Consolidation Therapy with Bortezomib, Thalidomide and Dexamethasone (VTD) Regimen After ASCT in Myeloma Patients Who Do Not Receive Bisphosphonates Reduces Bone Resorption and RANKL/OPG Ratio but Seems to Have No Effect On Bone Formation and Angiogenesis.

Abstract 3863

Poster Board III-799

Bortezomib (V) monotherapy is associated with increased osteoblastic activity, reduced osteoclast function and decreased angiogenesis in relapsed/refractory myeloma (MM). The co-administration of zoledronic acid in all reported studies to-date may suggest a synergistic stimulation on osteoclast/osteoblast interactions by the two agents but has not allowed the independent evaluation of V on bone metabolism. Furthermore, the combination of V with other agents, such as thalidomide (T), melphalan (M) and dexamethasone (D), although it reduced osteoclast activity, it did not enhance osteoblast function. We evaluated the effect of VTD consolidation on bone metabolism and angiogenesis in MM patients who underwent high-dose M followed by ASCT. In this prospective study, only patients in first remission or with primary refractory disease to one frontline treatment were included. Patients did not receive any bisphosphonate during or post-ASCT as well as throughout the period of VTD consolidation. VTD started on day 100 after ASCT: V was administered at a dose of 1.0 mg/m² on days 1,4,8,11; T was given at a dose of 100 mg/day, po, on days 1-21 and D at a dose of 40 mg/day on days 1–4 of a 21-day cycle. Patients received 4 cycles of VTD (first block), were followed without treatment for 100 days and then received another 4 cycles of VTD (2^nd block). Patients were assessed for skeletal-related events (SREs) throughout the period of the study (12 months). Bone remodeling was studied by the measurement of the following serum indices before and after each block of VTD (4 measurements for each patient): i) osteoclast regulators [sRANKL and osteoprotegerin (OPG)], ii) osteoblast inhibitor dickkopf-1 (Dkk-1), iii) bone resorption markers (CTX and TRACP-5b) and iv) bone formation markers [bone-specific alkaline phosphatase (bALP) and osteocalcin (OC)]. Angiogenic cytokines such as VEGF, angiogenin (ANG), angiopoietin (Angp)-1 and -2, and bFGF were also studied on the same dates. So far, 32 patients have completed the first block of VTD, while 16 patients have completed both VTD blocks. Just before VDT administration, 10 patients were in CR (4 in sCR), 14 in vgPR and 8 in PR. Although most of these patients were rated as vgPR or better, they had increased serum levels of sRANKL (p=0.037), Dkk-1 (p=0.001), CTX (p=0.002), TRACP-5b (p<0.001), VEGF (p<0.001), bFGF (p<0.001), ANG (p=0.006) and reduced levels of Angp-1/Angp-2 ratio (p<0.001) compared to 18 healthy controls of similar age and gender, indicating sustained osteoclast and angiogenic activity despite minimal tumor load. Levels of sRANKL and Dkk-1 positively correlated with resorption markers (p<0.01). The first block of VTD resulted in a significant reduction of sRANKL (p=0.001), sRANKL/OPG (p=0.005), CTX (p=0.001), TRACP-5b (p=0.032), but also of bALP (p=0.022) and OC (p=0.02), while Dkk-1 and the majority of angiogenic cytokines showed no alterations (only Angp-1/Angp-2 ratio had a borderline increase, p=0.044). After the first block of VTD, 39% of patients improved their status of response; however alterations of the studied molecules were irrespective of further response or not improvement. Before the administration of the 2nd block of VTD, RANKL, RANKL/OPG and CTX were reduced compared to values after the first block of VTD (p=0.01, p=0.027 and p=0.005, respectively). These parameters were further reduced after the completion of the study (p<0.05). On the contrary, Dkk-1 was increased between the end of the first block of VTD and the initiation of the 2^nd (p=0.008) but was reduced after the 2^nd block of VTD (p=0.037). OC had no further alterations, while bALP was increased before the 2^nd block of VTD (p=0.012) and showed no changes thereafter. VEGF, ANG, and Angp-1/Angp-2 were increased during the resting period between the two VTD blocks and remained unchanged thereafter. During the study period, only one patient developed a SRE (i.e. radiation to bone). As of July 2009, 8 of 32 patients have developed progressive disease. The median TTP after ASCT was 27 months (CI 95% 16.3-37.6). The results of this ongoing study suggest that VTD consolidation post-ASCT, without the presence of bisphosphonates, reduces RANKL and bone resorption and is associated with a very low incidence of SREs. However, bortezomib was not able to produce a significant anabolic effect on bones when combined with TD even in these patients with low myeloma burden, while its effect on angiogenic cytokines was modest.