Apixaban pharmacokinetics in newly diagnosed multiple myeloma patients treated in the benefit and isasocut clinical trials: The apixabor/mibapix study

Abstract Introduction The use of immunomodulatory drugs (IMiDs)-containing regimens (CD38 MAb +Rd or +VRd) is the standard of care (SOC) in newly diagnosed Multiple Myeloma (NDMM), and optimal thromboprophylaxis has become essential. Direct oral anticoagulant drugs (DOACs), such as apixaban, play a key role as supportive care drugs in NDMM to prevent the occurrence of venous thromboembolic events (VTE). DOACs are susceptible to drug-drug interactions (DDIs), and DDIs are a significant cause of adverse drug reactions. DOACs are impacted by medications affecting the permeability glycoprotein (P-gp) and CYP3A4 inhibitors/inducers and may modulate apixaban pharmacokinetics (PK). Bortezomib (V) is classified as a CYP3A4 inhibitor, while dexamethasone (DXM) is classified as P-gp and CYP3A4 inducers (Sorigue 2020). So, we sought to study the DDI interaction between apixaban and the NDMM SOC regimens. We present a study assessing (1) the apixaban concentration-time profile in NDMM receiving low dose d-containing regimens, (2) whether the addition of bortezomib increases apixaban concentration, (3) the thrombosis and bleeding rates within 6 months after the start of treatment. Methods This study was ancillary to the phase 3 randomized 2 arms BENEFIT (Isatuximab +VRd and IsaRd) and phase 2 single arm ISASOCUT (Isa 1400mg SC OBI +VRd) studies for transplant ineligible (TI) NDMM patients and was offered to patients receiving apixaban for thromboprophylaxis per protocol twice daily. V was administered weekly (1.3 mg/m² SC) for the first 12 months, then days 1 and 15 up to month 18 in BENEFIT, while V was administered biweekly in cycle 1, and weekly thereafter up to 12 months in ISASOCUT. Lenalidomide was given 25 mg daily, days 1 to 21, DXM was given 20 mg weekly up to 12 months in BENEFIT and ISASOCUT. Blood samples were collected before and after anti-MM treatment at day 15 of cycles 4 and 5. Apixaban concentrations were determined using mass spectrometry. A two-compartment model with first-order absorption and elimination was fitted to the observed apixaban concentration vs. time data (Leil 2024). Welch's t-test were used to evaluate bortezomib addition impact. Data were analyzed using monolix and GraphPad Prism software. Results The PK analysis used 308 apixaban concentrations from a total of 84 patients across the 2 studies and 24 IFM centers. The median age was 73 years (IQR: 71-75); 22 patients (26%) were ≥75 years old, median creatinine clearance was 66 mL/min (IQR: 55-79), 31% had albumin<35 g/L, and 2% had elevated liver enzymes. DXM was given in 96% and 68% received V. The apixaban dose was reduced (2.5 mg twice daily) for 82% of patients, while 18% received the full-dose (5 mg twice daily). The PK were adequately described with a two-compartment model and parameters were estimated with reasonable precision. For a typical subject, CLR/F (apparent renal clearance) and CLNR/F (apparent non-renal clearance) were estimated to be 2.09 L/h and 1.60 L/h, respectively. The estimates of ka (rate constant), Vc (apparent volume of central compartment), Q (apparent intercompartment clearance), Vp (apparent volume of distribution of the peripheral compartment) were 0.45 (standard deviation effect (SDE) 0.53), 29.13 L (0.25), 2.16 L/h (0.49) and 18.37 L (0.74), respectively. In patients receiving d-containing regimens, (IsaVRd and IsaRd), the average concentration prediction (C) max was 100 ng/mL [5-95 percentile: 62-202] and C min was 67 ng/mL [38-140]. Bortezomib was not significantly associated with variations in plasma apixaban concentration (Vc: -1.8 (95%CI -5.2 - 0.3), p = 0.08 and CLNR/F: -1.6 (-0.4 - 0.05), p = 0.12), suggesting no CYP3A4 inhibitor effect impact of bortezomib on apixaban exposition. After 6-month follow-up, thromboembolic event/minor bleeding/major bleeding rates were low (0%/3.6%/0%). Conclusion Plasma apixaban concentration is higher in NDMM TI patients compared to other product indications (surgery Cmax 77 ng/mL, ADAGE 2-3 study), suggesting no DXM impact at low dose. Bortezomib does not modify apixaban concentration. No thrombosis and no major bleeding events occurred. Our results support the use of apixaban as an optimal SOC for thromboprophylaxis in TI-NDMM treated with IsaVRd and IsaRd. Further studies will need to be conducted to determine the benefit/risk balance of continuing apixaban beyond 6 months from treatment start.