Carfilzomib in multiple myeloma: gold, silver, or bronze?

In this issue of Blood, Siegel and colleagues report that the next-generation proteasome inhibitor carfilzomib, when administered as a single agent, can produce meaningful disease control in heavily pretreated patients with relapsed/refractory multiple myeloma.¹ 

The treatment of multiple myeloma typically involves the judicious use of sequential regimens, each designed to induce a prolonged remission with acceptable toxicity. The introduction of novel agents, particularly the immunomodulatory derivatives (IMiDs) thalidomide and lenalidomide as well as the proteasome inhibitor bortezomib, has increased the achievement and durability of remissions, and led to improved survival in this malignancy^2-4  However, virtually all patients develop resistance to these agents at some point, and eventually succumb to the disease.⁵  The term “double refractory” has been coined to refer to patients who are resistant and/or intolerant to both lenalidomide and bortezomib and who have a poor prognosis. The identification of newer agents effective in double refractory myeloma represents a high priority and certainly merits a medal in the field of malignant hematology.

Siegel et al report the results of a large phase 2 trial of the new proteasome inhibitor carfilzomib in patients with progressive disease who had received all of the effective classes of agents, including bortezomib. Carfilzomib differs from bortezomib, the prototype proteasome inhibitor, in that it irreversibly binds to the proteasome more selectively, primarily inhibiting the chymotrypsin-like activity of this enzyme. In the current trial, patients had been exposed to a median of 5 prior lines of therapy, 28% were known to have adverse cytogenetic abnormalities, and 80% were considered to be double refractory. With single-agent carfilzomib, the overall response rate was 23.7%, and patients who were double refractory had a response rate of 20.1% (15.4% excluding those in this subset based on intolerance to the agent[s]). Although the progression-free survival was relatively short at 3.7 months, the duration of response for those achieving at least a partial remission was encouraging at 7.8 months, and was comparable in all subgroups, including double refractory. The median survival of the entire group was also promising at 15.6 months; those with double refractory myeloma experienced an overall survival of approximately 1 year.

Carfilzomib administration involved a stepwise dosing schedule designed to minimize toxicity: 20 mg/m² was used in cycle 1 along with dexamethasone premedication and hydration; the dose was increased to 27 mg/m² in cycle 2 if tolerated. For the most part, carfilzomib was indeed relatively well-tolerated with fatigue, nausea, anemia, and thrombocytopenia representing the most common side effects; the development of peripheral neuropathy was notable in its infrequency. However, 11 patients (4.1%) died within the first 2 cycles because of toxicity, including 2% who died of organ failure. Likely due in part to the use of lower, less effective dosing in cycle 1, the advanced disease status of these patients and the very early evaluation of response mandated by the trial design, 61 (23%) discontinued carfilzomib within the first 2 cycles due to disease progression. These observations suggest there are lessons to be learned about the optimal administration of carfilzomib in the setting of advanced and refractory disease. Nevertheless, the FDA has recently approved carfilzomib for myeloma patients with progression during or after therapy with bortezomib and an IMiD.⁶ 

Is carfilzomib deserving of gold, silver, or bronze? It may not be possible to judge right now, as the therapy of myeloma is evolving quickly. Patients with double refractory disease are the immediate beneficiaries, but the door has been opened for future endeavors involving more rapid dose escalation, use of higher doses, use in combination regimens, and application earlier in the disease course—all of which will likely significantly change our approach to myeloma for the better.^7,8