Bortezomib-Thalidomide-Dexamethasone as Primary Induction Therapy for Newly Diagnosed Multiple Myeloma Significantly Decreases Bone Resorption While Sparing Bone Formation as Compared to Thalidomide-Dexamethasone

Bone disease occurs in approximately 80% of patients with newly diagnosed multiple myeloma (MM) and is caused by the interaction of the neoplastic clone with bone marrow microenvironment, ultimately resulting in an altered balance between bone resorption and bone formation. It has been previously reported that therapies aimed at eradicating the myeloma clone could contribute to decrease bone resorption, even though bone formation remains impaired even in responding patients, due to the use of high-dose steroids. It has been recently demonstrated, both in vitro and in animal models, that Bortezomib improves bone formation by stimulating osteoblasts. In order to test whether this activity was retained also in vivo, we evaluated markers of bone resorption (serum crosslaps) and bone formation (serum osteocalcin-OC and bone alkaline phosphatase - BAP) in a series of patients who were enrolled in the “Bologna 2005” phase III clinical trial at our Center. By study design, after registration patients were randomized to receive three 21-days courses of induction therapy with either VTD (Bortezomib, 1.3 mg/sqm on d 1, 4, 8, and 11, plus Dexamethasone, 40 mg on each day of and after Bortezomib administration plus Thalidomide 200 mg/d from d 1 to 63.) or TD (Thalidomide as in VTD and Dexamethasone 40 mg/d on d 1–4 and 9–12 of every 21-d cycle), prior to stem cell collection and double autologous stem cell transplantation. As of January 2008, 27 patients (19 male and 8 female, median age = 57.5 yrs) entered the sub-study; of these, 15 and 12 patients were randomized in the VTD and TD arm, respectively. At diagnosis, both groups of patients showed a marked increase in serum crosslaps as compared to upper baseline limit (7321±1445pmol/L in the VTD arm and 11140±2576pmol/L in the TD arm) while both OC and BAP were reduced as compared to lower baseline limits. After completion of the induction therapy, serum crosslaps were significantly decreased in both treatment groups (2747±319pmol/L in VTD arm, p=0.007; 3686±1084pmol/L in the TD arm, p=0.0015). In the TD group a significant further reduction in bone formation markers was also observed (42% reduction in serum OC and 30% in BAP, p=0.03 and 0.04 as compared to pre-treatment values); on the contrary, in the VTD arm both OC and BAP were not significantly decreased as compared to baseline values (15% and 11% for OC and BAP, respectively). These data suggest that incorporation of Bortezomib into induction therapy counteracts the inhibitory effects of high-dose steroids on osteoblastogenesis, thus sparing bone formation.