Bone Effect of Low Dose Bortezomib in Patients with Relapsed/Refractory Multiple Myeloma Yogesh Jethava 1 , Karen Pena 2 , Donghoon Yoon 1 , Caleb Stein 1 and Maurizio Zangari 1* 1 University of Arkansas for Medical Sciences, Myeloma Institute for Research and Therapy, Little Rock, AR, USA 2 Huntman Cancer Institute, Department of Clinical Trials, Salt Lake City, UT, USA * Corresponding author: Maurizio Zangari, University of Arkansas for Medical Sciences, Myeloma Institute for Research and Therapy, Little Rock, AR, USA, Tel: 5016868230; E-mail: MZangari@uams.edu Rec date: Feb 4, 2015, Acc date: Mar 4, 2015, Pub date: Mar 12, 2015 Copyright: © 2015 Jethava Y, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Bone disease in myeloma patients result from the exaggerated osteoclast activity and suppression of osteoblast function in the myelomatous bone marrow and is responsible for most serious complications of myeloma. The bone anabolic effects of bortezomib with 1.3 mg/m 2 and 1 mg/m 2 dosages have been previously reported. In this study, we for the first time examined the effect of Bortezomib 0.7 mg/m 2 dose on bone metabolic parameters in six patients with relapse MM. Even with the low dose used in the trial, we observed increase in the PTH levels in 50% of treated patients and parallel changes in osteocalcin levels, suggesting osteoblastic activation. To our knowledge, this is the first report of bone anabolic effects of bortezomib associated proteasome inhibition at such small doses. Keywords: Multiple myeloma; Hematological malignancy; Bortezomib bone Introduction Multiple myeloma (MM) accounts for approximately 1% of all malignancies and 10% of hematological tumors, representing the second most frequently occurring hematological malignancy in the United States [1]. Bone disease in myeloma patients result from the exaggerated osteoclast activity and suppression of osteoblast function in the myelomatous bone marrow. Presently, the treatment of the bony complications of myeloma primarily involves induction of apoptosis of osteoclasts. In addition, bisphosphonates have been shown to inhibit stromal production of cytokines such as IL-6 and may alter tumor cell adhesion to stroma [2]. Bone disease is responsible for the most severe complications associated with multiple myeloma. As treatment and survival of myeloma patients improve, new therapies that directly stimulate bone formation, increase bone mass, and improves the quality of life of myeloma patients are vitally needed. Materials and Methods Six patients with documented progressive multiple myeloma were enrolled into the study over the period of 18 months. This single arm phase II exploratory study prospectively evaluated the effect of Velcade at 0.7 mg/m 2 dose, given in short course (i.e. 3 cycles) on inducing osteoblast activation as measured by ALP and other bone markers such as PTH in patients with relapsed/refractory myeloma. The secondary aim of the study was to evaluate the association between osteoblastic activation, myeloma response to Velcade in terms of disease progression and to identify predictive factors for Velcade- associated osteoblastic activation. Bortezomib was administered as a single agent in 3-5 second bolus IV injection at the dose of 0.7 mg/m 2 on days 1, 4, 8, and 11 q. 21 days times three cycles. The use of bisphosphonates was not allowed during the study period. Differences in bone markers (PTH, osteocalcin, ionized calcium, phosphorus, alkaline phosphatase) between different myeloma responses were evaluated using median and median percent difference from baseline values.A median two sample test was used to determine point wise differences within the 3 cycles. Smoothed spline plots will be used for visual comparison of responder category across all 3 cycles. Pre and post dose values for architectural parameters will be used to compare responders and non-responders via paired t-tests. The protocol was approved by ethical committee of the University of Utah (Protocol number-X05308/IRB #35813). Written consent was obtained from each patient. Results Six patients were enrolled in the study; with a median age of 69 yrs, 3 patients were IgG isotype, 1 was IgA isotype and two were kappa light chain myelomas. The baseline risk characteristics did not reveal abnormality on interphase FISH and none of the patients had 17p deletion at diagnosis or at the time of enrollment into study. All the patients experience relapse after autologous transplant and had received previously exposed in the course of the disease to proteasome inhibitor drugs and IMiDs. 5 patients had received single agent high dose Melphalan as a conditioning regimen, while one patient received BEAM as conditioning prior to auto-HCT. Post auto-transplant, 4 patients had received maintencance treatment for variable time period ranging 1 to 2 years. The changes in bone marrow plasmacytosis at baseline and the end of study are summarized in the table below (Table 1). Patient No Baseline BM after treatment Asp %PC Bx %PC Asp %PC Bx %PC 1 47.7% 50.0% 38.8% 50.0% Jethava et al., J Hematol Thrombo Dis 2015, 3:2 DOI: 10.4172/2329-8790.1000204 Research Article Open Access J Hematol Thrombo Dis ISSN:2329-8790 JHTD, an open access journal Volume 3 • Issue 2 • 1000204 J o u r n a l o f H e m a t o l o g y & T h r o m b o e m b o l i c D i s e a s e s ISSN: 2329-8790 Journal of Hematology & Thromboembolic Diseases