PHILADELPHIA-Several novel biological agents active against multiple myeloma have recently moved from the laboratory to clinical trials. These agents work by targeting the interaction of the tumor cell and its bone marrow microenvironment, offering the potential for more specific, less toxic treatment, compared with conventional chemotherapy.
PHILADELPHIASeveral novel biological agents active against multiple myeloma have recently moved from the laboratory to clinical trials. These agents work by targeting the interaction of the tumor cell and its bone marrow microenvironment, offering the potential for more specific, less toxic treatment, compared with conventional chemotherapy.
Paul Richardson, MD, instructor in medicine, Harvard Medical School, and clinical director of the Jerome Lipper Medical Center, Dana-Farber Cancer Institute, presented preliminary clinical data for two new biological agents at a symposium sponsored by the University of Pennsylvania and the Multiple Myeloma Research Foundation.
Novel thalidomide analogues are designed to duplicate that agent’s multiple mechanisms of antitumor activity, with higher potency and reduced toxicity. Two classes of thalidomide analogues, known as SelCIDs (selective cytokine-inhibitory drugs) and IMiDs (true immunomodula-tory drugs), are under investigation.
Both drug classes have similar cyto-kine-inhibitory effects, but the IMiDs also stimulate T-lymphocyte production. Phase I studies in multiple myeloma of one IMiD, CC5013 (Revamid, Celgene Corporation), have recently been completed, and phase II studies are now underway.
Typical of agents in its class, CC5013 is up to 2,000 times as potent as thalidomide in vitro and thus can be given at lower doses. The phase I study at Dana-Farber, which was led by Dr. Richardson, followed a typical phase I dose-escalating design (5, 10, 25, and 50 mg/d), with treatment for 28 days to identify the maximum tolerated dose and any antitumor activity, followed by a 1-year extension phase in patients who were benefiting from and tolerating the drug.
Study subjects had relapsed or refractory multiple myeloma. The 25 patients enrolled and treated had a median of three prior treatments, including stem cell transplant and thalidomide in nearly two thirds.
CC5013 was well tolerated, with no dose-limiting toxicity observed at any dose within the first month of treatment, Dr. Richardson said. However, cyto-penias developed during the extension phase in all patients receiving the highest dose (50 mg/d). These events were managed with colony-stimulating factors and dose reduction, and all patients were able to continue treatment. None of the well-known thalidomide side effectssomnolence, constipation, neuropathy, bradycardia, and skin rashwere observed to a significant degree in patients receiving CC5013.
Although this was not an efficacy study, the IMiD did show evidence of antitumor activity. Of the 24 patients evaluable for response, 19 (79%) had stable disease or serum paraprotein (tumor marker) reductions. A "remarkable" 71% had a greater than 25% paraprotein reduction, and 31% had at least a 50% reduction, Dr. Richardson said. These results are quite promising for a phase I trial, he noted.
There was some evidence of a dose-response effect, with 25- and 50-mg doses showing the greatest activity. The median time to maximum paraprotein reduction was 2 months, and the median duration of response was 6 months.
Based on these results, a phase II multicenter randomized trial has been launched, and accrual has been brisk. The study is evaluating twice-daily administration of 15 and 30 mg/d, and an intermittent dosing schedule (3 weeks on, 1 week off). Per protocol, dexamethasone has been added to CC5013 in some patients in the phase II study who do not respond to the biological agent alone, as preclinical evidence suggests that, like thalidomide, CC5013 appears to act at least additively with dexamethasone.
PS-341 (bortezomib, Velcade, Millennium Pharmaceuticals) represents another class of biological agents, proteasome inhibitors, which interfere with cellular adhesion, inhibit interluekin-6 (IL-6) and tumor necrosis factor (TNF) production, have antiangiogenic properties, and directly promote apoptosis. PS-341, the first clinically useful proteasome inhibitor, is a potent, selective, reversible agent administered by IV push. In vitroand apparently in vivoPS-341 also has at least additive effects with dexamethasone.
PS-341 is in ongoing phase II and III clinical trials. In a recently completed phase II trial of 202 patients, the first cohort included 78 patients with relapsed and refractory myeloma after multiple prior treatments, including thalidomide in three fourths and stem cell transplantation in more than half. According to a preliminary analysis, markers of disease activity showed stabilization or improvement in 77% of patients; 39% met the partial remission criterion of a 50% reduction in paraprotein level, and a significant number had a near-complete remission and/or complete remission.
Patients who responded usually did so within the first two cycles of treatment each given over 3 weeks. "This is important because in the refractory/resistant patient population, you don’t have much timethese patients are extremely sick," Dr. Richardson said. Some patients continued to improve with up to 6 months of treatment, and several have apparently had complete remissions.
The addition of dexamethasone in 25 patients with stable or progressive disease resulted in disease stabilization or improvement in two thirds. "In aggregate, the responses seen in this especially poor prognosis population are impressive," Dr. Richardson said.
Toxic effects appear to be manageable with dose reduction and/or symptomatic treatment. The most troublesome adverse effects included fatigue and exacerbation of existing peripheral neuropathy. Thrombocytopenia and neutropenia were also observed.
Pharmacogenomic analysis of tumor cells obtained in the phase II trial are now underway to identify markers useful in tailoring therapy with PS-341.