Efficacy of Daratumumab Monotherapy on Bone Metabolism of Patients with Advanced Relapsed/Refractory Multiple Myeloma: Results from the Phase 2 Rebuild Study
Authors: Terpos Evangelos , Kastritis Efstathios , 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 2020

Introduction: Osteolytic lesions (OL) is a devastating characteristic of multiple myeloma (MM) that decreases patients (pts) quality of life. The interaction between MM plasma cells and the bone microenvironment leads to intracellular and intercellular pathways that adversely alter the delicate balance between bone formation and bone resorption. Pre-clinical studies have shown that anti-CD38 therapy inhibit osteoclast formation. Daratumumab (dara), an IgG1κ human monoclonal antibody that targets CD38, has shown deep hematological responses in heavily pre-treated pts with relapsed/refractory MM (RRMM) as monotherapy. The aim of the REBUILD study is to evaluate the effect of dara monotherapy on bone metabolism in advanced RRMM pts.

Methods: REBUILD is a prospective, open-label, multicenter, phase 2 study which has completed the enrolment of 57 pts with documented RRMM and ≥2 prior lines of therapy, including lenalidomide and a proteasome inhibitor. Pts had a Karnofsky Performance Status score of ≥70, and a creatinine clearance of ≥30 mL/min. Exclusion criteria included previous treatment with dara or other anti-CD38 therapy. Pts receive dara 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 was 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 dara 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]); markers of osteoclast regulation (receptor activator of nuclear factor kappa-B ligand [RANKL], osteoprotegerin [OPG] and chemokine (C- C motif) ligand-3 [CCL-3]); markers of osteoblast control (sclerostin [SCL], dickkopf-1 [DKK-1]), and progression-free survival (PFS). This preliminary analysis included pts who received the first dose of study treatment at least 5 months before the cut-off date (01/05/2020).

Results: Fifty-one pts were enrolled in 6 sites; among them 29 pts had bone markers and clinical data available on baseline and after 4 months of study treatment and are included in the present analysis. Median age was 73 years, and approximately half of them were female (15 pts, 52%). Median number of previous therapies was 3 (range: 2-5). Fifteen pts (52%) had &gt;10 osteolytic lesions at study initiation, and only 4 pts (14%) received bisphosphonates together with dara monotherapy. The median changes in CTX and TRACP-5b levels for all pts (n=29) after 4 months in study treatment were 3.9% and -2.2%, respectively. Overall, 10 pts (35%) had ≥ 30% reduction in CTX and 5 pts (17%) in TRACP-5b levels. The median changes after 4 months of dara monotherapy for pts with a response [pts who achieved partial response or better (≥PR; n=18, 62%)] were 3% for CTX and -3% for TRACP-5b; among pts with no response [minimal response, stable disease, disease progression, or no response assessment prior to death (n=11; 38%)] 4% for CTX, and 9% for TRACP-5b. The median changes in bone formation markers for all pts after 4 months of dara were 24.5% for bALP, 116.8% for OC, and 15.7% for PINP. The differences for pts with a response versus pts without a response were respectively 26% versus 18% for bALP, 190% versus -61% (p=0.020) for OC, and 22% versus -3% for PINP. Other major differences in 4 months of dara monotherapy were the decrease in DKK-1 by 49% in pts with a response versus 2% increase in pts with no response, and the decrease in CCL3 by 15% in pts with response versus 101% increase in pts with no response (p=0.039). The median PFS for all 51 pts was 4.6 months (95% CI: 2.8-7.2).

Conclusions: Monotherapy with dara has a positive effect on bone metabolism even in these highly pre-treated pts with MM. Reduction of TRACP-5b and of CCL-3 in responsive pts suggests an inhibitory effect on osteoclasts by dara. Interestingly, we found that there is a strong bone formation effect in all pts treated with dara monotherapy, especially in those who responded to therapy, i.e. OC had a 2-fold increase after 4 months of therapy. This is at least partially due to the reduction of DKK-1 (osteoblast inhibitor) in responding patients. Based on these positive results a preclinical study on the effect of dara on bone cells is currently being performed.

Disclosures

Terpos: Amgen: Honoraria, Research Funding; BMS: Honoraria; Sanofi: Honoraria; Celgene: Honoraria; Takeda: Honoraria, Other: travel expenses , Research Funding; Janssen: Honoraria, Research Funding; Genesis pharma SA: Honoraria, Other: travel expenses , Research Funding. Kastritis:Janssen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Hatjiharissi:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Abbvie: Honoraria; Genesis pharma SA: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Katodritou:Theagenion Cancer Hospital: Current Employment; Karyopharm: Research Funding; Abbvie: Research Funding; Genesis Pharma: Honoraria, Other: Expenses, Research Funding; Takeda: Honoraria, Other: Expenses, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Verrou:Abbvie: Honoraria; Amgen: Honoraria; Genesis: Honoraria; Roche: Honoraria; Takeda: Honoraria; Karyopharm: Research Funding; Janssen Cilag: Honoraria, Research Funding. Gavriatopoulou:Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Leonidakis:Health Data Specialists S.A.: Current Employment. Delimpasi:Janssen: Honoraria; GENESIS: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Kyrtsonis:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis pharma SA: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Papaioannou:Gilead: Honoraria; Genesis Pharma: Honoraria; Janssen-Cilag: Honoraria; Alexion: Membership on an entity's Board of Directors or advisory committees. Symeonidis:Sanofi/Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; WinMedica: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding; Astellas: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dimopoulos:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees.