: A New Treatment Option? Merck Immunotherapy Keytruda Shows Promise in Multiple Myeloma Trial BY CHARLES BANKHEAD for MedPage Today Treatment of multiple myeloma has a strong basis for moving toward more effective therapies, building on the strengths of proteasome inhibitors, histone deacetylase (HDAC) inhibitors, and monoclonal antibodies, a German myeloma specialist said. The proteasome inhibitors bortezomib (Velcade) and carfilzomib (Kyprolis) have already established roles in myeloma therapy, and the orally available agent ixazomib introduce convenience as a new consideration in decision making, Christian Langer, MD, of the University of Ulm, said at the European Cancer Congress. The role of HDAC inhibitors in myeloma received a boost from results of a randomized clinical trial showing almost a 40% reduction in the hazard for progression with the addition of panobinostat (Farydak) to bortezomib and dexamethasone. Trials of two different monoclonal antibodies demonstrated improvement in progression-free survival in relapsed and refractory myeloma, and others are moving toward clinical investigation. However, the availability of new options will bring new challenges regarding how to optimize the drugs' use and manage the cost. "It certainly will be interesting to see how we combine these drugs and of course, it will affect cost," said Langer. Proteasome inhibition has proven to be "extremely effective" in the treatment of myeloma. Focusing on carfilzomib, Langer noted that the drug irreversibly inhibits the proteasome and leads to more prolonged inhibition as compared with bortezomib. Originally approved by the FDA in 2012 as single-agent third-line therapy, carfilzomib received an additional indication earlier this year for use in combination with lenalidomide in relapsed/refractory disease. The indication for combined treatment with lenalidomide came from results of a randomized phase III ASPIRE trial, wherein patients who had received one to three prior therapies were randomized to lenalidomide and dexamethasone with or without carfilzomib. The results showed an 8.7-month improvement in progression-free survival with carfilzomib (26.3 versus 17.6 months), translating into a 31% reduction in the hazard ratio. A preliminary analysis of overall survival showed a trend in favor of the carfilzomib arm, but the median overall survival was not yet estimable in either treatment arm, said Langer. The addition of carfilzomib did not add significantly to the adverse events observed with lenalidomide and dexamethasone. Carfilzomib and bortezomib were compared head-to-head (with dexamethasone) in the ENDEAVOR trial involving 929 patients with relapsed/refractory disease and one to three prior lines of therapy. The trial had a primary endpoint of PFS, and the results showed a clear advantage for carfilzomib, which was associated with a median PFS of 18.7 months versus 9.4 months with bortezomib. Follow-up for overall survival continues in ENDEAVOR. An exploratory analysis showed a median survival of 24.3 months with bortezomib and dexamethasone, whereas the median had yet to be reached with carfilzomib and dexamethasone. Ixazomib was evaluated in a randomized phase III trial in patients with relapsed myeloma (one to three prior regimens). Patients received lenalidomide and dexamethasone with or without ixazomib, and treatment continued until progression or development of unacceptable toxicity. The trial met the primary endpoint of PFS and could be reported in detail as soon as December at the American Society of Hematology meeting, said Langer. The rationale for using HDAC inhibitors in myeloma came from preclinical data suggesting that HDAC inhibition might prevent myeloma-cell escape during treatment with bortezomib, a possible mechanism of therapeutic synergy. The postulated synergy was tested in a randomized phase III PANORAMA I trial involving 768 patients with relapsed myeloma, who received bortezomib and dexamethasone with or without panobinostat add-on. PANORAMA I demonstrated a 3-month improvement in the primary endpoint of PFS with panobinostat. Overall survival data remain immature, but Langer said a preliminary analysis showed no difference and suggested "it's unlikely there ever will a difference." The addition of panobinostat did increase the incidence of several toxicities, including diarrhea, fatigue, nausea, peripheral edema, and decreased appetite. "The diarrhea led to a black-box warning from the FDA in the prescribing information," he said. The history of monoclonal antibodies for myeloma is marked by irony in that "the disease that made the production of monoclonal antibodies possible -- myeloma in the 1970s -- has no approved therapeutic monoclonal antibodies, so far," said Langer. That could change in the near future, as two different antibodies have shown outcome improvement in combinations for myeloma. Elotuzumab, an antibody against SLAMF7 (signaling lymphocyte activation molecule F7), was evaluated in a randomized phase III trial as add-on therapy to lenalidomide and dexamethasone. As recently reported, patients in the elotuzumab arm had a median PFS of 19.4 months versus 14.9 months with lenalidomide-dexamethasone, as well as 2-year PFS of 41% versus 27%. The addition of the monoclonal antibody increased toxicity, particularly lymphocytopenia (77% grade 3/4 versus 49%). A preliminary trial of the anti-CD38 antibody daratumumab showed single-agent activity in patients with double-refractory myeloma. The overall response rate was 36% in 42 patients who received the higher of the two doses evaluated in the trial. The median PFS with the higher dose was 5.6 months, and 65% of patients in the cohort remained progression-free at 12 months. "Daratumumab had significant single-agent activity," said Langer. "The main adverse event was transfusion-related reaction during the first application. Phase III trials investigating daratumumab in combinations are ongoing." Multiple other antigen targets in myeloma have been identified for potential development of monoclonal antibodies. They include NY-ESO-1, CD19, and BCMA. The expansion of potential treatment options has raised questions that extend beyond the substantial issue of cost, said Langer. Predictive biomarkers to guide patient selection and treatment decisions remain to be developed. Few clues have emerged to indicate which patients might benefit from single-agent therapy and deferral of combinations. Finally, clinicians and researchers continue to search for ways to identify patients who can safely stop therapy rather than continue indefinitely. To read the original article in MedPage Today, click here.
about the author
Lizzy Smith was diagnosed with myeloma in 2012 at age 44. Within days, she left her job, ended her marriage, moved, and entered treatment. "To the extent I'm able, I want to prove that despite life's biggest challenges, it is possible to survive and come out stronger than ever," she says.