Next-Generation Proteasome Inhibitors Cause Less Peripheral Neuropathy
The first-generation proteasome inhibitor bortezomib changed the treatment paradigm of multiple myeloma. Data are now maturing for the next-generation agent carfilzomib, with US Food and Drug Administration approval expected soon. Several novel agents in this class are also in the pipeline. These second-generation agents appear to be as effective as bortezomib but less neurotoxic, according to studies presented at ASH 2011.
High Response Rates with Carfilzomib Regimen
High response rates and minimal toxicity were seen when carfilzomib was combined with lenalidomide and low-dose dexamethasone in a phase 2 clinical trial presented by Andrzej Jakubowiak, MD, of the University of Chicago Medical Center.
“The carfilzomib/lenalidomide/dexamethasone [CRd] regimen is well tolerated and highly active, demonstrating rapid and deep responses in newly diagnosed myeloma,” Dr Jakubowiak said.
This study included 53 patients who received 8 cycles of CRd and at least 9 additional cycles for maintenance. The 24 patients who were transplant candidates received 4 cycles before their transplant and 4 afterward.
Partial responses or better were observed in 94% of patients after 1 cycle:
- 53% achieved complete response (CR) or stringent complete response (sCR)
- After 12 treatment cycles, 79% achieved a near-CR, CR, or sCR
- High response rates were not affected by stage or cytogenetics.
“These response rates compare favorably to our best frontline regimens, and the study is still early. Responses continue to improve with time. I think this is going to be one of those regimens that will potentially change the landscape of what we can do,” Dr Jakubowiak predicted.
First Oral Agent in Early Development
The first oral proteasome inhibitor, MLN9708, has “similar selectivity and potency, it dissociates from the proteasome faster, and has greater tissue penetration compared with bortezomib,” said Paul G. Richardson, MD, of Dana-Farber Cancer Center, Boston, who has led some of the trials.
“The activity of MLN9708 is dramatic,” he said. “Upfront, we are seeing 100% response rates, which is amazing; and in the relapsed/refractory setting, where we expect to see nothing because patients are so ill, we are seeing response rates, including some very good partial responses, and stable disease. That’s the signal we need in the advanced disease population.”
Dr Richardson reported the results of a phase 1 dose-escalation expansion cohort study of 56 patients who averaged 3.5 previous therapies; 88% had previous bortezomib therapy. MLN9708 was given orally twice weekly in 21-day cycles at a dose of 2 mg/m2.
Of the 46 patients evaluable for response, 6 achieved partial responses or better, including 1 CR. One patient achieved a minimal response, and 28 patients experienced stable disease. Five responders had previously received bortezomib. Disease stabilization has lasted nearly 16 months in many cases, and encouraging activity has been seen in bortezomib-resistant patients.
The drug activity in previously untreated patients is even more striking. Jesus G. Berdeja, MD, of Sarah Cannon Research Institute in Nashville, reported that of 10 treatment-naïve patients enrolled in a phase 1 and 2 study, 9 achieved partial responses or better, including 1 CR and 3 very good partial responses.
Comparing MLN9708 to carfilzomib, Dr Richardson said that although carfilzomib is a welcomed agent in myeloma, “you must give carfilzomib intravenously and weekly 2 days in a row, on days 1 and 2, 8 and 9, and 15 and 16. It is a great drug, and it is associated with less neurotoxicity, but its delivery is inconvenient for the patient. MLN9708 has the advantage of being an oral drug that produces very little neuropathy,” he said in an interview.
Dr Richardson said that this agent has “an excellent tolerability profile.” Fatigue, thrombocytopenia, and nausea are the most common adverse events reported, along with skin rash, especially as first-line treatment, “which patients find quite manageable.”
No peripheral neuropathy grade ≥3 has been reported. Dose reductions as a result of adverse events have been uncommon.
Phase 1 and 2 clicnial trials are evaluating oral and intravenous formulations, using different dosing schedules in a variety of tumor types. Phase 3 trials will begin next year.