SAN DIEGO, CA—The community-based, Phase 3b randomized, open-label, multicenter UPFRONT trial presented at the 53rd American Society of Hematology Annual Meeting and Exposition has found that three bortezomib-based regimens followed by weekly bortezomib maintenance therapy produced similar overall response rates (ORR), progression-free survival (PFS), and 1-year overall survival (OS) in elderly, newly diagnosed, transplant-ineligible multiple myeloma (MM) patients.
Ruben Niesvizky, MD, of the Center of Excellence for Lymphoma and Myeloma, Weill Cornell Medical College, New York Presbyterian Hospital, New York, and colleagues investigated the following regimens: bortezomib-dexamethasone (Vc-D); bortezomib-thalidomide-dexamethasone (Vc-TD); and bortezomib-melphalan-prednisone (Vc-MP). A total of 502 patients with symptomatic, measurable MM were randomized (1:1:1) to receive 49 weeks of therapy: 24 weeks (eight 21-day cycles) of induction with each regimen. For the respective regimens, the agents were given according to the following dosing: bortezomib 1.3mg/m2 on Days 1, 4, 8, and 11; dexamethasone 20mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 (during Cycles 1–4) and Days 1, 2, 4, 5 (during Cycles 5–8); thalidomide 100mg/day on Days 1–21; melphalan 9mg/m2 on Days 1–4 every other cycle; and prednisone 60mg/m2 on Days 1–4 every other cycle. All regimens were followed by 25 weeks (five 35-day cycles) of maintenance treatment with weekly bortezomib 1.6mg/m2, given on Days 1, 8, 15, and 22.
Patients’ ages as per regimen were a median of 74.5 years (vc-D), 73 years (Vc-TD), and 72 years (Vc-MP); 79%, 68%, and 74%, respectively, had International Staging System stage II/III disease.
A maximum of 13 treatment cycles were completed by patients. Patients receiving Vc-TD were given concurrent prophylaxis with aspirin, full-dose warfarin, or low-molecular weight heparin unless medically contraindicated. Patients received a median of eight (Vc-D), six (Vc-TD), and seven (Vc-MP) treatment cycles; 50%, 38%, and 42% of patients, respectively, received maintenance therapy.
The study’s primary endpoint was PFS; OS, ORR, and safety were three of the secondary endpoints. (See table for response and safety data). All induction regimens showed considerable effect: the ORR rates were 73% (Vc-D), 80% (Vc-TD), and 69% (Vc-MP). After a median follow-up of 21.8 months, median PFS was 14.3 months (Vc-D), 14.9 months (Vc-TD), and 17.3 months (Vc-MP); no significant difference in PFS was seen among treatments. One-year overall survival estimates were 87.4% (Vc-D), 86.1% (Vc-TD), and 88.3% (Vc-MP).
Grade ≥3 adverse events, serious adverse events, and discontinuations due to adverse events were greatest for patients receiving Vc-TD. The most common Grade ≥3 adverse events for all treatment groups included: peripheral neuropathy (23%), fatigue (10%), and diarrhea (9%). Grade ≥3 pneumonia occurred in 10% (Vc-D), 6% (Vc-TD), and 6% of patients (Vc-MP); deep vein thrombosis/pulmonary embolism occurred in 8%, 7%, and 2% of patients, respectively. Across the entire patient population, 5% of patients had Grade ≥3 peripheral neuropathy during cycles 9–13. There was little further toxicity with maintenance therapy when comparing that which occurred with induction therapy.
Dr. Niesvizky and colleagues concluded that patients receiving double-agent therapy (bortezomib-dexamethasone) seemed to have comparable long-term outcomes to patients receiving triple-agent therapy (bortezomib-thalidomide-dexamethasone and bortezomib-melphalan-prednisone).
“Preliminary outcomes data suggest that triplet therapy with VTD or VMP may offer little advantage over doublet therapy with VD for improving response rates and survival outcomes in this patient population,” the study authors added. Therefore, weekly V dosing may be more preferable in the community-based setting.