Pomalidomide
Pomalidomide (CC-4047) is the most recent IMiD to be evaluated in clinical trials. It is derived from thalidomide(Drug information on thalidomide) and believed to have overlapping mechanisms of action with lenalidomide and thalidomide.[4,47] Preclinical studies showed that it significantly increases serum IL-2 receptor and IL-12 levels.[48] A decrease in CD8+/CD45RA+ cells and CD4+/CD45RA+ cells during the first month of study was accompanied by a corresponding increase in CD8+/CD45RO+ cells and CD4+/CD45RO+ cells, suggesting a switch from naive cells to activated effector T cells.[48] In vitro studies also have shown potent inhibitory effects on osteoclast differentiation.[49] Pomalidomide affects inflammation via transcriptional inhibition of cyclooxygenase-2 (COX-2) production, which is associated with increased prostaglandins in human lipopolysaccharide (LPS)-stimulated monocytes.[50]
Clinical Studies of Pomalidomide in Relapsed Myeloma
Myelosuppression is the major and dose-limiting toxicity noted in all clinical trials. Grade 3/4 neutropenia has been seen in 30% to 60% of patients and is more common than thrombocytopenia or anemia. Thromboembolic complications occurred with a frequency similar to that reported with other IMiDs. New-onset neuropathy is infrequent, but worsening of preexisting neuropathy has been seen. Other common side effects include orthostatic hypotension, rash, and constipation. Like thalidomide, pomalidomide may have the potential for severe birth defects, so similar precautions should be taken.
Among patients with MM, pomalidomide has been studied extensively in the setting of relapsed disease (Table 2). Initial phase I trials established pomalidomide as well tolerated at a maximum tolerated dose (MTD) of 2 mg daily or 5 mg on alternate days.[48,51] Studies using pomalidomide predominantly as monotherapy have shown excellent activity with an overall response rate of 52%.[52]
The first phase II trial conducted by Lacy et al presented data on a cohort of 60 patients with relapsed myeloma, who had a history of two or three prior regimens. Patients were treated daily with pomalidomide, 2 mg orally, along with weekly dexamethasone(Drug information on dexamethasone), 40 mg orally.[53] Thirty-eight patients (63%) achieved confirmed response, including CR in 3 patients (5%), VGPR in 17 patients (28%), and PR in 18 patients (30%). Responses were seen in 40% of patients with lenalidomide-refractory disease, 37% of those with thalidomide-refractory disease, and 60% of those with bortezomib(Drug information on bortezomib)-refractory disease. In addition, 74% of patients with high-risk cytogenetic or molecular markers (such as hypodiploidy or karyotypic deletion of chromosome 13; fluorescence in situ hybridization [FISH] evidence of the presence of translocations t[4;14] or t[14;16] or deletion [del]17p; or plasma cell labeling index ≥ 3%) had a response. Pomalidomide was well tolerated, and the primary adverse effect was grade 3 or 4 hematologic toxicity, which was seen in one-third of the patients.[53] The median progression-free survival was 11.6 months and was not significantly different in patients with high-risk disease than in patients with standard-risk disease. To better define pomalidomide’s efficacy in lenalidomide-refractory disease, a subsequent phase II trial enrolled 34 patients whose disease was refractory to lenalidomide.[54] The best response was VGPR in 3 patients (9%), PR in 8 (23%), minimal response (MR) in 5 (15%), stable disease in 12 (35%) and progressive disease in 6 (18%), for an overall response rate (defined as MR or better) of 47%. Of the 14 patients who were considered to be at high risk, 8 (57%) had responses, including 4 who had PRs and 4 who had MRs. The median time to response was 2 months and response duration was 9.1 months. The median overall survival was 13.9 months in this group of patients with lenalidomide-refractory disease. In addition to its activity in patients with high-risk disease, pomalidomide is effective in the treatment of extramedullary disease, with a response rate of about 30%, including the extramedullary component.[55]
A third trial enrolled patients whose disease was refractory to both lenalidomide and bortezomib.[56] Patients whose disease is refractory to lenalidomide and bortezomib represent a group who have poor outcomes with current treatment strategies. Pomalidomide was given orally at either 2 mg daily
(n = 35 patients) or 4 mg daily (n = 35 patients), continuously in 28-day cycles along with dexamethasone (40 mg), which was given weekly. Patients enrolled at 2 mg could escalate their dose to 4 mg if there was lack of response or progression. Overall, the response rates were similar in the two groups, with 26% and 28% of patients in the 2-mg and 4-mg groups, respectively, achieving a PR or better. Adverse effects, especially hematologic toxicity, were higher in the 4-mg cohort. The optimal dose and schedule for pomalidomide remains a matter of debate. The original phase I studies showed the MTD to be 2 mg daily or 5 mg every other day.[48,51] The variations—continuous vs 3-out-of-4-weeks dosing, and the addition of dexamethasone in some trials—have led to considerable confusion about the correct strategy. In a recent phase I/II dose-escalation study, Richardson et al showed that 4 mg pomalidomide given daily for 3 of 4 weeks is the MTD for that dosing schedule.[57] Overall response rate in this study was 25%; the phase II study is currently ongoing. A study by Lacy et al has shown that starting with a higher pomalidomide dose (4 mg) has not demonstrated any superiority of response over starting with a 2-mg dose and is associated with a higher risk of myelosuppression.[56] The Intergroupe Francophone du Myélome performed a randomized phase II trial looking at two dosing schedules, 21 of 28 days or 28 of 28 days, with pomalidomide administered at 4 mg daily + weekly dexamethasone. The overall response rate and the duration of response were similar for the two strategies, as was the overall toxicity.[58]
Histone Deacetylase Inhibitors
Inhibition of histone deacetylase (HDAC) provides a novel approach to cancer treatment.[59] Histones are part of the core proteins of nucleosomes, and the acetylation and deacetylation of these proteins play an important role in the regulation of gene expression. Deacetylated histones bind tightly to DNA and limit access of transcription factors, thus inhibiting transcription. Acetylation neutralizes the charge of histones and generates a more open DNA conformation, allowing expression of the corresponding genes. The opposing activities of two groups of enzymes, histone acetyltransferase (HAT) and HDAC, control the amount of acetylation. In normal cells, a balance exists between HAT and HDAC activity. Several lines of evidence suggest that aberrant recruitment of HDAC and the resulting modification of chromatin structure may play a role in the changes in gene expression seen in transformed cells. For example, silencing of tumor suppressor genes at the chromatin level is common in human tumors[60-63], and HDAC complexes have been shown to be crucial to the activity of the acute myeloid leukemia (AML)-specific fusion proteins: promyelocytic leukemia zinc finger (PLZF)-retinoic acid receptor (RAR)-α, promyelocytic leukemia (PML)-RAR-α, and AML1/eight–twenty-one (ETO)[64]. HDAC inhibitors have been shown to induce differentiation, cell-cycle arrest, or apoptosis in cultured tumor cells and to inhibit the growth of tumors in animal models.[65-67] In addition, HDAC inhibitors have been shown to induce expression of p21, a key mediator of G1 arrest and differentiation.[68,69] HDAC inhibitors are thought to affect multiple pathways involved in MM and to correct the deregulation of genes involved in apoptosis and cell-cycle arrest, thus potentially sensitizing MM cells to apoptosis.[70,71]
Several HDAC inhibitors have been evaluated in the context of myeloma, including suberoylanilide hydroxamic acid (SAHA; vorinostat),[72] ITF2357,[73] LBH589 (panobinostat),[74] and romidepsin (Istodax).[75] Results so far suggest limited single-agent activity in patients with MM.[71]
A phase I trial of oral vorinostat (200 mg, 250 mg, or 300 mg twice daily for 5 days/week on a 4-week cycle or 200 mg, 300 mg, or 400 mg twice daily for 14 days on a 3-week cycle) was conducted in patients with R/R MM.[76] Thirteen patients were enrolled; MTD was not reached. Drug-related adverse effects included fatigue, anorexia, dehydration, diarrhea, and nausea, mostly grades 0 to 2. Of 10 evaluable patients, one had a minimal response and nine had stable disease.
Romidepsin (Istodax) is an HDAC inhibitor that has demonstrated cytotoxicity against MM cell lines in vitro. In a phase II trial, patients with MM whose disease was refractory to standard therapy were treated with romidepsin (13 mg/m2) given as a 4-hour intravenous infusion on days 1, 8, and 15 of a 28-day cycle.[75] No objective responses were seen among the 13 patients treated.
While this class of drugs does not seem to have significant single-agent activity, combinations of HDAC inhibitors with newer drugs (especially bortezomib) appear to be promising based on initial phase II trials. A phase I trial evaluated escalating doses of bortezomib (1 to 1.3 mg/m2 on days 1, 4, 8, and 11) and vorinostat (100 mg to 500 mg orally for 8 days of each 21-day cycle) in patients with R/R MM.[77] Twenty-three patients with a median of 7 prior regimens (range, 3 to 13), which included bortezomib in 19 patients, were enrolled. The most common toxicities were myelosuppression (n = 13), fatigue (n = 11), and diarrhea (n = 5). The overall response rate was 42%, including three PRs among nine bortezomib-refractory patients. In another phase I trial, patients with relapsed or refractory MM were randomly assigned to receive oral vorinostat (either 200 mg twice daily or 400 mg once daily for 14 days) in combination with bortezomib (0.7 mg/m2 or 0.9 mg/m2 on days 4, 8, 11, and 15; or 0.9 mg/m2, 1.1 mg/m2, or 1.3 mg/m2 on days 1, 4, 8, and 11 of a 21-day cycle).[78] The best responses observed in the 34 evaluable patients were PR 26%, MR 21%, and stable disease 53%, including PR in 38% of patients with previous bortezomib therapy. Vorinostat, 400 mg once daily, plus bortezomib, 1.3 mg/m2 on days 1, 4, 8, and 11, was considered the MTD.
The combination of panobinostat and bortezomib also has been explored in trials of early-stage disease. In a phase Ib trial, 29 patients were treated with escalating doses of panobinostat and bortezomib.[79] Overall, hematologic adverse events were frequent. Nonhematologic adverse effects included diarrhea, fever, nausea, fatigue, and asthenia. Encouraging clinical efficacy was observed, with 14 (50%) PRs (or better) among 28 evaluable patients, including 4 with a CR. The overall response rate was 64%, including minor responses, and activity was seen in patients with disease refractory to bortezomib alone. Similar results have also been noted with the combination of romidepsin and bortezomib.[80] These results have paved the way for two ongoing phase III trials that are evaluating the combinations of vorinostat or panobinostat with bortezomib compared with bortezomib alone. In addition, studies have also suggested that HDAC inhibitors can be combined with lenalidomide to show significant activity. This combination is going through clinical trials currently.
