Single-agent bortezomib in previously untreated multiple myeloma: efficacy, characterization of peripheral neuropathy, and molecular correlations with response and neuropathy

Abstract

PURPOSE To assess efficacy and safety of single-agent bortezomib in previously untreated patients with multiple myeloma, investigate prevalence of baseline and treatment-emergent polyneuropathy, and identify molecular markers associated with response and neuropathy. PATIENTS AND METHODS Patients received bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11, for up to eight 21-day cycles. A subset of patients underwent neurophysiologic evaluation pre- and post-treatment. Bone marrow aspirates were performed at baseline for exploratory whole-genome analyses. Results Among 64 patients, 41% had partial response or better, including 9% complete/near-complete responses; median duration of response was 8.4 months. Response rates did not differ in the presence or absence of adverse cytogenetics. After median follow-up of 29 months, median time to progression was 17.3 months. Median overall survival had not been reached; estimated 1-year survival was 92%. Thirty-two patients successfully underwent optional stem-cell transplantation. Bortezomib treatment was generally well tolerated. At baseline, 20% of patients had sensory polyneuropathy. Sensory polyneuropathy developed during treatment in 64% of patients (grade 3 in 3%), but proved manageable and resolved in 85% within a median of 98 days. Neurologic examination, neurophysiologic testing, and measurements of epidermal nerve fiber densities in 35 patients confirmed pretreatment sensory neuropathy in 20% and new or worsening neuropathy in 63%. Pharmacogenomic analyses identified molecular markers of response and treatment-emergent neuropathy, which will require future study. CONCLUSION Single-agent bortezomib is effective in previously untreated myeloma. Baseline myeloma-associated neuropathy seems more common than previously reported, and bortezomib-associated neuropathy, although a common toxicity, is reversible in most patients.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

(A) Kaplan-Meier estimates of time to progression (TTP), progression-free survival (PFS), and event-free survival (EFS). (B) Kaplan-Meier estimates of overall survival.

Fig 2.

Representative PGP9.5 immuno-labeled pretreatment images of axons in vertically sectioned punch skin biopsies from patients; stratum corneum of the epidermis is uppermost with dermis below. (A) Biopsy from a 46-year-old man that is devoid of expected axonal innervation at baseline. Quantitation of intraepidermal nerve fibers identified a neurite density of 65/mm2 skin surface area, at the third centile for age and diagnostic of small-fiber polyneuropathy. (B) Biopsy from a 54-year-old woman before therapy. Quantitation of intraepidermal nerve fibers identified a neurite density of 325/mm2 skin surface area, at the 78th centile for age, which is within the normal range. These tissues were photographed using a Leica Microsystems (Wetzlar, Germany) DM/LS light microscope (40x objective) coupled to an Olympus (Tokyo, Japan) DP25 Microscope Digital Camera. No digital processing was performed.