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
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
RR = withdrawn from dialysis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
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
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)
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
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)
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
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
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
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)
Overall survival
MYRE Study: biopsy-proven MCN – high flux vs HCO HD
Bridoux F, et al. JAMA 2017; 318: 2099-2110
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
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
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
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)
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)
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
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
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)
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
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
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
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
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
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
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
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
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
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
+ +
++++++++++
+
+++++++++++
++++
++++++++
+ ++++ ++ ++++ + +++++ + + ++ +++++ ++ +
+ +
++++++++
+ + ++
++
+++
+++ ++++++
+
++++ +++++ +++++++ +++++
+ +++ ++ ++
+ ++ + +++
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
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
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
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
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