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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RR = withdrawn from dialysis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)


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


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


Cumulative incidence of dialysis independence


Bridoux F, et al. JAMA 2017; 318: 2099-2110

Late HD-independence (after 3 months):

HCO (n=9) vs Control (n=2)

Overall survival


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


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


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)


Other diagnosis LCDD (n=2)

Myeloma + probable or proven MCN, no hemodialysis requirement

Bortezomib-Dexamethasone (BD)

R

Cyclophosphamide + BD (C-BD)


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]


* 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%)


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


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%


*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


Hematological response

PR and VGPR, ≥50% and ≥90% reduction in involved sFLC, respectively


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


Renal response


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


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


+ +

++++++++++

+

+++++++++++

++++

++++++++

+ ++++ ++ ++++ + +++++ + + ++ +++++ ++ +

+ +

++++++++

+ + ++

++

+++

+++ ++++++

+

++++ +++++ +++++++ +++++

+ +++ ++ ++

+ ++ + +++

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


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

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