Treatment of myeloma cast nephropathy: New insights from the MYRE study Frank Bridoux, MD, PhD Jean Paul Fermand, MD Department of Nephrology, University Hospital, Poitiers, France Department of Immunology and Hematology, Saint Louis Hospital, Paris, France IKMG Research Group - 4 th International Meeting Montreal, Canada May 23-24, 2019
Myeloma cast nephropathy • AKI at diagnosis of myeloma: 20-40%, 5-10% of patients require dialysis • Main cause = LC cast nephropathy ‒ Intra-tubular precipitation of monoclonal LC with uromodulin ‒ High tumor mass MM (LC-only MM ++) ‒ Predominant LC proteinuria (> 90%) ‒ Renal recovery rate if dialysis required: ~20% before novel agents
Dialysis-dependence and OS in myeloma • Survival of Dialysis-Dependent Myeloma Patients • IKMG cohort : - N = 85 – 2 year mortality rates: - Biopsy-proven MCN USRDS 2001-2010 - Severe AKI Myeloma – 41% - Hematologic response ≥ PR All others – 21% Leung N, et al. ASH 2011 – Median OS: RR = withdrawn from dialysis ERA-EDTA 1985-2005 Myeloma – 10.9 months NR = dialysis-dependent All others – 53.5 months French registry (REIN) 2002-2011 Myeloma – 16 months All others ~ 61 months
Myeloma cast nephropathy: treatment strategy 1. Urgent symptomatic measures: • Vigorous IV rehydration with saline/alkaline fluids • Correction of precipitating conditions: hypercalcemia, nephrotoxic drugs… 2. High-dose steroids (Dexamethasone 40 mg/day, D 1-4) 3. Chemotherapy preferentially based on agents without renal elimination • Alkylators: cyclophosphamide • Doxorubicine • Novel agents: ‒ Proteasome inhibitors: Bortezomib, Ixazomib, Carfilzomib ‒ Immunomodulating agents (Imids): Thalidomide, Pomalidomide, ( Lenalidomide) ‒ Anti-plasma cell (CD38) mAb: Daratumumab 4. Rapid removal of circulating nephrotoxic LCs? • Plasma exchanges Bortezomib + Dex = current standard of care • High-cutoff hemodialysis ~ No randomized study in MM patients with AKI
The MYRE study ClinicalTrials.gov NCT01208818 Phase III multicentric randomized controlled trial in 48 French centers (2011-2016) Aims of the study 1. Epidemiology of cast nephropathy Respective frequency of cast nephropathy and other Ig-related nephropathies in patients with multiple myeloma and other monoclonal gammopathies 2. Treatment of myeloma cast nephropathy revealing symptomatic myeloma Requiring dialysis: Comparison of intensive hemodialysis with high cutoff dialyzer vs . conventional high-flux dialyzer Not requiring dialysis: Comparison of Bortezomib + Dexamethasone (BD) vs . Cyclophosphamide + Bortezomib + Dex (C-BD)
MYRE randomized controlled trial Acute kidney injury (AKI) Monoclonal + serum creatinine > 170 µmol/L Immunoglobulin (MIg) (2.0 mg/dl) Screening period (4-15 days) Symptomatic measures Haematological Renal diagnosis (including high-dose steroids) Diagnosis Myeloma + MCN (proven or probable) + persistent AKI No dialysis requirement Hemodialysis requirement Randomization for dialyzer Randomization for chemotherapy Bortezomib-Dex vs. Cy-Bor-D HCO vs High flux
MYRE randomized controlled trial Assessed for eligibility (n=425) “ Excluded ” (n=141) (neither MM nor MCN, renal recovery …) Randomized (n=284) No HD requirement Patients actually requiring hemodialysis (HD) (n= 186) after symptomatic measures (n= 98) Classic membrane HCO membrane (n= 48) (n= 50) Other diagnosis (n=3) LCDD (n=2), ATN (n=1) Consent withdrawal (n=1) Analyzed (n= 48) Analyzed (n= 46) Creat. 6.4 [5.3;8.1] mg/dL Creat. 7.3 [5.2;9.2] mg/dL
MYRE randomized controlled trial Myeloma + persistent AKI with hemodialysis requirement + biopsy-proven MCN R HCO Theralite ™ Conventional (2.1 m 2 ) high-flux dialyser Stratification on age 8 sessions of 5 hours ≤65 yrs vs >65 yrs over the first 10 days then 3 per week Same Bortezomib-based chemo in the 2 arms Bortezomib (1.3 mg/m 2 D 1,4,8,11) + Dexamethasone (20 mg D 1-2, 4-5, 8-9, 11-12) 21-day cycles, reinforced with cyclophosphamide (750 mg/m 2 IV on day 1), if no haematological response after 3 cycles
MYRE Study: biopsy-proven MCN – high flux vs HCO HD Hematological response Control (n=48) HCO (n=46) P value After 1 cycle 71 % [22-91%] 89 % [61-99%] P=0.022 median sFLC reduction rate (%) [IQR] 31 % 43% P=0.29 sFLC <500 mg/L (%) At 3 months ≥PR 62 % 89 % P=0.003 ≥VGPR 44 % 61 % P=0.22 At 6 months ≥PR 60 % 78 % P=0.06 ≥VGPR 48 % 70 % P=0.033 PR and VGPR, ≥ 50% and ≥ 90% reduction in involved sFLC, respectively
MYRE Study: biopsy-proven MCN – high flux vs HCO HD Renal response Control (n=48) HCO (n=46) P value (Chi2 test) HD independence Cum incidence at 3 mo 33 % 41 % 0.42 at 6 mo 35 % 57 % 0.04 at 12 mo 37.5 % 61 % 0.02 Median time to HD 1 mo 2 mo independence Alive without HD 35 % 52 % 0.15 at 12 mo High dose melphalan N= 6 N =13 0.07 and autotransplantation
MYRE Study: biopsy-proven MCN – high flux vs HCO HD Cumulative incidence of dialysis independence Late HD-independence (after 3 months): HCO (n=9) vs Control (n=2) Bridoux F, et al. JAMA 2017; 318: 2099-2110
MYRE Study: biopsy-proven MCN – high flux vs HCO HD Overall survival Bridoux F, et al. JAMA 2017; 318: 2099-2110
MYRE Study: biopsy-proven MCN – high flux vs HCO HD Predictive indicators of renal response Univariate analyses Multivariate analysis Variable OR (95%CI) P-value OR (95%CI) P-value Age ≥ 65 0.85 (0.36-2.02) 0.72 Pre-existing MGUS 0.80 (0.28-2.25) 0.67 Pre-existing CKD 1.29 (0.36-4.56) 0.69 (eGFR > 30ml/min/1.73m 2 ) Lambda LC 1.18 (0.52-2.66) 0.69 Whole Ig-secreting myeloma 2.62 (1.14-6.05) 0.024 2.75 (1.11-6.80) 0.028 High-risk cytogenetics 1.00 (0.28-3.56) 1.00 sFLC at baseline 3,000-6,000 0.39 (0.12-1.32) 0.13 6,000-12,000 0.77 (0.20-2.92) 0.70 >12,000 0.40 (0.12-1.32) 0.13 sFLC <500 mg/L after 1 cycle 3.00 (1.25-7.18) 0.014 2.51 (1.00-6.33) 0.049 Randomization in HCO arm 2.59 (1.13-5.97) 0.025 2.78 (1.13-6.80) 0.026
MYRE Study: biopsy-proven MCN – high flux vs HCO HD Conclusions Both groups received same hemodialysis dose (daily 5h-sessions) and same BD regimen HCO-HD vs high-flux HD: • Good feasibility in standard hemodialysis facilities • Good tolerance profile: SAE: 39% in HCO group vs 37% in control group • Higher efficacy of HCO-HD for sFLC removal, whatever the isotype • No difference in HD-independence rate at 3 months, but study underpowered • Significantly higher HD-independence rates at 6 and 12 months • No difference in overall survival
90 randomized patients, followed for 2-years • Randomization upfront (no pre-inclusion) • Same chemotherapy with Bortezomib-Dexamethasone-Adriamycin (PAD) • Different dialyzers and different dialysis dose: HCO group (n= 43): daily 8h-sessions with 2 HCO dialyzers in series (1.1 m 2 surface) - (8 sessions over 10 days, alternate days from D12 to D21), then 6h thrice weekly Control group (n= 47): 3 weekly 4h-sessions with conventional HF dialyzer -
EuLITE : renal responses Renal response at 3 months: 56% in HCO group vs 51% in control group (NS) Overall renal response (24 months): 58% in HCO group vs 66% in control group (NS) Hutchison CA et al. Lancet Haematol 2019; 6: e217-e228
EuLITE : overall survival Lung infections in the first 3-months : n=13 in HCO group vs n=3 in control group (P=0.008) OS at 2-years : 63% in HCO group vs 81% in control group (P=0.03) Hutchison CA et al. Lancet Haematol 2019; 6: e217-e228
HCO hemodialysis in myeloma cast nephropathy MYRE EuLITE Inclusion of patients who might have Randomization After a screening period At diagnosis lost indication for HD after steroids Including symptomatic measures and a 4- day HD steroid course and symptomatic treatment? Doublet (Bortezomib Dex) Triplet (Bort.-Adri.-Dex.) Chemo regimen ± Cyclophosphamide Dialysis schedule Similarly intensive in both groups Highly intensive in HCO group Daily 5h-sessions x 8, then thrice weekly Daily 8hr session for 10 days, thrice Higher infectious risk and higher weekly days D12-D21, then 6h treatment interruption (21%) in Standard in control group HCO group 4h-session thrice weekly Two 1.1 m 2 dialyzers in series Single 2.1 m 2 dialyzer HCO dialyzer HD independence at 3 months 41% (HCO) vs . 33% (HF) p= 0.42 56% (HCO) vs . 51% (HF) p= 0.81 at 6 months 56.5% (HCO) vs. 35% (HF) p= 0.04 58% (HCO) vs . 66% (HF) p= 0.76 at 12 months 61% (HCO) vs. 37.5% (HF) p= 0.02 58% (HCO) vs. 66% (HF) p= 0.76
Treatment of myeloma cast nephropathy In patients with AKI not requiring hemodialysis: • What is the best chemotherapy ? • Are triplet regimens superior to the standard bortezomib dexamethasone doublet ?
MYRE randomized controlled trial Assessed for eligibility (n=425) “ Excluded ” (n=141) (neither MM nor MCN, renal recovery …) Randomized (n=284) Hemodialysis (HD) No HD requirement requirement (n= 98) (n= 186) BD C-BD (n= 93) (n= 93) Other diagnosis LCDD (n=2) Analyzed Analyzed (n= 92) (n= 92)
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