P16: DARATUMUMAB MONOTHERAPY HAS A FAVORABLE EFFECT ON BONE METABOLISM IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA; RESULTS OF THE PHASE 2 REBUILD STUDY

Introduction: Non-invasive biomarkers of bone metabolism are indicative of bone dynamics during anti-myeloma treatment. Daratumumab (dara) inhibits in vitro osteoclastogenesis and bone resorption. We assessed the impact of dara monotherapy on bone remodeling in patients (pts) with relapsed/refractory multiple myeloma (RRMM). Methods: REBUILD was a prospective, open-label, phase 2 study conducted in six centers in Greece. Eligible pts were adults with RRMM, who had ≥2 prior lines of therapy including lenalidomide and a proteasome inhibitor (PI). Exclusion criteria included previous treatment with anti-CD38 antibodies, including dara. Pts received intravenous dara according to the usual clinical practice. The primary endpoint was the percent change from baseline in values of bone resorption markers C-terminal cross-linking telopeptide of type 1 collagen (CTX) and tartrate-resistant acid phosphatase isoform 5b (TRACP-5b) after 4 months of dara monotherapy. Secondary endpoints included the change from baseline to 4 months of dara monotherapy in bone formation markers (e.g., bone-specific alkaline phosphatase [bALP], osteocalcin [OC], and procollagen type-I N-propeptide [PINP]), markers of osteoclast regulation (RANKL, osteoprotegerin, dicckopf-1 [DKK-1], sclerostin and C-C motif ligand-3 [CCL3]), progression-free survival (PFS), and overall survival (OS). Results: The present analysis is based on 33 pts with available data. The pts’ median (range) age was 73.0 (52.0–84.0) years, and most were female (18, 54.5%). Most (16, 48.5%) pts had >10 lytic bone lesions at baseline. Six (18.2%) pts received bisphosphonates along with dara monotherapy. The ORR (Partial Response or better [≥PR]) was 63.6% (CR: 3.0%, VGPR: 21.2%, PR: 39.4%). The CTX median change from baseline to 4 months was 3.9%, with 13 (39.4%) and 11 (33.3%) pts having a ≥20% and ≥30% reduction in CTX levels, respectively. The TRACP-5b levels decreased from baseline to 4 months by a median of 2.6%, with 10 (30.3%) and 6 (18.2%) pts having a ≥20% and ≥30% reduction in TRACP-5b levels, respectively. The median changes from baseline to 4 months in the CTX and TRACP-5b levels for pts with a ≥PR at 4 months were -1.3% and -2.6%, respectively; the respective changes for pts without response (i.e., pts with minimal response, stable disease, disease progression, or no response assessment before death) were 5.3% and -7.2%. The levels of the bone formation markers bALP, OC, and PINP increased from baseline to 4 months, the median changes being 18.4%, 92.6% and 10.2%, respectively. For pts with ≥PR at 4 months, the median changes from baseline to 4 months in bALP, OC, and PINP levels were 25.3%, 146.0% and 15.7%, respectively; the respective changes for pts without response were 18.3%, 15.6% and -7.3%. Other major differences at 4 months included the decrease in DKK-1 by a median of 17.5%, the decrease in CCL3 by 16.0%. The median (95% confidence interval) PFS and OS were 9.3 (6.7–15.3) and 21.2 (11.4–not reached) months, respectively; the respective results in all 57 patients were 4.7 (3.0–7.2) and 10.5 (8.4–18.1) months. Conclusions: In these highly pre-treated pts with MM, monotherapy with dara showed a positive effect on bone metabolism; OC had a 3-fold increase after 4 months of therapy. The reduction in TRACP-5b and in CCL-3 but not in CTX suggests a mild inhibitory effect on osteoclasts by dara.