stable disease as their best response, while the remainder showed disease progression. Overall, tivantinib as a single agent did not show promise for unselected relapsed/refractory myeloma patients. However, the ability to achieve stable disease does suggest that combination regimens incorporating targeted inhibitors in patients with c-MET pathway activation could be of interest.
Highlights
Multiple myeloma is the second most commonly diagnosed hematologic malignancy, and the total number of new cases may show a 60% increase between 2010 and 2030 [1], indicating that it is an increasing health care burden
Sixteen patients enrolled between January, 2012, and April, 2013, and received a median of 3 cycles of therapy, with one patient continuing until February, 2014
The c-MET receptor tyrosine kinase proto-oncogene regulates cell growth, survival, and migration, and c-MET signaling after engagement of its ligand, hepatocyte growth factor (HGF), is a contributor to the pathogenesis of myeloma
Summary
Multiple myeloma is the second most commonly diagnosed hematologic malignancy, and the total number of new cases may show a 60% increase between 2010 and 2030 [1], indicating that it is an increasing health care burden. Patients still experience multiple relapses and decreasing remission durations with each additional line of therapy [2], and those with refractory disease in particular may not respond favorably to standard agents. Biomarker studies demonstrated the efficacy of tivantinib in inhibiting MET receptor kinase, as well as inducing apoptosis of target tumor cells [11]. Together, these findings supported the hypothesis that suppressing HGF/c-MET signaling could be a rational strategy against relapsed/refractory myeloma, and we performed a phase II clinical trial testing this possibility
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