treatment of myeloma cast nephropathy: new insights from ... · hd independence cum incidence at 3...
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Treatment of myeloma cast nephropathy:
New insights from the MYRE study
IKMG Research Group - 4th International Meeting
Montreal, Canada
May 23-24, 2019
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
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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
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Dialysis-dependence and OS in myeloma
RR = withdrawn from dialysis
NR = dialysis-dependent
• IKMG cohort : - N = 85
- Biopsy-proven MCN
- Severe AKI
- Hematologic response ≥ PR
Leung N, et al. ASH 2011
• Survival of Dialysis-Dependent Myeloma Patients
– 2 year mortality rates:
USRDS 2001-2010
Myeloma – 41%
All others – 21%
– Median OS:
ERA-EDTA 1985-2005
Myeloma – 10.9 months
All others – 53.5 months
French registry (REIN) 2002-2011
Myeloma – 16 months
All others ~ 61 months
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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
• High-cutoff hemodialysisBortezomib + Dex = current standard of care
~ No randomized study in MM patients with AKI
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The MYRE studyClinicalTrials.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)
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Symptomatic measures(including high-dose steroids)
HaematologicalDiagnosis
Renal diagnosis
Screening period (4-15 days)
MYRE randomized controlled trial
No dialysis requirement
Randomization for chemotherapyBortezomib-Dex vs. Cy-Bor-D
Hemodialysis requirement
Randomization for dialyzerHCO vs High flux
Monoclonal
Immunoglobulin (MIg)
Acute kidney injury (AKI) serum creatinine > 170 µmol/L
(2.0 mg/dl) +
Myeloma + MCN (proven or probable) + persistent AKI
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Assessed for
eligibility
(n=425)
Randomized
(n=284)
“Excluded” (n=141) (neither MM nor MCN,
renal recovery …)
No HD requirement
(n= 186)
Classic membrane
(n= 48)HCO membrane
(n= 50)
Analyzed (n= 48)
Creat. 6.4 [5.3;8.1] mg/dLAnalyzed (n= 46)
Creat. 7.3 [5.2;9.2] mg/dL
Other diagnosis (n=3) LCDD (n=2), ATN (n=1)
Consent withdrawal (n=1)
MYRE randomized controlled trial
Patients actually requiring hemodialysis (HD)
after symptomatic measures (n= 98)
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Same Bortezomib-based chemo in the 2 arms
Bortezomib (1.3 mg/m2 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/m2 IV on day 1),
if no haematological response after 3 cycles
+ biopsy-proven MCN
Myeloma + persistent AKI with hemodialysis requirement
8 sessions of 5 hours
over the first 10 days
then 3 per week
HCO Theralite™(2.1 m2)
R
Conventional
high-flux dialyser
Stratification on age
≤65 yrs vs >65 yrs
MYRE randomized controlled trial
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Hematological response
PR and VGPR, ≥ 50% and ≥ 90% reduction in involved sFLC, respectively
Control (n=48) HCO (n=46) P value
After 1 cycle
median sFLC
reduction rate
(%) [IQR]
71 % [22-91%] 89 % [61-99%] P=0.022
sFLC <500 mg/L (%) 31 % 43% P=0.29
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
MYRE Study: biopsy-proven MCN – high flux vs HCO HD
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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
independence
1 mo 2 mo
Alive without HD
at 12 mo
35 % 52 % 0.15
High dose melphalan
and autotransplantation
N= 6 N =13 0.07
MYRE Study: biopsy-proven MCN – high flux vs HCO HD
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Cumulative incidence of dialysis independence
MYRE Study: biopsy-proven MCN – high flux vs HCO HD
Bridoux F, et al. JAMA 2017; 318: 2099-2110
Late HD-independence (after 3 months):
HCO (n=9) vs Control (n=2)
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Overall survival
MYRE Study: biopsy-proven MCN – high flux vs HCO HD
Bridoux F, et al. JAMA 2017; 318: 2099-2110
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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
(eGFR > 30ml/min/1.73m2)1.29 (0.36-4.56) 0.69
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
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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
Conclusions
MYRE Study: biopsy-proven MCN – high flux vs HCO HD
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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 m2 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
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EuLITE : renal responses
Hutchison CA et al. Lancet Haematol 2019; 6: e217-e228
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)
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EuLITE : overall survival
Hutchison CA et al. Lancet Haematol 2019; 6: e217-e228
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)
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MYRE EuLITE
Randomization After a screening periodIncluding symptomatic measures and a 4-
day HD steroid course
At diagnosis
Chemo regimen Doublet (Bortezomib Dex)
± Cyclophosphamide
Triplet (Bort.-Adri.-Dex.)
Dialysis schedule Similarly intensive in both groups Daily 5h-sessions x 8, then thrice weekly
Highly intensive in HCO groupDaily 8hr session for 10 days, thrice
weekly days D12-D21, then 6h
Standard in control group4h-session thrice weekly
HCO dialyzer Single 2.1 m2 dialyzer Two 1.1 m2 dialyzers in series
HCO hemodialysis in myeloma cast nephropathy
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
Inclusion of patients who might have
lost indication for HD after steroids
and symptomatic treatment?
Higher infectious risk and higher
treatment interruption (21%) in
HCO group
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In patients with AKI not requiring hemodialysis:
• What is the best chemotherapy ?
• Are triplet regimens superior to the standard bortezomib dexamethasone doublet ?
Treatment of myeloma cast nephropathy
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Assessed for
eligibility
(n=425)
Randomized
(n=284)
“Excluded” (n=141) (neither MM nor MCN,
renal recovery …)
No HD requirement
(n= 186)
Hemodialysis (HD)
requirement (n= 98)
BD
(n= 93)C-BD
(n= 93)
Analyzed
(n= 92)
Analyzed
(n= 92)
MYRE randomized controlled trial
Other diagnosis LCDD (n=2)
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Myeloma + probable or proven MCN, no hemodialysis requirement
Bortezomib-Dexamethasone (BD)
R
Cyclophosphamide + BD (C-BD)
MYRE randomized controlled trial
BD group:
• Bortezomib (1.3 mg/m2, bi-weekly)
+ dexamethasone (20 mg, Days 1-2, 4-5, 8-9, 11-12)
C-BD group:
• Same BD regimen
+ cyclophosphamide (750 mg/m2 IV day 1)
• 21-day cycles
• After the first cycle, patients over 70 continued on 28-day cycles of bortezomib (1.3 mg/m2 weekly) plus dex
• In the absence of hematological response after 3 cycles :
BD : reinforcement with cyclophosphamide (750 mg/m2 IV day 1)
C-BD: reinforcement with thalidomide (50 mg/d for 15 days, then increased to 100mg/d if well tolerated)
Endpoints
Primary: renal response at 3 months (eGFR ≥ 40 ml/min/1.73m2)
Stratification on age
≤65 yrs vs >65 yrsStratification on AKIN stage
<3 vs 3 (creat. ≥ 354 µmol/L
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BD (n=92) C-BD (n=92)
Age (yr), median [IQR] 68 [61;75] 68 [59;75]
> 65 yrs (%) 37 (40%) 36 (39%)
Sex (M/F, %) 56% / 44% 64% / 36%
Past medical history
Diabetes / HTN (%) 8 (9%) / 47 (51%) 17 (18%) / 44 (48%)
Cardiovascular disease 8 (0%) 13 (14%)
Urologic disease 16 (17%) 20 (21%)
Known MGUS or indolent MM 18 12
Patient characteristics
MYRE Study: Myeloma cast nephropathy – BD vs C-BD
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Renal presentation at randomization
BD (n=92) C-BD (n=92)
Known preexisting CKD
(eGFR* >30 ml/min/m2)*9 (10%) 5 (5%)
De novo AKI 83 (90%) 87 (95%)
Median serum creatinine at
randomization (µmol/L)305 [220; 375] 273 [219; 397]
eGFR (ml/min/1.73 m2) 17 [11; 23] 18 [13; 25]
AKIN stage 3
(s.creat > 354 µmol/L)33 (36%) 30 (33%)
Proteinuria
g/24h 3.3 [1.3; 5.5] 2.7 [1.4; 4.4]
Urine protein/creatinine 337 [166; 600] 212 [104; 485]
MYRE Study: Myeloma cast nephropathy – BD vs C-BD
* Preexisting CKD) defined by eGFR (MDRD) ≤ 30 ml/min/1.73m2 was a criterion of exclusion
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NCM precipitating factors
BD (n=92) C-BD (n=92)
Precipitating factor
At least 1 46 % 52%
≥2 25% 26%
Contrast media 3 (3%) 2 (2%)
Infection 3 (3%) 11 (12%)
ACEI / ARA2 9 (10%) 7 (8%)
Dehydration / diuretics 7 (8%) 13 (14%)
Hypercalcemia 16 (17%) 15 (16%)
NSAIDS 30 (33%) 28 (30%)
MYRE Study: Myeloma cast nephropathy – BD vs C-BD
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Renal pathological data
BD (n=92) C-BD (n=92)
Kidney biopsy performed 40 (43%) 41 (45%)
Bleeding complication 1 2
Unsuccessful biopsy 1 0
LC cast nephropathy 39 41
Associated nephropathy 5 (13%) 9 (22%)
LCDD by IF only 3 5
LHCDD 0 1
Malignant PC tubulo-interstitial
infiltration2 2
IgA nephropathy 0 1
MYRE Study: Myeloma cast nephropathy – BD vs C-BD
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Myeloma characteristics
BD (n=92) C-BD (n=92)
Light chain isotype (%) kappa 53 % / lambda 47 % kappa 49 % / lambda 51%
Myeloma type
LC MM only (%) 47 (51 %) 38 (41 %)
Entire Ig
IgG/ IgA/ IgD
45 (49%)
24/ 14/ 7
54 (59%)
34/ 14/ 5
Serum FLC (mg/L) 6820 [2805;12850] 4630 [2265;10610]
Hb (g/dl) 9.5 [8.6;10.3] 8.9 [8.2;9.7]
Platelets (x109/L) 187 [137;228] 189 [144;260]
CRP (mg/L) 7 [3;20] 8 [4;17]
Serum β2 microgl. (mg/L) 15 [8;20] 13 [9;19]
Serum albumin (g/L) 37 [31;41] 36 [31;39]
LDH (IU/L) 279 [207;415] 285 [208;410]
Bone marrow PC (%) 35% [20;54] 33% [17;54]
Lytic bone lesions (%) 60% 70%
*High risk cytogenetics (%)
del17p or t(4;14)
19 % 24%
MYRE Study: Myeloma cast nephropathy – BD vs C-BD
*Cytogenetic studies were performed in 62 patients (67%) from each group
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Chemotherapy courses
* BD reinforced with cyclophosphamide (C-BD)
* C-BD reinforced with thalidomide
BD (n=92) C-BD (n=92) P value
≥ 3 cycles received 88 (96%) 83 (90%)
Reinforcement after 3 cycles * 6 (7%) 7 (8%)
Toxicity
At least 1 SAE (%) 30 (33%) 40 (43%) 0.13
Periph. neurop. grade ≥3 3 (3%) 2 (2%)
Cytopenia grade ≥3 5 9 0.27
Sepsis/pneumonia 2 5
Premature ttt interruption 11 (12%) 16 (17%) 0.30
MYRE Study: Myeloma cast nephropathy – BD vs C-BD
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Hematological response
PR and VGPR, ≥50% and ≥90% reduction in involved sFLC, respectively
BD (n=92) C-BD (n=92) P value
After 1 cycle
sFLC reduction rate
(%) [IQR]
-86%
[-96%; -69%]
-88%
[-98%; -71%%] 0.68
sFLC <500 mg/L (%) 75% 73% 0.74
At 3 months
≥PR 78 % 77 % 1.00
≥VGPR 39% 51 % 0.10
At 6 months
≥PR 74 % 76 % 0.73
≥VGPR 47 % 53% 0.38
MYRE Study: Myeloma cast nephropathy – BD vs C-BD
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Renal response
BD (n=92) C-BD (n=92) P value
Cumulative incidence of renal response (eDFG ≥ 40 ml/min/1.73 m2)
at 3 months 44.6% 51% 0.46
at 6 months 55.4% 60.9% 0.55
at 12 months 52.2% 51.1% 1.00
eGFR (ml/min/1.73 m2) [IQR]
at 3 months 30 [21-46] 35.5 [26-56] 0.05
at 6 months 35.5 [24-52] 42.5 [29-61] 0.15
at 12 months 36 [25-50] 39 [25-56] 0.39
Alive at 12 mo with renal response 41/76 (53.9%) 43/75 (57.3%) 0.80
ESRD within 12 months 2 (2%) 5 (5%) 0.25
HDM/ASCT (months from rando) 29% (4.5) 32% (4.6) 0.75
MYRE Study: Myeloma cast nephropathy – BD vs C-BD
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Predictive indicators of renal response
Univariate analyses Multivariate analysis
Variable OR (95%CI) P-value OR (95%CI) P-value
Age ≥ 65 0.43 (0.22-0.82) 0.011
Pre-existing MGUS 1.57 (0.65-3.77) 0.31
Entire Ig-secreting myeloma 1.44 (0.79-2.65) 0.23
Precipitating factor 1.82 (0.99-3.36) 0.055
Pre-existing CKD
(eGFR > 30ml/min/1.73m2)0.08 (0.017-0.36) 0.001 0.59 (0.47-0.75) <0.0001
Serum creatinine at randomization 1.00 (0.99-1.00) 0.009
AKIN stage 3 0.52 (0.28-0.97) 0.039 0.86 (0.75-0.98) 0.026
sFLC <500 mg/L after 1 cycle of
chemotherapy1.52 (0.81-2.85) 0.19
Hematological response ≥ PR 7.67 (2.41-24.4) 0.0006 1.44 (1.14-1.82) 0.003
Randomization in C-BD group 1.33 (0.73-2.43) 0.36
MYRE Study: Myeloma cast nephropathy – BD vs C-BD
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+ +
++++++++++
+
+++++++++++
++++
++++++++
+ ++++ ++ ++++ + +++++ + + ++ +++++ ++ +
+ +
++++++++
+ + ++
++
+++
+++ ++++++
+
++++ +++++ +++++++ +++++
+ +++ ++ ++
+ ++ + +++
p = 0.99
0.00
0.25
0.50
0.75
1.00
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 78
Months after randomisation
Overa
ll S
urv
ival P
robabili
ty
+
+
BD
C-BD
92 90 89 87 76 66 58 51 44 39 31 28 25 22 17 15 12 11 9 6 3 1 0 0 0 0 0
92 84 84 79 75 70 63 61 53 50 41 37 35 29 21 16 15 12 10 6 4 3 3 1 0 0 0C-BD
BD
No. at risk
Overall survival
BD (n=92) C-BD (n=92)
MM progression 4 (4.3%) 4 (4.3%)
Infections 0 † 3 (3.3%)
Cardio-vascular 3 (3.3%) 1 (1.1%)
Hemorrhage 0 1 (1.1%)
Unknown 0 1 (1.1%)
Total 7 (7.6%) 10 (10.9%)
Causes of deaths within 12 months
† Deaths occurred at day 7, 16 and 30 post-randomization
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BD vs C-BD in patients with myeloma cast nephropathy not requiring dialysis:
• No significant differences in hematological response rates
• Higher risk of toxicity with the C-BD triplet
• No difference in renal response rates
MYRE Study: Myeloma cast nephropathy – BD vs C-BD
Conclusions
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Treatment of myeloma cast nephropathy: Conclusions
1. Not questionable
‒ Importance of prevention: NSAIDS should not be prescribed to myeloma patients
‒ Urgent treatment
‒ Importance of symptomatic measures and high-dose steroids
2. What is the best chemotherapy?
‒ Current standard of care : bortezomib+dexamethasone–based regimens
‒ Triplet therapy?
Benefit of the C-BD not demonstrated by the MYRE study
Efficacy/toxicity balance should be carefully assessed
Indications should be adapted to patient frailty
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Treatment of myeloma cast nephropathy: Conclusions
3. Role for HCO-hemodialysis ?
‒ Rationale is still pertinent !• Rapid sFLC reduction whatever the LC isotype
• Increased half life of nephrotoxic FLCs in severe AKI
• Rapid sFLC reduction with chemo alone?
Unlikely to be achieved in all newly-diagnosed patients
Very unlikely in patients with cast nephropathy at myeloma relapse
‒ Further investigation is required:• HCO-HD combined with efficient but tolerable chemotherapy (anti-CD38 mAb)
• Indication based on assessment of renal prognosis with kidney biopsy
High risk of ESRD (numerous casts): HCO + chemotherapy
Lower risk: chemotherapy alone
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Acknowledgements
All investigators, research assistants, and patients who participated
in the MYRE trial
Sylvie Chevret, MD, PhD
Department of Biostatistics and Medical Information, UMR 1153, Hôpital
Saint Louis, Paris, France