SAN DIEGO – The potent, next-generation immunomodulatory inhibitor pomalidomide works in at least one-third of patients with relapsed and/or refractory multiple myeloma when nothing else does, a series of studies shows.
MM-002: With Dexamethasone or Alone. One of the most closely watched presentations at the recent American Society of Hematology annual meeting was the one showing phase II results from the phase I/II MM-002 study of pomalidomide with or without low-dose dexamethasone in relapsed and refractory myeloma. The heavily pretreated 221-patient cohort had received a median of five prior regimens (range 2-13), 60% were refractory to lenalidomide (Revlimid) and bortezomib (Velcade), and 99% had received prior dexamethasone.
Dr. Paul G. Richardson
In all, 34% of patients given pomalidomide plus dexamethasone achieved at least a partial response, compared with 13% of those given pomalidomide alone, said Dr. Paul G. Richardson, clinical director of the Jerome Lipper Center for Multiple Myeloma at the Dana-Farber Cancer Institute in Boston. Complete responses were observed in 1% of both groups.
The responses were rapid and the duration of response appeared durable at a median of 8.5 months with single-agent pomalidomide and 7.9 months with the combination. Importantly, stable disease or better was observed in 81% of patients overall, he said.
As observed in the phase I portion of the study, pomalidomide plus dexamethasone was active in the vulnerable population of lenalidomide-refractory patients, with 29% achieving at least a partial response vs. 15% on single-agent pomalidomide. Equally encouraging were similar rates of response in patients refractory to lenalidomide and bortezomib (30% vs. 16%), Dr. Richardson said.
The median time to progression for patients on both drugs was 4.7 months, compared with 2.7 months for those on pomalidomide monotherapy.
Median overall survival reached 16.9 months with both drugs, compared with 14 months with pomalidomide alone. Dr. Richardson pointed out that median overall survival was just 5.4 months for patients with progressive disease as their best response.
Among patients refractory to lenalidomide and bortezomib, the use of pomalidomide and dexamethasone increased the median time to progression from 2.0 months with pomalidomide alone to 3.9 months, and median overall survival from 12.7 months to 13.7 months.
Oral pomalidomide 4 mg/day was administered on a 3-week on, 1-week off schedule with or without dexamethasone 40 mg/week. All patients received daily low-dose aspirin. Notably, 56% of the 108 patients given pomalidomide alone went on to receive dexamethasone due to progression, as per protocol.
During a discussion of the study, Dr. Richardson said the contribution of dexamethasone is critical to the pomalidomide backbone, but that investigators have been struck with how well both regimens are tolerated.
"I’m impressed that it doesn’t have the same muscle cramping and so forth that lenalidomide can sometimes be associated with, and it’s not associated with the diarrhea that can sometimes be a challenge with thalidomide," he said.
Neutropenia was the dominant grade 3-4 adverse event, occurring in 45% of those on single-agent pomalidomide and in 38% on both drugs. Thrombocytopenia was observed in 21% and 19% of patients, respectively. Both adverse events were manageable and required dose reduction in a minimum of patients, Dr. Richardson said.
Importantly, there was no grade 3/4 peripheral neuropathy, an important side effect of treatment with bortezomib, thalidomide, and cisplatin.
On the basis of the findings, pomalidomide is being investigated in phase III trials in the United States and Europe as part of combination treatments including low- and high-dose dexamethasone and bortezomib, he noted.
With Cyclophosphamide and Prednisone. Dr. Antonio Palumbo presented phase II results from a phase I/II study of relapsed or refractory myeloma evaluating continuous pomalidomide 2.5 mg daily in combination with cyclophosphamide 50 mg every other day and prednisone 50 mg every other day. Maintenance therapy with pomalidomide 2.5 mg/day and prednisone 25 mg every other day was given until disease progression.
The 29 evaluable patients had received a median of three prior therapies, and 62% were refractory to lenalidomide.
The most striking findings were the response rates and toxicity, said Dr. Palumbo, chief of the myeloma unit at the University of Torino (Italy).
After a median of four cycles, a partial response or better was observed in 65.5% of patients, at least a very good partial response in 28%, and a complete response in 7%. In the 11 lenalidomide-refractory patients, these response rates reached 81%, 27%, and 9%, respectively, he said.
Responses in the refractory population were described as amazing by an attendee, who asked for a possible explanation. Dr. Palumbo responded that the first explanation is "caution" and that experience shows that a three-drug combination increases efficacy. He went on to say that pomalidomide plus cyclophosphamide and prednisone is a "nice combination with a good risk-benefit ratio."