Abstract
Background: Acute renal failure (ARF) is a frequent complication of multiple myeloma (MM) and most frequently due to clonotypic light chains (LC) causing cast nephropathy, which is associated with fast deterioration of renal function, increased risk for infections and shortened survival. Here we present the final results of a phase II study employing lenalidomide-dexamethasone as treatment for patients with acute light-chain induced ARF.
Patients and methods: 35 patients with LC-induced ARF have been enrolled. Cast nephropathy was confirmed in all 15 patients who had a renal biopsy. Patients with previously unknown MM must have presented with eGFR < 50ml/min and serum creatinine ³2.0mg/dL, and those with previously established diagnosis must have had documented eGFR ³ 60ml/min and serum creatinine ≤1.2mg/dL within 6 weeks before deterioration of eGFR to < 50ml/min and of serum creatinine to ≥ 2mg/dL due to LC-induced kidney injury.
Nine cycles of Lenalidomide, day 1-21, q28 days, with dose adaptation according to eGFR (eGFR 30 – 50ml/min: 10 mg daily, eGFR < 30ml/min without requiring dialysis: 15mg q 48 hrs., eGFR < 30ml/min requiring dialysis: 5 mg daily following each dialysis) and dexamethasone (Dex), 40 mg, day 1-4, 9-12 and 17-21 during the first cycle and thereafter 40 mg once weekly were planned. Renal response was defined as previously described (Dimopoulos et al, Clin Lymphoma Myeloma. 2009, Ludwig et al. JCO 2010).
Results: Patient's median age was: 66 (45-87), 28 patients had newly diagnosed and 7 previously established MM. 5.7% had ISS stage II, 94.3% stage III. 18 patients had light chain myeloma, 14 IgG, and 3 IgA isotype. Adverse cytogenetics t (4; 14) ± del17q ± 1q21 were detected in 14/29 patients.
4/35 patients died and 5 discontinued therapy (3 due to AEs, 1 due to PD, and 1 due to withdrawal of consent) within the first 2 cycles, leaving 26 patients for per protocol (PP) analysis. Median follow up was 17.7 months. Responses were seen in 25/35 (71.4%) patients; 7 (20%) had CR, 3 (8.6%) VGPR, 14 (40%) PR, and 1 (2.9%) MR. Median time to first and to best myeloma response was 28, and 92 days, respectively.
Median baseline concentration of involved FLC was 5.465mg/L (range: 147–42.700mg/L) and 8350mg/L (range: 234– 35.500mg/L) in patients reaching ≥PR and ≤MR, respectively, and decreased significantly to a median of 95.75mg/L (range: 11.3–5.630mg/L, p <0.001) in the former, but not in the latter group.
Renal response was observed in 16 (45.7%) of 35 patients (CRrenal, 5(14.2%), PRrenal, 7(20%), MRrenal, 5(14%)). Median time to renal and to best renal response was 28 and 157 days, respectively. Median eGFR increased significantly in patients with ≥ PR from 17.1ml/min at baseline to 39.1ml/min at best response (p<0.001), and from 23.7ml/min to 26.0ml/min in patients with ≤ MR (p=0.469) (figure 1A).
Median PFS and OS were 5.5 and 21.8 months in the ITT and 12.1 and 31.4 months, respectively, in the PP group (figure 1B).
Grade 3/4 anemia was seen in 43%, thrombocytopenia in 23% and neutropenia in 15% patients. Other non-haematologic AEs consisted mainly of grade 3-4/5 infection in 38%/9%, and of grade 3-4/5 cardiac toxicity in 11%/9% patients. Grade 3 diarrhea and vomiting/emesis were noted in 1 patient each.
Conclusion: Lenalidomide (with dose adapted to eGFR) plus initial high dose Dex during the first cycle and low dose Dex during subsequent cycles resulted in rapid reduction of involved LC within 28 days in patients with ≥ PR. Overall, 71.4% of patients had a myeloma and 45.7% a renal response. Median eGFR increased significantly in patients with ≥ PR from 17.1ml/min at baseline to 39.1ml/min. Elderly patients experienced more toxicity and had more treatment discontinuations.
Figure 1A. Median eGFR in patients with CR-PR and MR-NR at baseline and at best response. Figure 1A. Median eGFR in patients with CR-PR and MR-NR at baseline and at best response.
Figure 1B. PFS and OS in the intent to treat and per protocol population. Figure 1B. PFS and OS in the intent to treat and per protocol population.
Disclosures
No relevant conflicts of interest to declare.
Myeloma Cast Nephropathy Manifesting only as Unexplained Acute Renal Failure