DVD as salvage treatment for a patient with relapsed IgD myeloma and renal failure
Presentation and treatment
A 53-year-old woman presented with anaemia, nephrotic range proteinuria and acute kidney injury with creatinine (Cr) level of up to 915 μmol/L in July 2015. Renal biopsy revealed cast nephropathy. No monoclonal band was detected on serum protein electrophoresis. Immunoglobulin D (IgD) was markedly elevated at 6,463.2 mg/L. Bone marrow examination confirmed the diagnosis of plasma cell myeloma. Fluorescence in situ hybridization study revealed gain of CKS1B at 1q21.
The patient was prescribed bortezomib, thalidomide and dexamethasone (VTD) and received eight sessions of high cut-off haemodialysis, followed by peritoneal dialysis. Complete remission (CR) was achieved after two cycles of treatment. There was partial renal recovery with Cr down to 300 μmol/L. Peritoneal dialysis was stopped 5 months after initial presentation. The patient was put on thalidomide maintenance after five cycles of VTD. (Figure)
Her disease relapsed 2 years after initial presentation. Investigations showed acute on chronic renal impairment, a significant increase in IgD from a normal level to 655.5 mg/L, as well as 14 percent plasma cell infiltration in the bone marrow aspirate. She required haemodialysis support and was started on daratumumab, bortezomib and dexamethasone (DVD) for disease relapse. IgD was swiftly normalized after one cycle of DVD. She was able to stop haemodialysis after three months of treatment. (Figure)
The patient’s disease has remained in CR for 22 months. No significant treatment-related adverse event was reported.
Renal failure is a frequent complication of multiple myeloma (MM) and was reported in approximately one-fifth of patients at disease onset.1 Cast nephropathy is by far the most common form of renal damage. The coprecipitation of free light chains with Tamm-Horsfall protein causes obstruction of the ascending limb of loop of Henle, leading to rapid decline of renal function. Intratubular casts also incite intense inflammation, resulting in tubulointerstitial injury and fibrosis.2 Patients with IgD myeloma have a unique light chain λ variable domain somatic hypermutation, which confers resistance to proteolysis by lysosomal enzymes, favouring crystallization of light chains.3,4
Prior to the era of novel therapeutic agents, the median survival of patients with MM and renal failure was less than 2 years.1 The advent of proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs) has significantly improved the outcome of this group of patients. Bortezomib-based induction is associated with rapid responses, typically occurring within the first two cycles of treatment.5 The pharmacokinetics of bortezomib are independent of renal clearance, and dose adjustment is not required for patients with renal insufficiency. Our patient received induction with VTD, which led to CR after two cycles of treatment and dialysis independence after five cycles. This case illustrates the importance of timely intervention in disease control and reversal of renal injury.Despite tremendous advances, myeloma remains an incurable disease and relapse is inevitable in almost all patients. In the past few years, multiple drugs have been approved for use in the treatment of relapsed/refractory (R/R) MM, including carfilzomib, ixazomib, pomalidomide, elutozumab, daratumumab and panobinstat, based on the positive results shown in various randomized controlled trials.
The DVD regimen was evaluated in the phase III CASTOR study in patients with R/R MM who had received at least one prior line of treatment. In a prespecified interim analysis, the 12-month progression-free survival (PFS) rates were 60.7 percent in patients on DVD and 26.9 percent in patients on bortezomib plus dexamethasone (VD) (median PFS, not reached vs 7.2 months; hazard ratio [HR], 0.39; 95 percent confidence interval [CI], 0.28 to 0.53; p<0.001). The overall response rate (ORR) was 82.9 percent with DVD vs 63.2 percent with VD (p<0.001).6 In an updated analysis, median PFS remained significantly longer in the DVD vs VD arm (16.7 months vs 7.1 months; HR, 0.31; 95 percent CI, 0.25 to 0.40; p<0.0001), with 42-month PFS rates of 22 percent vs 1 percent.7
Latest data from an updated analysis of CASTOR, reported after a median follow-up of more than 3 years, continued to show superior efficacy of DVD vs VD. Of note, patients with high-risk cytogenetics were included in the analysis. Among patients with high-risk cytogenetics, median PFS was 12.6 months in the DVD arm vs 6.2 months in the VD arm (HR, 0.41; 95 percent CI, 0.21 to 0.83; p=0.0106). Among those who received only one prior line of therapy, like our patient, DVD significantly prolonged PFS vs VD for patients with standard-risk cytogenetics (median, 29.8 months vs 7.5 months; HR, 0.25; 95 percent CI, 0.15 to 0.42; p<0.0001) and high-risk cytogenetics (median, 20.1 months vs 8.4 months; HR, 0.20; 95 percent CI, 0.06 to 0.62; p=0.0026). PFS on subsequent line of therapy (PFS2) was also prolonged with DVD vs VD in both standard-risk cytogenetics (median, 34.2 months vs 18.5 months; HR, 0.41; 95 percent CI, 0.30 to 0.58; p<0.0001) and high-risk cytogenetics (median, 28.1 months vs 19.7 months; HR, 0.58; 95 percent CI, 0.30 to 1.10; p=0.0915) subgroups. ORR was significantly higher and rates of CR were numerically higher with DVD vs VD, regardless of cytogenetic risk status (high-risk patients: ORR, 85 percent vs 56 percent; p=0.0512; CR, 18 percent vs 6 percent). Among patients with high-risk cytogenetics, a similar proportion discontinued DVD or VD treatment due to treatment-emergent adverse events (DVD, 10 percent; VD, 9 percent).8
Since patients with severe renal impairment (Cr clearance <20–30ml/min) were excluded from CASTOR and POLLUX trials, there is limited data on the pharmacokinetic, pharmacodynamic and safety profile of daratumumab in dialysis-dependent patients. However, based on the notion that daratumumab is not metabolized by the kidneys, renal failure does not constitute a contraindication to daratumumab. A retrospective study suggests that daratumumab is an effective and safe therapeutic option for patients with R/R MM and end-stage renal failure. The toxicity profile is comparable to that observed in patients with normal or moderately impaired renal function.9 Our patient, who required haemodialysis at the time of relapse, tolerated DVD well without any treatment-related adverse events.
In conclusion, the updated CASTOR trial data reinforce the effectiveness and tolerability of the DVD regimen as a second-line treatment for MM and highlight its utility in high-risk patients. Treatment of relapsed myeloma with renal failure is challenging. Our case also shows that timely treatment with DVD potentially reverses renal failure and leads to dialysis independence.