– Two-thirds of patients respond
The combination of carfilzomib, pomalidomide, and dexamethasone (CPD), a highly active combination for heavily-pretreated patients with relapsed or refractory multiple myeloma, was well tolerated in the first clinical trial to evaluate the combination in that population.
In a multicenter, phase 1, open-label, dose-finding study, the overall response rate in an intent-to-treat analysis involving 32 patients was 50% and the clinical benefit rate [defined as ≥minimal response (MR)] was 66%.
Sixteen percent of the patients achieved a very good partial response while 34% achieved a partial response and another 16% had a minimal response and disease stabilized in roughly 25% of patients.
After a median follow-up of 26.3 months (range 1-37 months), the median progression-free survival was 7.2 months (95% CI 3-9 months) while the median overall survival was 20.6 months (95% CI 11.9-28.7 months), some 67% of patients still being alive at 12 months.
Notably, both progression-free and overall survival rates were significantly better in patients who achieved either a partial response or a very good partial response at P values of <0.001 and 0.03, respectively.
However, among five patients with deletion of the short arm of chromosome 17, 60% of patients still had not progressed at 12 months and 80% of this small subset of patients was still alive at 12 months — rates that were better than the respective rates of 29% and 67% seen in the overall cohort.
At the maximum tolerated dose of carfilzomib 20/27 mg/m2; pomalidomide, 4 mg, and dexamethasone, 40 mg, the CPD regimen was also judged to be well tolerated.
Of the 32 enrolled patients, 28 experienced either an adverse event related to treatment or developed an infection.
Some 63% of patients experienced any grade 3 event while 31% developed a grade 4 event and two patients developed a fatal event in the form or either pneumonia or pulmonary embolism.
“The promising overall response rate and durable responses seen in patients, regardless of risk stratification, support further clinical trials of the combination in earlier lines of therapy as well as in high-risk myeloma,” Shah and colleagues observed.
“The combination may also provide a backbone for the incorporation of additional anti-myeloma therapies.”
As the authors noted, this was a heavily pretreated patient population with a median of six lines of prior therapy.
Patients progressing on low-dose lenalidomide maintenance were not eligible for study enrolment.
Deep vein thrombosis prophylaxis was mandatory and given as either low-dose aspirin or full anti-coagulation for those with a prior history of deep vein thrombosis.
At least 48 hours prior to day 1 of cycle one, patients received oral hydrate of approximately six to eight cups of liquid per day continuing up to the time of treatment and additional intravenous (IV) hydration was given immediately before and after each carfilzomib dose during cycle one.
Carfilzomib was dosed on days 1 and 2 of cycle one for all cohorts at a starting dose of 20 mg/m2 and was given as an IV infusion over 30 minutes on days 1,2,8,9,15, and 16 and every 28 days for the first six cycles.
Pomalidomide was dosed orally once daily on days 1 to 21, every 28 days.
Dexamethasone, 40 mg, was given weekly either orally or IV on days 1, 8, 15 and 22, every 28 days but after the first four cycles, the dose was halved to 20 mg.
After completing six cycles of treatment, patients could proceed to the maintenance phase of the study, during which carfilzomib was dosed on days 1, 2, 15 and 16, every 28 days while pomalidomide was given on days 1 through to 21, every 28 days.
“If disease progression occurred on maintenance dosing, patients could resume full dosing and add back the day-8 and 9 doses of carfilzomib,” investigators observe.
Patients continued on treatment as long as they were receiving in clinical benefit, they add.
Hematological adverse events (AEs) occurred in 60% or more of patients, including 11 patients who developed grade three or higher anemia.
On the other hand, grade three or higher non-hematological toxicities were uncommon and patients were able to receive a median of 7.7 cycles of therapy, only seven patients discontinuing treatment due to toxicity.
Overall, 12 patients required a reduction in the dose of either carfilzomib or pomalidomide during therapy due to AEs.
As the authors note, the majority of patients at 22 out of the 32 enrolled discontinued treatment because of disease progression.
In the future, a subsequent dose escalation is planned in less heavily pretreated patients to re-evaluate the maximum tolerated dose of carfilzomib in this particular combination of agents.
Asked to comment on the study, Amrita Krishnan, MD, Judy and Bernard Briskin Multiple Myeloma Center, City of Hope National Medical Center, Los Angeles, California, told MedPage Today that they themselves have been using this particular combination based on early results of phase 1 trials.
“We agree that it’s a very active combination in patients with advanced disease,” Krishnan said.
“And I’m glad to see that patients with high-risk cytogenetics are showing these kinds of progression-free survival rates. Results are certainly encouraging.”
Krishnan added that the adverse event profile reported by study investigators was not out of line in patients who had been exposed to so many prior lines of therapy.
“A lot of these adverse events just reflect the fact that bone marrow function in these patients was less robust because of extensive prior therapy,” she said.
“And otherwise, we have found this regimen to be generally well tolerated and the side effects are what we might expect from these drugs.”
Building on the idea of using new generation proteasome inhibitors in relapsed or refractory multiple myeloma, Krishnan and colleagues are currently in the process of evaluating one of the latest generation of proteasome inhibitors, ixazomib plus pomalidomide and dexamethasone in a multicenter phase I, II trial led by the City of Hope investigators.
By Pam Harrison
Original article: http://www.medpagetoday.com/clinical-context/MultipleMyeloma/53697