A Multicenter Phase II Trial of Bortezomib in Patients with Previously Untreated Multiple Myeloma: Efficacy with Manageable Toxicity in Patients with Unexpectedly High Rates of Baseline Peripheral Neuropathy.

Background: Bortezomib (Bz, VELCADE^®) is a novel proteasome inhibitor that has demonstrated efficacy and safety in patients (pts) with relapsed and/or refractory multiple myeloma (MM) in clinical trials. In a large randomized phase 3 trial, Bz achieved superior response rates (RR), TTP, and survival compared with high-dose dexamethasone in relapsed MM pts after 1–3 prior therapies. Peripheral neuropathy (PN) has been dose limiting, especially in pts with pre-existing PN. The objective of this multicenter phase 2 trial was to evaluate the activity and safety of Bz as monotherapy in previously untreated MM pts and prospectively examine PN at baseline (BL) and across treatment.

Methods: Pts received Bz 1.3 mg/m² on d 1, 4, 8, 11 of a 21-d cycle, with RR (CR + PR; EBMT) assessed every 2 cycles. Eligible pts had symptomatic MM with measurable disease and no prior chemotherapy. Concomitant steroids (> 10 mg/d), plt count < 30 x 10⁹/L within 14 d of enrollment or > grade (G) 2 PN were exclusion criteria. RR, TTP, safety and incidence/severity of PN were evaluated. The effect on PN of dose modification (DM) and supplements with specified interventions for symptoms was assessed. Neurologic evaluation involving a pt questionnaire and neurologist’s exam was performed before and after treatment. A 33 pt subset had BL nerve conduction studies (NCS), quantitative sensory testing (QST), autonomic testing, and skin biopsy for quantitation of small-diameter neurite densities (ND). Toxicities were assessed by NCI-CTC, v3.0.

Results: 63 pts (median age 60 y) have been treated. Data are available for 50 pts; 27 pts had IgG kappa MM and 21 pts had stage III disease. BL small-fiber neuropathy (SFN; normal NCS but abnormal QST or autonomic studies) was seen in 16/33 pts (48%). BL skin biopsy showed that 18/30 pts (60%) had small-fiber ND at the 15th percentile of age-adjusted norms; global mean density was at the 23rd percentile. NCS revealed BL axonal PN in 3/33 pts (9%). Among 46 pts evaluable for response, best response after ≥ 2 cycles was CR in 5 pts (11%) and PR in 9 pts (20%) for a RR of 30%. 13 pts (28%) achieved MR, 17 (37%) had SD, and 2 had PD (4%). The most common adverse events were PN, fatigue and rash. 24 pts (48%) developed PN, including 18 with G1 and 5 with G2. One pt had G3 PN and was discontinued. DM (dose reduction or discontinuation) was required in 9 pts. 23 pts have been studied after treatment. New large-fiber neuropathy (LFN) was seen in 4/23 pts (17%) and new SFN in 8 pts. Of 3 pts with BL LFN, 1 was not restudied, 1 had worsening SFN and 1 was unchanged. Small-fiber neurite counts were increased to the 35th percentile. Of 16 pts with BL SFN, 7 had worsening SFN (by QST). Bz was otherwise generally well tolerated.

Conclusion: Bz as monotherapy has shown activity in newly diagnosed MM pts, with a CR of 11% and manageable toxicity. Underlying SFN appears more common in MM than appreciated. Treatment-emergent ≥ G2 PN was observed in 12% of pts and was G3 in 1 pt. Assessment of PN, the effect of interventions and skin biopsy analyses are ongoing.