Carfilzomib demonstrates efficacy as new frontline treatment regimen for multiple myeloma

Tuesday, 05 June 2012

Multiple myeloma is cancer of the plasma cells, the white blood cells in the bone marrow that normally produce infection-fighting antibodies. Myeloma tumor cells overproduce certain antibodies, which may damage the kidneys and other organs, weaken the normal immune system, and also commonly cause bone destruction, leading to pain and fractures.

Until recently, chemotherapy and steroids were used as standard treatments for multiple myeloma. However, these traditional therapies are not very effective at eradicating tumor cells and generally cause high toxicities, as they destroy normal bone marrow cells along with tumor cells. In recent years, the introduction of new drugs, such as bortezomib, lenalidomide, and thalidomide, specifically toxic to tumor cells as compared to normal cells, has revolutionized the treatment of multiple myeloma, increasing the depth and duration of remissions and extending the life of myeloma patients, with limited toxicity as compared to standard chemotherapy. An emerging agent for the treatment of multiple myeloma is carfilzomib, a second-generation proteasome inhibitor, that has shown promising results in clinical trials involving patients with relapsed (disease that returns after a successful course of treatment) and/or refractory (disease that does not respond to treatment) multiple myeloma.

"In addition to demonstrating promising single-agent activity, a prior study investigating carfilzomib when combined with lenalidomide and low-dose dexamethasone in relapsed multiple myeloma has shown that the combination provides very encouraging responses with lower toxicity, as compared with standard treatment approaches," said Andrzej Jakubowiak, MD, PhD, the study's first author and Professor of Medicine at The University of Chicago School of Medicine. "Our study aimed at investigating the agent's efficacy and safety in newly diagnosed multiple myeloma with this fairly novel treatment regimen."

Led by Dr. Jakubowiak, investigators performed a multicenter phase I/II trial involving 53 patients with newly diagnosed multiple myeloma who received a carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) regimen in 28-day cycles for up to 24 treatment cycles (initial cycles followed by CRd maintenance) or until disease progression or intolerable toxicity.

Study results indicate that patients experienced a rapid and good initial response to CRd, and their responses improved as the trial continued. Of the 49 patients who completed four treatment cycles, 67 percent achieved at least near complete response (nCR), with 45 percent in stringent complete response (sCR), defined as no detectable tumor cells or myeloma protein in the blood or bone marrow. Of the 36 patients who completed eight or more treatment cycles, 78 percent achieved nCR with 61 percent in sCR. Overall, 62 percent of trial participants had achieved at least nCR,with 42 percent achieving sCR. The investigators also found progression-free survival (PFS) rates were 97 percent at 12 months and 92 percent at 24 months, with all patients who achieved sCR maintaining response for a median of nine months, demonstrating the durability of responses to this regimen. Importantly, these periods of extended treatment were well tolerated, including low rates of peripheral neuropathy, a treatment-limiting side effect of bortezomib, the first-generation proteasome inhibitor.

"Our final results continue to demonstrate the efficacy and safety of carfilzomib when combined with lenalidomide and dexamethasone," said Dr. Jakubowiak. "Our data support the potential for CRd as a new frontline treatment option for patients with multiple myeloma with results that are comparable to or better than those achieved with other established frontline regimens followed by high-dose chemotherapy and stem cell transplant."

Dr. Jakubowiak and other investigators are continuing to study this novel drug regimen in the ongoing phase III ASPIRE trial to evaluate lenalidomide and dexamethasone with or without carfilzomib in relapsed myeloma. The U.S. Food and Drug Administration is currently reviewing carfilzomib for the treatment of relapsed and refractory myeloma.

"Our hope is that our results will provide an effective treatment option for patients with multiple myeloma to help bring us one day closer to curing this deadly disease," added Dr. Jakubowiak.

This manuscript was presented as an abstract at the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting on June 3, 2012.