SAN DIEGO, CA—The first prospective study to assess bortezomib + dexamethasone as second-line treatment in patients with multiple myeloma (MM) found the regimen to be feasible and active, investigators concluded during the 53rd American Society of Hematology Annual Meeting and Exposition. In addition, overall renal function was shown to improve with treatment.

While bortezomib + dexamethasone previously has shown efficacy in patients with MM as a frontline induction therapy and in patients who have relapsed, no studies to date have prospectively assessed the combination as a second-line regimen. In a Phase 2 study, Meletios A. Dimopoulos, MD, University of Athens School of Medicine, Athens, Greece, and colleagues from institutions in Turkey, France, the United Kingdom, the Netherlands, and Germany, evaluated the efficacy and safety of the bortezomib + dexamethasone regimen in patients with relapsed or refractory MM following one prior line of therapy.

Patients ≥18 years of age who had measurable MM, were bortezomib-naive, and had no Grade ≥2 peripheral neuropathy received bortezomib 1.3mg/m2 Days 1, 4, 8, 11 and dexamethasone 20mg Days 1, 2, 4, 5, 8, 9, 11, 12, in 21-day cycles for four cycles. Those who achieved at least a partial response (PR) received an additional four cycles of bortezomib + dexamethasone, while patients with stable disease (SD) were randomized to receive either four cycles of bortezomib + dexamethasone, bortezomib + dexamethasone + cyclophosphamide 500mg Days 1, 8, 15, or bortezomib + dexamethasone + lenalidomide 10mg Days 1–14 for Cycles 5–8. Patients with disease progression were discontinued from treatment.

Primary endpoint was response rate. Secondary endpoints included time to response, duration of response, time to progression (TTP), progression-free survival (PFS), overall survival (OS), safety, and improvement in renal function (defined by glomerular function rate [GFR], assessed prior to treatment on Day 1, Cycles 1–5).

A total of 190 patients were screened and 163 were treated; no patients remain on treatment. Median age was 63 years (range 34–86), 53% were male, 20% had KPS ≤70, and median time from prior therapy was 13.9 months (range 0–119). Prior therapy included dexamethasone, melphalan, vincristine, doxorubicin, prednisone/prednisolone, cyclophosphamide, and high-dose chemotherapy and stem cell transplant.

Of 163 patients treated, response was not evaluable or applicable in 37; in the 126 patients with an independently validated best confirmed response, overall response rate was 52% over cycles 1–4 and 58% at the end of the one-year follow-up period. Median time to first response was 1.4 months; to best response, 2.8 months; and duration of response, 13.7 months. Discontinuations after ≤4 cycles were due to toxicity (n=12), death (n=5), disease progression (n=6), or other reasons (n=5).

According to investigators, 81% experienced a response; 17% had stable disease and 2% disease progression. Median follow-up was 16.9 months (range 0–34.2); median TTP was 9.5 months (95% CI: 7.7–13.3); median PFS was 8.6 months (95% CI: 7.2–11.6), and 55 patients have died. Median OS has not been reached (95% CI: 32.3 months, not evaluable). Estimated 1-year OS rate was 81% (95% CI: 75–87).

Patients receiving sequential therapy were randomized to bortezomib + dexamethasone (n=7), bortezomib + dexamethasone + cyclophosphamide (n=8); or bortezomib + dexamethasone + lenalidomide (n=4). Due to the high response rate for the first four cycles, the second randomization arm was not completed; 77 patients (47%) completed 8 cycles of treatment.

Baseline GFR was determined in 162 patients. In patients who had baseline and on-study assessments, median GFR was 62.8mL/min at baseline and increased after Cycles 1, 2, 3, 4, 5, 6, 7 by 4.5, 5.9, 8.8, 8.8, 6.4, 9.5, and 9.6mL/min, respectively. Median number of treatment cycles was 7 (range 1–8).

Of 24 patients with baseline GFR <50mL/min and renal response with stage migration from baseline GFR to best GFR at Cycle 8, 13 had CR renal, 11 had MR renal. Grade 3/4 adverse events (AEs) occurred in 64% of patients. The most common (>5%) were thrombocytopenia (17%), anemia (10%), and constipation (6%); serious AEs led to dose reductions in 46%, treatment discontinuation in 31%, or death (9%).

In Cycles 1–8, overall rates of sensory peripheral neuropathy (PN) were 20%; for polyneuropathy, 18%; PN, 13%, and motor PN, 1%; Grade 3/4 rates were 5%, 5%, 4%, and 1%, respectively. PN events were reversible in 55% of patients, with resolution in 43%.

The bortezomib-dexamethasone regimen was found to be effective and well tolerated, with <10% of patients receiving subsequent cyclophosphamide or lenalidomide in addition to bortezomib-dexamethasone. PN was manageable, with good reversal rates.