Updated results from MM-003 trial of pomalidomide plus low-dose dexamethasone: cytogenetics and long-term survival

The MM-003 clinical trial compared the use of pomalidomide plus either low- or high- dose dexamethasone, for the treatment of patients with relapsed and refractory (RR) Multiple Myeloma (MM), after failed treatment with bortezomib and lenalidomide. A favorable outcome was observed for pomalidomide plus low-dose dexamethasone. In an updated analysis, long-term survival was assessed along with a cytogenetic sub-group analysis, and was published in Haematologica in July 2015, by Meletios A. Dimopoulos from the National and Kapodistrian University of Athens, School of Medicine, Greece, and colleagues. Study design and treatment regimen are detailed in a previous MMHub article.

Key Findings:

Patients (pts) were randomly assigned into pomalidomide plus low-dose dexamethasone (POM+LoDEX) or pomalidomide plus high-dose dexamethasone (POM+HiDEX)

Data are given as: POM+LoDEX vs POM+HiDEX:

• Median PFS = 4.0 vs 1.9 months; HR = 0.50; P<0.001
• Median OS = 13.1 vs 8.1 months; HR = 0.72; P=0.009
• Safety profile was consistent with that reported in the original publication
• The most common grade 3/4 adverse events were neutropenia (49% vs 17%), anemia (33% vs 39%), and infections (33% vs 24%)
• Discontinuation due to adverse events (AEs): 9% vs 10%
• POM+LoDEX treated for ≥1 year: most frequent grade 3/4 AEs = neutropenia (52%) and infections (43%); anemia and thrombocytopenia (both 9%) were less frequent than POM+LoDEX safety population
• PFS survival benefit was observed in all cytogenetic subgroups:
  • del(17p) = 4.6 vs 1.1 months; HR = 0.34; P<0.001
  • t(4;14) = 2.8 vs 1.9 months; HR = 0.49; P=0.028
  • standard-risk = 4.2 vs 2.3 months; HR = 0.55; P<0.001
• OS by cytogenetic subgroup:
  • del(17p) = 12.6 vs 7.7 months; HR = 0.45; P=0.008
  • t(4;14) = 7.5 vs 4.9 months; HR = 1.12; P=0.761
  • standard-risk = 14.0 vs 9.0 months; HR = 0.85; P=0.380
  • OS benefit achieved despite HiDEX pts subsequently receiving POM: 46% of del(17p)/t(4;14) and 64% of standard-risk
• Within the HiDEX arm, del(17p) and t(4;14) are associated with worsened outcomes:
  • median PFS: standard-risk = 2.3 months, del(17p) = 1.1 months, t(4;14) = 1.9 months (P=0.023 and 0.161, respectively).
  • median OS: standard-risk = 9.0 months, del(17p) = 7.7 months, t(4;14) = 4.9 months               (P=0.019 and 0.516, respectively)
• Within the LoDEX arm, ORR differed dramatically: del(17p) = 31.8%, standard risk = 35.1%, t(4;14) = 15.9%
• Rate of response to HiDEX: del(17p) = 4.3%, standard risk = 9.7%, t(4;14) = 13.3%
• Subsequent treatments: 33/63 pts in POM+LoDEX arm who progressed following achievement of a PR or better were treated with at least one subsequent therapy
• Median time from progression to next therapy = 1.8 months (range, 0.02–7.8 months)

This updated analysis further confirms the benefit of pomalidomide plus low-dose dexamethasone for RRMM patients across all subgroups, including those with high-risk genetic subtypes. Particular benefit of POM+LoDEX was observed for patients with del(17p), for whom outcomes were comparable to standard-risk patients. Therefore, this further supports the use of pomalidomide plus low-dose dexamethasone as a viable treatment pathway for RRMM patients, following the exhaustion of bortezomib and lenalidomide regimens.