Phase II trial of pomalidomide plus low-dose dexamethasone in RRMM patients with renal impairment 

Renal Impairment (RI) is a major issue faced by 20–30% of Multiple Myeloma (MM) patients. RI in MM is associated with poor prognosis and an Overall Survival (OS) of less than two years. Due to the impact of RI on the pharmacokinetics of drugs excreted by the kidneys, RI limits treatment options in patients with Relapsed and Refractory MM (RRMM). MM-013 is the first phase II, open-label, noncomparative study to assess the efficacy, renal response, safety, and pharmacokinetics of pomalidomide plus low-dose dexamethasone (LoDEX) in RRMM patients with moderate or severe RI, with the inclusion of patients receiving hemodialysis. The study was conducted by Meletios Dimopoulos, from National and Kapodistrian University of Athens, School of Medicine, Athens, Greece, and colleagues and was published in the Journal of Clinical Oncology in February 2018.

Study design:

• N = 81 patients (pts) enrolled
• Pts must have received ≥1 prior anti-myeloma regimens, including lenalidomide
• All pts had impaired renal function with an estimated glomerular filtration rate (eGFR) of < 45 mL/min/1.73 m²
• Pts were enrolled in three cohorts:
  • cohort A: moderate RI (eGFR: 30 to < 45 mL/min/1.73 m²)
  • cohort B: severe RI (eGFR: < 30 mL/min/1.73 m²)
  • cohort C: severe RI requiring hemodialysis
• Pts received pomalidomide at 4 mg/d on days 1–21
• Pts also received LoDEX at 20 mg (if age > 75 years) or 40 mg (if age ≤ 75 years) once per week in 28-day cycles
• Primary endpoint was Overall Response Rate (ORR)

Key Findings:

• Patient (pt) numbers: Cohort A = 33; Cohort B = 34; Cohort C = 14
• Median age of population = 72 years (52–86)
• Median time from MM diagnosis to enrollment = 3.8 years (0.5–19.4)
• Pts received a median of four prior anti-myeloma regimens
• Most pts had chronic (> 1 month) renal insufficiency
• All pts received prior lenalidomide treatment and 97.5% had received prior bortezomib
• Prior stem cell transplantation in 25% of pts
• Kidney biopsy results in 23.5% of pts and confirmed MM-related renal disease

All data is given as cohort A (moderate RI), cohort B (severe RI) and cohort C (severe RI requiring hemodialysis):

• Cytogenetic abnormalities at baseline level = 45.5%, 35.3% and 85.7% pts
• Cutoff date = January 28, 2017 (13 pts still on treatment)
• ORR = 39.4%, 32.4% and 14.3%
• Clinical Benefit ((CB) minimal response or greater) = 51.5%, 41.2% and 21.4%
• Disease control (stable disease or greater) in cohort C = 78.6%
• Pts who achieved Partial Response (PR) or greater:
  • Median time to response (months) = 0.99, 95 and 1.91
  • Median duration of response (months) = 14.7, 6 and not estimable
• Baseline eGFR, prior therapy, and time since diagnosis met a threshold of P < 0.2 and were entered into a multivariable analysis
• Significant predictors of myeloma response in multivariable analysis:
  • Prior therapy: Odds Ratio (OR) = 3.25; 95% CI, 1.03–10.25; P = 0.0438
  • Time since diagnosis: OR = 3.65; 95% CI, 1.17–11.43; P = 0.0260
• Median duration of treatment (months) = 6.7, 4.9 and 2,4
• Median number of treatments cycles = 7 (range 1–21), 5.5 (range 1–20) and 3.0 (range 1–11)
• Median PFS (with a median follow-up of 4.6 months, in months) = 6.5 (95% Cl, 4.60–10.62), 4.2 (95% Cl, 2.79–6.51) and 2.4 (95% Cl, 0.95–6.41)
• Median time to progression (months) = 8.3, 5.5 and 4.0
• Median OS (with a median follow-up of 8.6 months) = 16.4 (95% Cl, 7.79–25.18), 11.8 (95% Cl, 6.35–13.45) and 5.2 (95% Cl, 1.81–9.67) months
• Renal response = 6, 12 and 1 pts
• Worsening of renal function = 6 pts; cohort A = 2 pts and cohort B = 4 pts
• Overall median time to renal response = 0.95 months
• Pharmacokinetics: maximum plasma concentration for pomalidomide absorption (in µg/L) = 75.6, 111.0 and 75.6

Safety:

All data is given as cohort A (moderate RI), cohort B (severe RI) and cohort C (severe RI requiring hemodialysis):

• Pomalidomide dose reductions as a result of adverse events (AEs) = 6, 5 and 2 pts
• Dose interruptions in 49 pts = 19, 22 and 8 pts
• Hematologic AEs (grade 3 or 4):
  • Neutropenia (53.1%), anemia (35.8%), and thrombocytopenia (27.2%)
• Non-hematologic TEAEs (grade 3 and 4):
  • Pneumonia (32.1%), hypocalcemia (4.9%), renal failure (6.2%), and fatigue (6.2%)
• Second Primary Malignancies (SPMs) = 3 pts
• A total of 23 pts (28.4%) died during treatment; the most common cause was disease progression

Conclusion:

This study is the first prospective trial to demonstrate that patients with severe RI and high disease burden have a clinically relevant outcome when treated with pomalidomide plus LoDEX. Additionally, this study demonstrated that the recommended dose of pomalidomide 4 mg/d can be safely administered to all patients in these cohorts.