Evolving Treatment Strategies for Myeloma

Orlando—Since 2000, the number of treatments for myeloma has expanded with the introduction of proteasome inhibitors and other immunomodulatory agents. Still, the disease is complex, and there are multiple options available for the treatment of patients with the disease.

Before making a treatment decision for relapsed/refractory myeloma, providers should consider the types and response to previous therapies as well as patients’ characteristics and other prognostic factors, according to Melissa Alsina, MD, associate professor of medicine at the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Florida.

Dr. Alsina discussed several new therapies at the Spring Managed Care Forum during a session titled Current and Emerging Treatment Options in the Management of Relapsed/Refractory Myeloma. Celgene Corporation, Millenium: The Takeda Oncology Company, and Onyx Pharmaceuticals supported the session with educational grants.

In 2010, there were an estimated 20,180 new cases of multiple myeloma and 10,650 deaths from the disease in the United States, according to Dr. Alsina. More men than women have multiple myeloma, and 2 times more blacks than whites have the disease. The mean age of diagnosis is 69 years for men and 71 years for women. Dr. Alsina said multiple myeloma is associated with bone pain, fatigue, weight loss, anemia, renal disease, infections, and neurologic dysfunction. Patients are at an increased risk of myeloma if they are >65 years of age and have decreased serum albumin, low platelet count, cytogenetic abnormalities, renal dysfunction, and extensive bone disease.

In July 2012, the FDA approved Kyprolis^®(carfilzomib), a proteasome inhibitor administered intravenously. It is intended for patients with multiple myeloma whose disease has progressed after receiving at least 2 prior therapies, including Velcade^®(bortezomib) and an immunomodulatory agent.

The drug’s approval was based on results of an open-label, single-arm, phase 2 trial published in Blood [2012;120(14):2817-2825]. The 266 patients each received 20 mg/m² of carfilzomib twice weekly for 3 of 4 weeks in the first cycle and then 27 mg/m² of carfilzomib twice weekly for <12 cycles. The overall response rate was 23.7%, median duration of response was 7.8 months, median progression-free survival was 3.7 months, and median overall survival was 15.6 months. Common hematologic adverse events included anemia, thrombocytopenia, and lymphopenia, while common nonhematologic adverse events included fatigue, nausea, dyspnea, diarrhea, pyrexia, and headache.

The FDA also approved Pomalyst^®(pomalidomide) in February 2013 to treat patients with multiple myeloma whose disease progressed after taking bortezomib and lenalidomide. It is in the same class of immunomodulatory agents as lenalidomide and thalidomide.

The accelerated approval was based on an open-label, phase 1/2 trial that randomized 221 patients to receive pomalidomide plus low-dose dexamethasone (n=113) or pomalidomide alone (n=108). The overall response rate was 7.4% in the pomalidomide group and 29.2% in the combination group, while the median duration of response was 8.5 months and 7.9 months, respectively. The rates of hematologic, grade 3 or 4 adverse events were similar between the groups, including for neutropenia, thrombocytopenia, and anemia. Pneumonia and fatigue were more common in the patients who took pomalidomide plus low-dose dexamethasone.

Dr. Alsina also discussed a phase 3 trial presented at the American Society of Hematology (ASH) annual meeting in December 2012 that randomized 455 patients in a 2:1 ratio to take pomalidomide plus low-dose dexamethasone (n=302) or high-dose dexamethasone alone (n=153). The progression-free survival was 3.6 months in the combination group compared with 1.8 months in the monotherapy group (P<.001). The median overall survival had not been reached in the pomalidomide plus low-dose dexamethasone group and was 7.8 months in the high-dose dexamethasone group. The overall response rate was 21% in the combination group and 3% in the high-dose dexamethasone group (P<.001).

Other drugs in the pipeline are also promising, according to Dr. Alsina, including the combination of carfilzomib, lenalidomide, and dexamethasone. She discussed a dose-escalation, phase 1b trial [Clin Cancer Res. 2013;19(8):2248-2256] that enrolled 40 patients. During a 28-day cycle, they received 15 to 27 mg/m² of carfilzomib on days 1, 2, 8, 9, 15, and 16; 10 to 25 mg of lenalidomide on days 1 to 21; and 40 mg of dexamethasone on a weekly basis.

The overall response rate was 62.5%, the median duration of response was 11.8 months, and the median progression-free survival was 10.2 months. Common adverse events included fatigue, neutropenia, and diarrhea, while grade 3 or 4 toxicities included neutropenia, thrombocytopenia, and lymphopenia.

Dr. Alsina also mentioned a phase 1/2 trial presented at the 2012 ASH annual meeting that evaluated lenalidomide and dexamethasone in combination with ixazomib, an oral agent taken once weekly. The trial included patients with previously untreated multiple myeloma and found an overall response rate of 90%. There were 2 cases of grade 3 peripheral neuropathy.

The ASH meeting also featured an open-label, dose-escalation, phase 1b trial that evaluated the effectiveness of oprozomib, an investigational structural analog of carfilzomib. The oral proteasome inhibitor comes in 2 formulations: (1) a powder-in-capsule split dose and (2) a once-daily, modified release pill. Dr. Alsina noted that only 9 patients with hematologic malignancies were enrolled in the study, but the drug was well tolerated and adverse events were mild and manageable.

In addition, Dr. Alsina discussed a single-arm, phase 2 trial that combined bortezomib and dexamethasone with panobinostat, a potent, investigational histone deacetylase inhibitor. The overall response rate for the 55 patients with relapsed, bortezomib-refractory multiple myeloma was 50%. The responses were typically found within 1 to 2 treatment cycles. The most frequent grade 3 or 4 adverse events were thrombocytopenia, anemia, and neutropenia.

Further, Dr. Alsina spoke about a phase 2 study that evaluated lenalidomide, low-dose dexamethasone, and elotuzumab, an investigational immunotherapy. The overall response rate was 92% in patients who took 10 mg/kg of elotuzumab and 76% in patients who received
20 mg/kg of elotuzumab. The median progression-free survival was 26.9 months in the 10 mg/kg elotuzumab group and 18.6 months in the 20 mg/kg elotuzumab group.

The final drug that Dr. Alsina mentioned was daratumumab, a monoclonal antibody. In a phase 1/2 dose-escalation study, 32 patients took daratumumab for 8 weeks. Of the patients, 47% had a reduction in paraprotein, 13% had a partial response, 19% had a minimal response, and 16% had stable disease. The drug was associated with a favorable safety profile, according to Dr. Alsina.

Dr. Alsina concluded that the novel therapies are innovative in that they target the tumor cell and its microenvironment and have led to improvements in end points such as overall response, complete response, and overall survival. She added that future studies would likely find that combination therapies can help the majority of patients achieve a durable complete response.