Abstract
Background: Pomalidomide has demonstrated excellent activity in patients with relapsed, lenalidomide refractory, multiple myeloma (MM). Between November 2007 and March 2012, we enrolled 285 patients with relapsed MM on 5 sequential phase 2 trials; patients received pomalidomide at 2mg or 4 mg daily with weekly dexamethasone (Pom/dex). The approved dose of pomalidomide is 4 mg for 21 of 28 days. We wished to compare efficacy, tolerability and long-term outcomes between cohorts treated with 2 mg or 4mg daily continuously and 4mg daily for 21/28 days.
Methods: After excluding two ineligible patients, 283 patients with lenalidomide refractory, relapsed MM from 5 sequential cohorts were analyzed. These patients were divided into 3 groups: Group1 received Pom 2mg for 28/28 day cycle (N= 69), Group 2 received Pom 4 mg for 28/28 day cycle (N= 95) and Group 3 received Pom 4mg for 21/28 day cycle (N= 119). All patients received oral dexamethasone given 40 mg daily on days 1, 8, 15, and 22. Response was assessed by the IMWG Uniform Response criteria. All patients received aspirin 325 mg daily for DVT prophylaxis or full dose anticoagulation.
Results: The median age was 63 years (32-85); 35% were female. The median time from diagnosis was 53 months and the median number of prior regimens was 4. 127 (46%) had high-risk molecular markers. Prior therapies (% received) included lenalidomide (100%), thalidomide (46%), bortezomib (78%), autologous stem cell transplant (71%), and allogeneic transplant (4%). The median follow-up is 16.4 months (3.2-64.4). Forty eight percent are alive and 26% remain progression free; 15 patients are continuing to receive treatment. Frequency of AEs by groups are shown in Table 1. The most notable difference is grade 3+ neutropenia seen in 39% of group 1 and 56% and 57% of groups 2 and 3. Confirmed responses of PR or better were seen in 29% (group1), 35% (group2) and 24% (group3). Median duration of response (DOR) was 14.1 months (group1), 14.5 months (group2) and 10.2 months (group3). Median PFS was 5.5 months (group1), 6.9 months (group2) and 4.3 months (group3). Although the dose level cohorts were sequential rather than randomized, we compared OS between the dose levels in an exploratory manner. There was no significant difference in OS between dose levels (p=0.26). Median overall survival (OS) was 16.6 months (group1), 21.9 months (group2) and 16.0 months (group3).
Conclusions: Pom/dex is active and well tolerated even in heavily pretreated patients Responses are durable. Response rates and overall toxicity are similar between the 2 mg and 4 mg doses. Neutropenia is more common in those receiving doses of 4mg daily or for 21/28 days compared to those receiving 2 mg daily.
| All Grades | Grade 3+ | |||||
|---|---|---|---|---|---|---|
| 2mg 28 Day | 4mg 28 Day | 4mg 21 Day | 2mg 28 Day | 4mg 28 Day | 4mg 21 Day | |
| Anemia | 68% | 58% | 74% | 14% | 15% | 27% |
| Lymphopenia | 22% | 51% | 11% | 16% | 32% | 8% |
| Neutropenia | 71% | 82% | 77% | 39% | 57% | 56% |
| Thrombocytopenia | 51% | 61% | 63% | 10% | 9% | 23% |
| Leukopenia | 59% | 77% | 72% | 26% | 38% | 39% |
| Pneumonia | 7% | 11% | 12% | 6% | 7% | 11% |
| Fatigue | 51% | 65% | 60% | 9% | 5% | 8% |
| Neuropathy | 28% | 32% | 28% | 0% | 3% | 0% |
| Elevated Blood Glucose | 10% | 21% | 8% | 4% | 6% | 3% |
| Pneumonitis | 3% | 2% | 3% | 3% | 1% | 1% |
| VTE (Thrombosis) | 3% | 3% | 3% | 1% | 3% | 3% |
| Secondary Malignancy | 0% | 2% | 1% | 0% | 2% | 1% |
| All Grades | Grade 3+ | |||||
|---|---|---|---|---|---|---|
| 2mg 28 Day | 4mg 28 Day | 4mg 21 Day | 2mg 28 Day | 4mg 28 Day | 4mg 21 Day | |
| Anemia | 68% | 58% | 74% | 14% | 15% | 27% |
| Lymphopenia | 22% | 51% | 11% | 16% | 32% | 8% |
| Neutropenia | 71% | 82% | 77% | 39% | 57% | 56% |
| Thrombocytopenia | 51% | 61% | 63% | 10% | 9% | 23% |
| Leukopenia | 59% | 77% | 72% | 26% | 38% | 39% |
| Pneumonia | 7% | 11% | 12% | 6% | 7% | 11% |
| Fatigue | 51% | 65% | 60% | 9% | 5% | 8% |
| Neuropathy | 28% | 32% | 28% | 0% | 3% | 0% |
| Elevated Blood Glucose | 10% | 21% | 8% | 4% | 6% | 3% |
| Pneumonitis | 3% | 2% | 3% | 3% | 1% | 1% |
| VTE (Thrombosis) | 3% | 3% | 3% | 1% | 3% | 3% |
| Secondary Malignancy | 0% | 2% | 1% | 0% | 2% | 1% |
Kaplan Meier Overall Survival Curves
Lacy:Celgene: Research Funding. Fonseca:Medtronic, Otsuka, Celgene, Genzyme, BMS, Lilly, Onyx, Binding Site, Millennium, AMGEN: Consultancy, patent for the prognostication of MM based on genetic categorization of the disease. He also has sponsored research from Cylene and Onyx Other, Research Funding. Bergsagel:Novartis: Research Funding; Constellation Pharmaceutical: Research Funding; OncoEthix: Research Funding; MundiPharma: Research Funding. Stewart:Novartis: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Array BioPharma: Consultancy; Sanofi: Consultancy; Takeda Pharmaceuticals International Co.: Research Funding. Reeder:Millennium, Celgene, Novartis: Research Funding. Mikhael:Onyx: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding.
