PAD Combination Therapy (PS-341/Bortezomib, Adriamycin and Dexamethasone) for Previously Untreated Patients with Multiple Myeloma.

Background: The most favourable outcomes for patients with MM are seen in those achieving a complete or near complete response following initial therapy. Therefore, it is logical to explore strategies aimed at improving initial response rates. Bortezomib has shown significant activity in patients with advanced MM and has been shown to be superior to pulsed dexamethasone in this setting. Additional efficacy is seen when dexamethasone is combined with bortezomib and in vitro synergy is observed with cytotoxic agents such as adriamycin. On this basis, the PAD regimen was investigated as front line therapy for patients with MM.

Aims: The primary objective of this Phase I/II study was to assess the feasibility of harvesting PBSCs after PAD, with secondary objectives being assessments of safety, toxicity, response rate (RR), PFS and OS.

Methods: Patients with previously untreated MM were eligible. Patients were treated with 4x21 day cycles of PAD comprising bortezomib 1.3 mg/m² on days 1,4,8 & 11 along with 40 mg dexamethasone on days 1–4, 8–11 & 15–18 during cycle 1 and days 1–4 during cycles 2–4. During days 1–4 of each cycle, patients also received 0 mg/m², 4.5 mg/m² or 9 mg/m² of adriamycin at levels 1,2 & 3 respectively. Following harvesting, patients received high dose melphalan (MEL200) with stem cell (PBSC) rescue. Gene expression profiling was performed on purified plasma cells from diagnostic samples for pharmacogenomic analysis.

Results: Thus far, 21 patients have been enrolled (19 male 2 female, median age 55 years [range 36–66]). All 21 have completed PAD with a 95% PR/CR rate. 20/21 patients mobilised PBSC successfully (median collection 3.8 x 10⁶ CD34+ cells/kg, range 1.6–10.4). 16 patients have received MEL200 with median neutrophil (>0.5 x10⁹/L) and platelet engraftment (>20 x10⁹/L) of 15 (1–24) and 13 (10–33) days respectively. Of patients who are assessable at 3 months post MEL200, 11/12 have achieved at least a PR (CR 4, nCR 1, VGPR 4 & PR 2). Toxicities have generally been acceptable with 15 grade 3 events: 6 infections, 4 episodes of shingles, 2 nausea and vomiting, 2 neuropathy and 1 postural hypotension. Overall, 48% of patients have experienced sensory or painful neuropathy which is of Grade 1 severity in 43% of cases. Of note, neuropathic symptoms are improving in all patients after completion of therapy.

Summary: These preliminary data show that PAD is well tolerated in the majority of patients, is highly effective and does not prejudice subsequent PBSC collection. A further cohort of patients will receive PAD with bortezomib at 1.0 mg/m² in order to determine whether the frequency of neuropathy can be reduced whilst preserving efficacy. PAD should be further evaluated as first line therapy in prospective randomised trials.