Once Weekly Bortezomib (Velcade) Preserves Bone Health by a Direct Effect on Osteoclast Function Independent of Its Effect on the Malignant Plasma Cells.

Abstract

Bone resorption is increased in multiple myeloma (MM) due to increased osteoclast activity leading to osteoporosis and osteolytic bone lesions. Assays of urinary excretion of N-telopeptide (NTX), a highly specific marker of bone resorption, decrease by 20–70% following treatment with bisphosphonates. Receptor activator of NF-kB (RANK) ligand increases osteoclast mediated bone resorption in part through activation of nuclear factor kappa-B(NF-kB). Preclinical studies have shown bortezomib to decrease osteoclast function through inhibition of NF-kB. However, no clinical data exists on the effect of bortezomib on markers of bone resorption. We designed a prospective clinical trial aimed at measuring the effect of bortezomib on urinary NTX excretion and serum osteocalcin levels in patients with MM. Patients received six cycles of consolidation bortezomib 1.3mg/m2 given once weekly (for ease of administration) for 4 of every 5 weeks, 90–120 days post transplant. Urinary NTX excretion and serum osteocalcin were measured on day 1 of cycles 1, 2 and 3 of therapy. Treatment with bisphosphonates was prohibited from 42 days prior to stem cell collection and until cycle 3 of post transplant bortezomib therapy. To date, 31 of 40 enrolled patients have proceeded to receive bortezomib consolidation therapy and are evaluable for markers of bone metabolism. Characteristics of the patient population and disease include (no. of patients): male (21), female (10), median age 56 years (range 39–70), Stage II (8), Stage III (23), IgG (20), IgA (9), free light chain (2). The median duration between discontinuation of prior bisphosphonate therapy and initiation of post transplantation weekly bortezomib was 158 days (Range 132–196). Of the 19 patients who have completed all 6 prescribed cycles of consolidation bortezomib, only one patient has had a 50% or greater reduction in paraprotein, 16 had stable disease and 2 had disease progression. Nevertheless, excretion of NTX decreased by a mean of 7.4 nmol/mmol creatinine over each 5 week treatment cycle (p=0.007) with a mean decline of 33% over baseline values after 2 cycles of consolidation, once weekly bortezomib therapy (see table). Only one patient displayed an increase in urinary NTX of greater than 30%. This was the only patient with evidence of disease progression during this period of consolidation. Contrary to preclinical and clinical reports of proteasome inhibition resulting in increased osteoblastic bone formation, a decrease was seen in serum osteocalcin. This data suggests that bortezomib, given just once weekly, has a substantial inhibitory effect on osteoclastic bone resorption in MM even in the absence of effects on the malignant plasma cells. The magnitude of effect appears comparable to that achieved with bisphosphonates. Given concerns regarding long term toxicities of bisphosphonate therapy, including nephrotoxicity and osteonecrosis of the jaw, bortezomib may represent an alternative agent effective in controlling both the myeloma and bone disease in this patient population.Cycle 1 Day 1Cycle 2 Day 1Cycle 3 Day 1Mean Changep valueMean Osteocalcin (Range)(ng/ml)28.16 (9.30 – 81.90) (n = 28)26.69 (9.50 – 57.40) (n = 25)26.12 (11.60 – 73.00) (n = 21)−4.6 (16%)0.02Mean NTX excretion (Range)(nmol/mmol Cr)44.87 (10 – 121) (n = 23)36.00 (7 – 65) (n = 24)30.43 (9 – 87) (n = 21)−14.8 (33%)0.007