An open-label, pharmacokinetic study of lenalidomide and dexamethasone therapy in previously untreated multiple myeloma (MM) patients with various degrees of renal impairment - validation of official dosing guidelines.

Lenalidomide is a backbone agent in the treatment of multiple myeloma, but dose adjustment is required for those with renal impairment (RI). We evaluated the pharmacokinetics (PK) and safety of lenalidomide and dexamethasone as frontline pre-transplant induction, with doses adjusted at start of each cycle based on creatinine clearance, as per the official dosing guidelines. After 4 cycles, PK studies showed that patients with moderate RI (30 ≤ CrCl < 60 mL/min) receiving 10 mg dosing may be under-dosed and those with severe RI (CrCl <30ml/min) appeared appropriately dosed initially, but sustained significant decreases in maximum serum concentration (Cmax) after repeated dosing, due to rapid clinical improvement and enhanced drug clearance. PK drug monitoring during cycle 1 may facilitate appropriate and timely dose adjustments. Adverse events rates did not vary based on severity of RI. No patient discontinued lenalidomide for toxicity. This supports the feasibility and safety of frontline lenalidomide in transplant-eligible patients with RI.

A phase 2 study of ofatumumab (Arzerra®) in combination with a pan-AKT inhibitor (afuresertib) in previously treated patients with chronic lymphocytic leukemia (CLL).

AKT plays a centralized role in tumor proliferation and survival and is aberrantly activated in chronic lymphocytic leukemia (CLL). In this phase 2 trial, 30 relapsed/refractory CLL patients were treated with combination afuresertib, a novel oral AKT inhibitor, and ofatumumab for 6 months, followed by afuresertib maintenance for 12 months. We aimed to achieve deeper and more durable responses, without requiring long-term continuous treatment. Treatment was generally well tolerated but respiratory infections were common, with 18% severe requiring hospitalization. Hematologic toxicities were manageable (grade 3-4 neutropenia 39%). At a median follow-up of 13.4 months, overall responses were 50% (complete responses 3.6%). Median progression-free survival was 8.5 months and overall survival 34.8 months. Combination therapy with ofatumumab and afuresertib is active and well tolerated, but does not appear to lead to durable responses and may not provide additional benefit over single-agent ofatumumab in relapsed/refractory CLL. Novel agent combinations are currently undergoing intense investigation.

A phase 2 study of lenalidomide and dexamethasone in previously untreated patients with chronic lymphocytic leukemia (CLL).

Lenalidomide has anti-tumor activity in CLL but can be complicated by tumor lysis syndrome (TLS) and tumor flare (TF). In our previous study using low-dose lenalidomide in treatment-naive CLL, TLS was averted but TF remained frequent and complete responses (CR) were rare, despite treatment to progression. The addition of dexamethasone may mitigate TF and enable lenalidomide dose escalation, achieving durable response without long-term use. In this phase 2 trial, 31 treatment-naive CLL patients received lenalidomide (target 25mg daily) plus dexamethasone for a finite 18 cycles. No patients developed TLS and TF was infrequent. Overall responses were 74.2% (CR 9.7%) and median progression-free survival 27 months. Cereblon-binding proteins IKZF1 and IKZF3 were largely downregulated, with associated increased IRF4 levels. We therefore report that lenalidomide plus dexamethasone can achieve durable responses in a subset of patients without continuing therapy until progression. Upregulation of IRF4 may contribute to anti-CLL activity of immunomodulatory agents. This trial was registered at www.clinicaltrials.gov as NCT01133743.