Novel Thrombogenic Biomarkers In Patients with Relapsed/Refractory Multiple Myeloma (MM) Treated with Lenalidomide (LEN) and Dexamethasone (Dex) Therapy
Authors: Burbury Kate , Gambell Peter C , Choo Amanda , Curnow Jennifer , Lynch Kevin , Harrison Simon J. , Quach Hang , Ritchie David , Prince Miles , Westerman David Alan A 
Published: October 2019

Abstract
Abstract 3187
Thromboembolism (TE) is an important complication of cancer with substantial clinical implications. MM, treated with thalidomide (thal) and LEN, has TE rates up to 25%, particularly when used in combination with chemotherapy and corticosteroids. Given disease heterogeneity, bleeding and TE risks are different for all patients and individuals over time. With the emergence of novel antithrombotic agents, further understanding of the pathophysiology of both MM- and therapy-related hemostatic dysfunction and the identification of important biomarkers, may promote a risk-stratification process and allow a targeted therapeutic strategy. We prospectively and sequentially assessed novel thrombogenic biomarkers, with a plan to correlate with functional assays (thrombin generation and microparticles) in R-MM, before and after exposure to LEN/dex as part of a 150-patient phase-II clinical trial. Hemostatic assessments were performed at enrolment, 1-, 4-, 12-months and/or end of study. 27 patients at our institution, 15 males, median age 69 years (range 58–80) were included in the analysis: 16 had IgG monoclonal protein (13 kappa [k]), 9 IgA (6 k), 2 were k light chain only. The karyotype was diploid in 18, complex in 4 and 3 patients had t(4;14), t(11;14) or t(8;14) respectively. Median number of prior lines of therapy was 3 (range 1–7); 18 had prior thal and 15 had received a melphalan-based autologous stem cell transplant. Median (range) for Hb was 111g/L (80-137) and creatinine clearance 66.6mL/min (23-182). 6/27 had a prior TE: 1 arterial, 5 venous. All patients commenced antithrombotic therapy at enrolment: 20 received aspirin (100mg/day), 4 prophylactic and 2 therapeutic dose enoxaparin, 1 treatment dose warfarin. At enrolment (pre-LEN/dex) and after 4 weeks of therapy, the median (range) for the individual assays are outlined in table 1. Pre-LEN/dex: FVIIIc, vWFAg, Fib Mon, TAT, PF1+2 and TM were markedly elevated in the majority of patients. After 4 weeks of therapy, many biomarkers remained elevated, however, Fib Mon and PMN-E near normalised in all patients; FVIIIC and vWFAg was elevated in less patients; while Fib, PF1+2 and TAT increased. This early promising data demonstrate inflammatory, endothelial and hemostatic dysregulation in R-MM with an altered biomarker profile after exposure to LEN/dex. Further results of sequential analyses will be presented at the meeting.
Study (cycle, day) C1D1 (pre–LEN/dex) n* C2D1 (4–weeks LEN/dex) n* Biomarker (units, NR) Median Range >ULN, <LLN Median Range >ULN <LLN APTT (s, 24–34) 34 24–48 13 0 33 26–52 8 0 PT (s, 11.8–14.6) 13.5 12–25.6 10 0 13.2 11.2–45.2 2 3 Fib (g/L, 2.0–4.0) 4 2.4–6.8 12 0 5.5 0.7–8.4 21 2 D-dimer (mg/L, 0.0–0.5) 0.5 0.1-1.5 9 NA 0.6 0.1–6.4 15 NA Plt (×109/L, 150–450) 214 43–372 0 7 225 30–385 0 6 FVIIIc (%, 50–150) 298 96–600 22 0 236.5 159–600 10 0 vWFAg (%, 50–160) 206 98–325 18 0 298 148–364 12 0 APC-R ratio (2–3.5) 2.3 1.7–3.4 0 3 3.2 1.7–3.6 1 1 AT (%, 80–120) 98 69–135 3 3 108 77–126 4 1 Fib Mon (μg/ml, 0.1– 6) 4.3 2.0–61.2 8 0 3.1 0–95 2 1 TAT (μg/L, <2.0–4.2) 1.1 0.4–37.6 9 14 8.1 2.7–54.7 19 0 PF1+2 (pmol/L, 69–229) 192.3 0.7–705.5 11 2 197.3 35.8–1266.5 8 5 anti-CG (U/ml, <15) 0.2 0-5.2 0 NA 0.1 0–0.6 0 NA TM (pg/mL, 2353–4541) 4739.1 2628–11656.3 15 0 4050.3 244–10613.2 8 2 PMN-E (ng/mL, 0–90) 44 22–276 6 NA 34.8 14–92 1 NA NR: Normal range; APTT: Activated partial thromboplastin time; PT: Prothrombin time; Fib: Fibrinogen; Plt: Platelet count; FVIIIc: Factor VIII-coagulant; vWFAg: von Willebrand factor Antigen; APC-R: Activated protein C resistance ratio; AT: Antithrombin; Fib Mon: Fibrin Monomers; TAT: Thrombin-antithrombin complex; PF1+2: Prothrombin fragments1+2; CG: Cathepsin G; TM: Thrombomodulin; PMN-E: PMN Elastase; NA: values <LLN or >ULN not clinically applicable. * Number of patients (n) within the cohort (n=27), in whom measured level was >upper limit of normal (>ULN) or <lower limit of normal (<LLN).

Disclosures:
Curnow: Celgene: Research Funding; Novartis: Consultancy. Lynch:Celgene Pty Ltd: Employment, Equity Ownership. Harrison:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Prince:Celegene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Westerman:Celgene: Research Funding.