Phase II Trial of Single Agent Bortezomib (VELCADE®) in Patients with Previously Untreated Multiple Myeloma (MM).

Abstract

Introduction: Bortezomib, a first in class proteasome inhibitor, has become a standard of care in the treatment of relapsed and refractory MM. A recent randomized Phase 3 trial showed an improvement in time to progression (TTP) and overall survival relative to dexamethasone (dex) in patients with relapsed MM and 1–3 prior lines of therapy. In relapsed MM, the rate of treatment -emergent significant peripheral neuropathy (PN) with bortezomib was higher in patients with baseline neuropathy. The incidence and severity of PN in front-line treatment will be important to define. This multi-center, Phase 2 study was planned to evaluate the activity and toxicity (in particular PN) of single agent bortezomib in previously untreated pts. Methods: Response rate, TTP, tolerability, incidence and severity of PN, and the effect of dose modification, symptomatic treatment and nutritional supplements on PN were evaluated in previously untreated, symptomatic MM pts. Pts received bortezomib 1.3 mg/m2 on D 1, 4, 8, and 11 of a 21-d cycle and response to treatment was assessed every 2 cycles. Dex was not permitted. Neurologic evaluation was required before and after treatment, and if significant PN developed during therapy. Results: 28 pts with symptomatic MM have been treated with a median age of 60 yrs, IgG isotype in 68% and Stage III disease in 52%. Analysis of best paraprotein response after ≥ 2 cycles revealed CR in 1 (5%) pt and PR in 8 (36%), for an ORR of 41% in 22 evaluable pts. An additional 5 pts (23%) achieved MR, with stable disease in 6 pts (27%); 2 pts progressed (9%). The most commonly reported adverse events included PN, fatigue, GI symptoms and rash. Neurological evaluation has been performed in all pts, including nerve conduction studies (NCS), assessment of autonomic function and skin biopsy for EM imaging of small fibers in a subset (n=19). Six of 28 pts (21%) so far have developed PN with most being G2: 1 pt experienced G3 PN and drug was discontinued. Dose modification was required in 4 pts and supplements have been used in all pts with PN. Preliminary results of neurological testing and NCS have indicated subclinical PN at baseline prior to therapy in 6/19 (30%) of pts evaluated by NCS, with small fiber, axonal PN documented in 1 pt with treatment-emergent PN. Bortezomib-related toxicity has otherwise been manageable. Conclusion: Single agent bortezomib is a promising approach for newly diagnosed pts and is without the complications of high-dose dex. The incidence of subclinical PN by NCS at baseline prior to therapy is currently 30%; G2 or greater treatment-emergent PN has occurred in 21% of pts and was G3 in only 1 pt (4%) to date. Further assessment of PN including analysis of skin biopsies is ongoing.

The Emerging Role of Targeted Therapy for Hematologic Malignancies: Update on Bortezomib and Tipifarnib

“…Two studies have been conducted that demonstrate the efficacy of single-agent bortezomib as first-line treatment in newly diagnosed patients. In a multicenter phase II study, 1.3 mg/m 2 bortezomib in the usual regimen was administered as a single agent to 22 patients with previously untreated multiple myeloma; dexamethasone was not permitted [24]. Overall response rate after more than two cycles of therapy was 41% (CR in one patient [5%]; PR in eight patients [36%]); MR was noted in an additional five patients (23%), six patients (27%) had stable disease (SD), and two patients (9%) progressed.…”

Constitutive Activation of STAT3 in Myeloma Cells Cultured in a Three-Dimensional, Reconstructed Bone Marrow Model

“…The value of this 3D system was further demonstrated in the same study that a relatively high dose of bortezomib eliminated only a subset of MM cells growing in the 3D culture, and this finding contrasted with the observation in conventional culture in previous studies in which nano-molar doses of bortezomib were sufficient to induce substantial cytotoxicity [33,34]. Importantly, the partial resistance to bortezomib seen with this 3D model appears to correlate with the poor response rate to bortezomib monotherapy in MM patients [35,36]. In light of these findings, two more recent studies have adapted the same 3D model for assessment of the efficacy of novel anti-MM agents.…”

Multiple myeloma: 2011 update on diagnosis, risk‐stratification, and management

“…Bortezomib, alone and in combination with dexamethasone (Rd), has shown the activity in newly diagnosed myeloma [58, 88–90]. Harousseau and colleagues compared VD versus vincristine, adriamycin, and dexamethasone (VAD) as pretransplant induction therapy [71].…”