Impact of Daratumumab Monotherapy on Bone Parameters in Patients with Relapsed and/or Refractory Multiple Myeloma Who Have Received at Least 2 Prior Lines of Therapy Including Lenalidomide and a Proteasome Inhibitor; Interim Analysis of a Phase 2 Study (the REBUILD Study)
Authors: Terpos Evangelos , Kastritis Eftathios , Hatjiharissi Evdoxia , Katodritou Eirini , Eleutherakis-Papaiakovou Evangelos , Verrou Evgenia , Gavriatopoulou Maria , Leonidakis Alexandros , Ntanasis-Stathopoulos Ioannis , Delimpasi Sosana , Kyrtsonis Marie-Christine , Papaioannou Maria , Symeonidis Argiris , Dimopoulos Meletios A. 
Published: November 2019

Introduction: A major clinical feature of multiple myeloma (MM) is osteolytic bone disease, with bone resorption prevailing bone formation. Daratumumab, an IgG1κ human monoclonal antibody that targets CD38, has been licensed for use in patients (pts) with relapsed or refractory MM (RRMM); however, its effect on bone disease has not yet been determined in a clinical setting. CD38 expression has been associated with osteoclast formation and bone resorption in in vitro studies and treatment with daratumumab has demonstrated an inhibitory effect on osteoclastogenesis. This study aims to evaluate the impact of daratumumab monotherapy on biochemical markers of bone metabolism in RRMM pts.
Methods: REBUILD is an ongoing prospective, multicenter, non-comparative, open-label, phase II study aiming to enroll 57 adult pts with documented RRMM who have had ≥2 prior lines of therapy, including lenalidomide and a proteasome inhibitor. Pts should have a Karnofsky Performance Status score of ≥70, and a creatinine clearance of ≥30 mL/min. Exclusion criteria include previous treatment with daratumumab or other anti-CD38 therapy. Pts receive daratumumab at a weekly dose of 16 mg/kg for Cycles 1-2, every 2 weeks for Cycles 3-6 and every 4 weeks thereafter. The primary endpoint of this study is the change from baseline in the bone resorption markers C-terminal telopeptide of collagen type I (CTX) and tartrate-resistant acid phosphatase isoform 5b (TRACP-5b) after 4 months of daratumumab monotherapy. Secondary endpoints include the change at 4 months from baseline in bone formation markers (bone-specific alkaline phosphatase [bALP], osteocalcin [OC], and procollagen type-I N-propeptide [PINP]), in markers of osteoclast regulation (receptor activator of nuclear factor kappa-B ligand [RANKL], osteoprotegerin [OPG] and chemokine (C-C motif) ligand-3 [CCL-3]), osteoblast control (sclerostin, dickkopf-1 [DKK-1]), and progression-free survival (PFS). This interim analysis included pts who received the first dose of study treatment at least 6 months before the cut-off date (26/04/2019).
Results: Twenty-seven pts had been enrolled in 5 study centres of the Greek Myeloma Study Group, and among them 15 had both biomarker and clinical data available after 4 months of therapy and they were included in the present analyses. The median number of previous therapies was 3. Nine (60%) pts had >10 lytic bone lesions at screening. Only 3/15 (20%) pts received bisphosphonates along with daratumumab monotherapy. Regarding the primary endpoint, the median change of CTX and TRACP-5b levels at 4 months from baseline was 13.4%, and -2.6%, respectively. The median change in CTX and TRACP-5b levels at 4 months from baseline for pts with partial response or better (≥PR) (n=7, 46.7%) was 13.4% and -9.4%, respectively; among pts with minimal response or stable disease (n=6, 40%) the change in CTX and TRACP-5b levels was 16.4% and 14.3%, respectively. The levels of all bone formation markers bALP, OC, and PINP showed a median increase at 4 months from baseline by 18.4%, 190.5%, and 19.3%, respectively. For pts with ≥PR, the median change at 4 months from baseline in bALP, OC, and PINP levels was even higher: 25.3%, 338.7%, and 19.3%, respectively. Interestingly, the median change at 4 months from baseline in osteoblast inhibitors sclerostin and DKK-1 levels was -20.3%, and -6.5%, respectively. The median PFS for all 27 pts enrolled was 7.1 months.
Conclusions: Regarding the primary endpoint of the REBUILD study, results from this interim analysis indicate that daratumumab monotherapy decreases TRACP-5b levels, which was more pronounced in responders, but this is not accompanied by a reduction in CTX. An effect on CTX levels may become evident with additional follow-up. However, a clear increase in serum levels of all markers of bone formation tested (bALP, OC, PINP) was observed, especially among responders, which might at least partially be explained by a reduction of the osteoblast inhibitors sclerostin and DKK-1. Thus, daratumumab monotherapy in this RRMM population (heavily pre-treated pts with multiple lytic bone lesions and limited use of bisphosphonates) results in a decrease in TRACP-5b and osteoblast inhibitors and an increase in bone formation markers, suggesting an overall positive impact on bone remodeling. The study is ongoing and updated results will be presented at the meeting.

Disclosures
Terpos: Takeda: Honoraria, Other: Travel expenses, Research Funding; Genesis: Honoraria, Other: Travel expenses, Research Funding; Janssen: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria; Medison: Honoraria. Kastritis:Amgen: Honoraria, Research Funding; Pfizer: Honoraria; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Prothena: Honoraria; Genesis: Honoraria. Hatjiharissi:Janssen: Honoraria. Katodritou:Takeda: Honoraria; Janssen: Honoraria; Genesis: Honoraria; Amgen: Honoraria. Gavriatopoulou:Takeda: Honoraria, Other: Travel expenses; Genesis: Honoraria, Other: Travel expenses; Janssen: Honoraria, Other: Travel expenses; Amgen: Honoraria. Leonidakis:HeaDS: Employment. Delimpasi:Janssen: Honoraria; Genesis: Honoraria, Other: Travel grant; Amgen: Honoraria; Takeda: Honoraria. Symeonidis:MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dimopoulos:Sanofi Oncology: Research Funding.