The Addition of Bortezomib to the Combination of Lenalidomide and Dexamethasone Increases Bone Formation in Relapsed/Refractory Myeloma: a Prospective Study in 91 Patients.

Abstract 1815

Poster Board I-841

Bortezomib is the first-in-class proteasome inhibitor with established activity in multiple myeloma (MM), which also increases osteoblast function both in vitro and in vivo. The addition of bortezomib to the combination of lenalidomide and dexamethasone (RD) regimen seems to increase the RD efficacy. There are very limited data in the literature for the effect of RD on bone metabolism while there are no reports for the effect of BRD on myeloma bone disease. The aim of this study was to evaluate the effect of BRD and RD on bone remodeling of patients with relapsed/refractory MM. We studied 91 patients who participated in a prospective study in which patients with pre-existing peripheral neuropathy (PN) grade <2 received BRD, while patients with PN of grade 2 or more received RD, regardless of their performance status and renal function. In BRD arm, patients received bortezomib at a dose of 1 mg/m² on days 1, 4, 8 and 11; lenalidomide 15 mg on days 1-14 (or at a lower dose if creatinine clearance (CrCl) was <30 ml/min) and dexamethasone 40 mg, PO, on days 1-4, in a 21-day cycle. In RD arm, patients received lenalidomide on days 1-21 at a dose based on their CrCl, according to guidelines, and dexamethasone 40 mg, PO, on days 1-4 and 15-18 for the first 4 cycles and only on days 1-4 thereafter, every 28 days. All patients also received 4 mg zoledronic acid, iv, monthly. Bone remodeling was studied by the measurement of a series of serum indices, on day 1 of cycles 1, 4 & 7, in patients and in 31 healthy controls of similar age and gender: i) osteoclast regulators [sRANKL and osteoprotegerin (OPG)], ii) osteoblast inhibitor dickkopf-1 (Dkk-1), iii) bone resorption markers [C-telopeptide of collagen type-I (CTX) and 5b-isoenzyme of tartrate resistant acid phosphatase (TRACP-5b)], and iv) bone formation markers [bone-specific alkaline phosphatase (bALP) and osteocalcin (OC)]. Radiological skeletal survey was performed at baseline, after 6 cycles of therapy and then as needed, while patients were assessed for skeletal-related events (SREs) throughout the period of the study. As of July 2009, 80 patients (43M/37F, median age 67 years) have received 6 cycles of therapy (40 in each treatment arm) and the bone markers measurements have been completed and analyzed. Myeloma patients at baseline had increased serum levels of Dkk-1 (p<0.001), sRANKL (p=0.006), and bone resorption markers (p<0.01) compared to control group. On the contrary, both markers of bone formation were significantly reduced compared to controls (p<0.001). Strong correlation was observed between Dkk-1 and sRANKL/OPG ratio (r=0.639, p<0.001). Objective response was 60% (24/40 patients) in RD and 62.5% (25/40 patients) in BRD. BRD administration resulted in a significant reduction of Dkk-1 (p=0.031) and increase of OC (p=0.002) after 3 cycles of therapy which was continued after 6 cycles of therapy. Furthermore, BRD led to a reduction of sRANKL (p=0.023) and sRANKL/OPG ratio (p=0.027) and a significant increase of bALP (p=0.01) after 6 cycles of treatment. These changes were irrespective of treatment response. In BRD patients, percentage reduction of Dkk-1 strongly correlated with percentage increase of bALP after 6 cycles of therapy (r=-0.682, p=0.004). In patients who received RD no significant alterations in markers of bone remodeling were observed. However, patients who responded to RD showed a reduction in CTX (p=0.039) compared with those who did not respond after 6 cycles of therapy. Patients who received 6 cycles of RD showed an increase of Dkk-1 levels: responders had a median increase of 9% while non-responders had a median increase of 91% compared to baseline values (p<0.01). The percentage change of sRANKL (p=0.007) and Dkk-1 (p=0.009) was significantly different between patients who received BRD and those who received RD: both molecules were reduced after 6 cycles of BRD while both were increased after six cycles of RD. No SREs were observed in the BRD arm while two patients treated with RD who had not responded to therapy developed a vertebral pathological fracture. Our study suggests that RD regimen does not seem to have any effect on bone formation even in responding patients with relapsed/refractory MM, possibly due to the presence of high dose dexamethasone and to the enhancement of Dkk-1 expression by lenalidomide. On the contrary, patients who received BRD had an increased bone formation, at least partially due to a significant reduction of Dkk-1, reflecting the strong anabolic effect of bortezomib in MM patients.