Pomalidomide in lenalidomide-refractory multiple myeloma and carfilzomib in refractory and newly diagnosed multiple myeloma

Treatment of multiple myeloma is evolving rapidly. It is tough to keep up with the rapid pace of new drugs, updates, and changes in the standard of care. In this issue of Community Oncology we bring to you two new exciting drugs on the horizon, pomalidomide and carfilzomib. In addition to introducing these two new drugs, we have asked Dr. Noopur Raje to explain how she treats a newly diagnosed patient with multiple myeloma.

Pomalidomide, a thalidomide (Thalomid) analog, is a promising myeloma drug with encouraging responses in relapsed/refractory myeloma patients. Carfilzomib is a novel proteasome inhibitor. When combined with lenalidomide (Revlimid) in the first-line setting, it produced a 100% response rate. Phase III studies are in progress or being completed. It will be exciting to see the final results of these studies. 

With this issue we are changing the format of Community Translations to incorporate the mechanism of action or pathophysiology of some of these new advances so that a clinician can relate to them in a clinical setting. 

Two of the most promising drugs on the horizon for patients with multiple myeloma (MM) are pomalidomide and carfilzomib. Both agents have shown significant single-agent activity in clinical trials. They seem to work in patients whose MM is resistant to other treatments and are being studied in combination regimens.

Pomalidomide is a new immunomodulatory drug (IMiD) with high in vitro potency. In initial experience with pomalidomide and low-dose dexamethasone in relapsed MM, Lacy and colleagues found an overall response rate of 63% and observed responses in some patients who were refractory to lenalidomide (Revlimid), suggesting an absence of cross-resistance between pomalidomide and other IMiDs. In a recently reported phase II study,¹ these investigators assessed the combination of pomalidomide and low-dose dexamethasone in patients with lenalidomide-refractory MM, finding the combination to be highly active and well tolerated.

In this study, 34 patients with lenalidomide-refractory MM were treated with oral pomalidomide (2 mg daily) and dexamethasone (40 mg once weekly) in 28-day cycles. Patients had a median age of 61.5 years, 68% were male, 85% had an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1, and 41% were categorized as high risk. The median time from diagnosis was 62 months. The median number of prior chemotherapy regimens was four. In addition to lenalidomide, 58% of patients had received prior thalidomide (Thalomid), and 59% had received prior bortezomib (Velcade); 68% of patients had undergone prior autologous stem cell transplantation, and 53% had prior radiation therapy. Twenty patients (59%) had peripheral neuropathy at baseline.

Patients received a median of 5 cycles (range, 1−14) of pomalidomide plus low-dose dexamethasone. Prophylaxis for venous thromboembolism was given in 204 of 209 treatment cycles (aspirin in 150 cycles and warfarin in 54 cycles). Treatment responses consisted of a very good partial response in 9%, a partial response in 23%, and a minimal response in 15%, for an overall clinical benefit rate of 47%; 35% of patients had stable disease, and 18% had disease progression. The median time to response was 2 months. Response was observed in 8 of 14 (57%) high-risk patients, in 8 of 19 (42%) who received previous thalidomide treatment, and in 9 of 20 (45%) who were given previous bortezomib treatment. In eight patients with stable disease, the pomalidomide dose was increased to 4 mg/d, with one patient improving to a partial response. The median duration of response in 11 patients with a partial response or better was 9.1 months. The median progression-free survival was 4.8 months, and progression-free survival did not differ between high-risk and standard-risk patients. The median overall survival was 13.9 months. During follow-up, treatment was stopped due to disease progression in 23 patients, 3 withdrew from the study due to patient/physician discretion, and 8 continued to receive treatment. Seven patients died, all due to disease progression. The median follow-up of patients remaining alive was 8.3 months.

Pomalidomide/dexamethasone treatment was well tolerated. Toxicity consisted mostly of myelosuppression. Grade 3 or 4 hematologic toxicity at least possibly related to treatment occurred in 38% of patients, including neutropenia in 29%, anemia in 12%, and thrombocytopenia in 9%. The most common grade 3/4 nonhematologic toxicity was fatigue, which occurred in 9% of patients (all grade 3); grade 3 pneumonitis, edema, pneumonia, and folliculitis were each observed in one patient. Nine patients (26%) had neuropathy during treatment (six grade 1, three grade 2); they included six patients with neuropathy at baseline, three of whom had a worsening of grade.