Session: 653. Myeloma/Amyloidosis: Therapy, excluding Transplantation: Poster II
Hematology Disease Topics & Pathways:
multiple myeloma, Diseases, Plasma Cell Disorders, Lymphoid Malignancies
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 >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.
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