Immunomodulatory Drugs in Multiple Myeloma

Swati Andhavarapu; Vivek Roy

Disclosures

Expert Rev Hematol. 2013;6(1):69-82. 

In This Article

Pomalidomide (CC4047)

Pomalidomide, a new IMiD, showed high in vitro potency and anti-TNF activity compared with the parent compound resulting in further studies in human subjects. Schey et al. conducted a Phase I trial of pomalidomide in 24 patients with relapsed or refractory MM.[74] The MTD was 2 mg/day. Treatment resulted in a >25% reduction in paraprotein in 67% of patients, 13 patients (54%) experienced a greater than 50% reduction in paraprotein, and four (17%) of 24 patients achieved complete remission. Dose-limiting grade 4 neutropenia occurred in a total of six patients at a median of 3 weeks after starting therapy. Nonhematologic toxicity consisted of DVT in four patients. Other nonhematologic toxicity was mild and consisted of grade 1 or 2 gastrointestinal toxicity (36%), grade 1 skin rash (21%), grade 1 neuropathy (16%) and grade 1 or 2 edema (12%). CC4047 treatment was associated with significantly increased serum IL-2 receptor and IL-12 levels, consistent with activation of T cells and monocytes and macrophages suggesting a potential role for pomalidomide as an immunostimulatory compound.[74] In another Phase I trial by the same group, 20 patients with relapsed MM were treated at MTD of 5 mg on alternate days. Alternate-day treatment with pomalidomide was associated with marked reduction of thrombotic episodes (no events observed), while maintaining the antimyeloma activity (>50% PR or better; 10% CR). The median OS and PFS were 33 and 10.5 months, respectively.[75]

In a Phase II trial of relapsed/refractory MM, the combination of pomalidomide–dexamethasone was very active, resulting in response rates of 63% (38 of 60 patients enrolled), including CR in three patients (5%), VGPR in 17 patients (28%) and PR in 18 patients (30%).[76] In patients refractory to lenalidomide, thalidomide and bortezomib, the response rate was 40, 37 and 60%, respectively, suggesting its potential role in treatment of patients who are refractory to other novel agents. Responses were also seen in 74% of patients with high-risk cytogenetics defined as the presence of a plasma cell labeling index ≥3%, deletion of chromosome 13 by conventional cytogenetics, or t(4;14), t(14;16) and del(17p) by FISH. The median PFS time did not differ significantly between the standard-risk and high-risk disease groups. On the basis of these results, another cohort of lenalidomide-refractory patients (34 patients) were accrued and treated with pomalidomide–dexamethasone regimen.[77] Overall remission rate was 47% including VGPR + PR rate of 32% and minimal response of 15%. Of the 14 patients that were considered high risk, 8 (57%) had responses including four PR and four minimal response consistent with previous response rates seen in lenalidomide-refractory patients. The major toxicity was myelosuppression with grade 3 or 4 toxicity seen in 18 patients (53%).[77]

Recently, two sequential Phase II trials using the pomalidomide–dexamethasone regimen reported no advantage of 4 mg over the 2 mg daily pomalidomide dosing in patients who progressed on both lenalidomide and bortezomib. The two cohorts had comparable ORRs (43% in 4 mg vs 49% in 2 mg) suggesting noncross resistance between the agents and its efficacy in dual-refractory disease.[78] Several Phase II and III trials are ongoing evaluating the efficacy of pomalidomide alone or in combination with other agents (bortezomib and dexamethasone) in MM. Preliminary results have reported increased efficacy with the addition of cyclophosphamide to pomalidomide–prednisone (PCP regimen) and clarithromycin to pomalidomide–dexamethasone (ClaPD regimen).[79]

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