current criteria for renal response in light chain cast ......2019/06/05 · current criteria for...
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Current criteria for renal response in light chain cast nephropathy
Efstathios KastritisPlasma Cell Dyscrasia unit
Department of Clinical Therapeutics National and Kapodistrian University of Athens
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Renal response criteria in myeloma cast nephropathy
1. Why do we need them?
2. What do they represent?
3. How are they developed ?
4. How are validated?
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Why do we need renal response criteria for MM?
• RI one of the most common and serious complications of MM
• We have multiple therapies with different effects on renal function
• We need to evaluate therapies and strategies that also improve renal function and patients’ quality of life
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Past Renal response criteria in MM
1. Alexanian R, et al Arch Intern Med 1990;150: 1693-5.2. Blade J, et al Arch Intern Med 1998; 158:1889-93.3. Knudsen LM, et al Eur J Haematol 2000;65:175-81.4. Kastritis E, et al Haematologica 2006
• Renal response based on reduction of creatinine levels only• Sustained reduction to <1.5 mg/dl 1-4
• Renal responses in 24% - 73% 1-4
• Mostly patients treated with alkylators, high dose dexamethasone, thalidomide and only few with bortezomib1-4
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Current renal response criteria in MM
Response BASELINE eGFR*(mL/min/1.73 m2)
Best CrCl RESPONSE
CRrenal <50 mL/min ≥60 mL/min
PRrenal <15 mL/min 30-59 mL/min
MRrenal <15 mL/min15-29 mL/min
15-29 mL/min30-59 mL/min
*eGFR based on MDRD equation
Dimopoulos et al. J Clin Oncol 2010;28:4976-84 (IMWG consensus statment)
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Myeloma renal response criteria
• Myeloma associated renal damage is usually cast nephromathy but..
– MIDD or amyloidosis or other damage may also be present..
• No histologic response criteria may apply (?)
• Only functional response criteria my be used (?)
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What do these criteria represent
• Functional improvement
• No or very few data on histology/pathology
• Strong association with renal response and FLC reduction
• Probably not a strong association with OS
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Have these criteria helped us?
• Helped identify the best available therapies for MM patients with RI
– Bortezomib vs other therapies
• Helped evaluate additional aspects of anti-MM therapy
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Studies using renal response criteria
• Studies evaluating renal response using current criteria: 46
Drug Number of studies using current renal response criteria
Bortezomib 17
Lenalidomide 14
Carfilzomib 4
Pomalidomide 3
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Renal response is associated with deep hematologic response: is hematologic response
adequate to predict renal response ?
Ludwig H et al J Clin Oncol 2010
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Myeloma response and Major Renal response
0
0,1
0,2
0,3
0,4
0,5
sCR CR VGPR PR NR
N=116 patients with baseline eGFR < 30 ml/min
Major Renal Response
No Major Renal Response
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Myeloma response and Renal responses
0
0,05
0,1
0,15
0,2
0,25
0,3
0,35
0,4
0,45
CR VGPR PR NR
NRR
MRrenal
PRrenal
CRrenal
N=116 patients with baseline eGFR < 30 ml/min
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Impact of renal function improvement (renal response) to OS
Dimopoulos MA et al J Clin Oncol 2009
Renal response in VISTA trial
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Improvement of renal function and OS
K-M plot comparing OS at a 6-month landmark based on renal function at diagnosis and responseto therapy: group 1, CrCl⩾40 at diagnosis; group 2, CrCl<40 at diagnosis but improved to ⩾40after therapy; and group 3, CrCl<40 at diagnosis and remained <40 after therapy.
Gonsalves WI et al BCJ 2015
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Restoration of renal function in patients with newly diagnosed multiple myeloma is not associated with improved survival: a
population-based study
De Vries JC et al LEUKEMIA & LYMPHOMA, 2017
Patients with <2 months of F/Up were omitted
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ENDEAVOR: renal responses
Dimopoulos MA et al Blood 2019
Renal responses (CRrenal) Median time to CRrenalVd: 14.1% 1.9 months (0.4-7.2)Kd: 15.3% 1.5 months (0.1-4.7)
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MM-013 PomDex Renal response
Dimopoulos MA et al J Clin Oncol
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Renal response and survival
All patients Excluding early deaths
N=116 patients with baseline eGFR < 30 ml/min
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Renal response criteria in patients requiring dialysis
Hutchison CA et al Lancet Haematol 2019Bridoux F et al JAMA 2017
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Outcomes of newly diagnosed myeloma patients requiring dialysis: renal recovery, and
survival benefit
6-month landmark for OS for dialysis independence
p=0.002
-- remain on dialysis
-- D/C dialysis
Dimopoulos MA et al Blood Cancer Journal (2017) 7, e571
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Renal toxicity and renal response
0 10 20 30 40 50
0.0
0.2
0.4
0.6
0.8
1.0
Months on CFZ
% w
ith
eve
nt
1 1
1 2
1 3
1 4
--- Progressive disease --- TMA--- Proteinuria--- ARF
N=114 RRMM patients treated with CFZ
N= 33 with eGFR < 50 ml/min
19/114 developed renal complications probably related to CFZ
18/33 improved eGFR to >60 ml/min
0 10 20 30 40 50
0.0
0.2
0.4
0.6
0.8
1.0
Months on CFZ
% w
ith e
ven
t
1 1
1 2--- Progressive disease --- CFZ related Renal complication (Any)
Kastritis E et al ASH 2018
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Simplified criteria ?
• Patients who presented with stage 5 RI (eGFR<15 ml/min or on dialysis) should double their eGFR and improve to at least stage 4 RI (eGFR 15-29 ml/min) or become independent of dialysis
• Patients with stage 4, increase their eGFR by at least 50% and improve to at least stage 3 (eGFR 30-59 ml/min).
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Comparison of IMWG renal response criteria and simplified renal response criteria
41,50% 45%
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
IMWG renal response Simplified criteria
Major Renal(PR+CR)
RenalCR
RenalPR
RenalMR
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Renal response by current and simplified criteria and survival
Εικ.6
---CR+PR renal---MR renal---No renal response
p=0.351
p=0.370
---Renal Response---No renal response
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Does it make any difference which equation we use?
34% 33%
7,5% 7,5%
31% 32%
0%
10%
20%
30%
40%
MDRD CKD-EPI
CRrenal
PRrenal
MRrenal
IMWG Renal Response criteria based on eGFR calculated by MDRD or CKD-EPI
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Comparison of CKD staging of RI based on eGFR calculated by MDRD or CKD-EPI
0 10 20 300
10
20
30
eGFR by MDRD
eG
FR
by
CK
D-E
PI
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Renal Response according to simplified renal response criteria based on eGFR calculated by
MDRD or CKD-EPI
45% 45%
0%
20%
40%
60%
80%
MDRD CKD-EPI
Renal response
Simplified criteria:
• Patients who presented with stage 5 RI should double their eGFR and improve to at least stage 4
• Patients with stage 4, increase their eGFR by at least 50% and improve to at least stage 3 (GFR ≥ 60 mL/min/1.73 m2)
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Εικ.3 Εικ.4
26%
58%
35%
26%
53%
37%32%
63%
35%
0%
20%
40%
60%
80%
High-Dose Dexa Bortezomib IMiDs
IMWG-MDRD
IMWG-CKD-EPI
Simplified
Evaluation of different therapies for renal response by different criteria
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How can we improve the current renal response criteria
• Do we need new criteria? – Based on creatinine?
– Based on new biomarkers?
– Do we need to incorporate RIFLE / AKIN ?
– Add urine tests ??
• Is 60 ml/min threshold justified ?
• Should we further adjust for age ?
• Should we consider a “renal progression” category?
• Is survival a valid end point for renal response criteria development?
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✓ Renal response : in 60% of patients (including 50% major Rrenal) and 34% of patients ondialysis became dialysis independent.
✓ Median time to Rrenal was one month - Median time to dialysis independence: 2 months.
✓ Lower levels of NGAL (p=0.009) and CysC (p=0.014) were associated with higherprobability of major Rrenal among patients with severe RI but not on dialysis, whilebaseline eGFR was not associated with higher probability for major Rrenal (p=0.346).
Biomarkers to predict Renal response
N=50 patients with eGFR < 30
Dimopoulos MA et al EHA 2018
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Implementing current criteria in clinical practice
• Should we change or modify therapy if renal responses not obtained ?
• Should we discuss additional tests (renal biopsy??) if the renal response is not adequate?
• Should we use the current criteria as end points for clinical trials ?
• Are these criteria applicable in RRMM also?
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To summarize
• Current renal response criteria have limitations but have helped us evaluate several therapies in the context of RI in MM
• Developing new renal response criteria should be considered following a targeted approach
• Perhaps we should consider adopting biomarkers
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Back up slides
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Endpoints
• Is survival a valid end point for renal response criteria ?
• Should other endpoints be examined ?
– Serum creatinine / eGFR levels
– Markers of renal damage
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N=105 with at least severe RI (eGFR<30 ml.min/1.73 m2)
N=105 patients
Age (Median/range)Age > 65 yearsAge > 75 years
72 (37-91)68%36%
ISS-3 92%
LDH > 300 U/L 17.5%
High-Dose Dexa- basedBortezomib-basedThalidomide-basedLenalidomide-based
19%38%34%9%
eGFR < 30 ml/min 1.73 m2eGFR < 15 ml/mon/1.73 m2
100%49%
Dialysis 13%
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Renal response and survival
Median OS: 31,3 months Median OSCKD 4: 38 monthsCKD 5: 31 months
P=0.230
➢Η διάμεση επιβίωση για όλους τους ασθενείς ήταν 31 μήνες και 15 ασθενείς(14%) κατέληξαν σε <2μήνες από την έναρξη τηςθεραπείας) (3% των ασθενών ≤65 ετών έναντι 20% των ασθενών>65 ετών(p=0,022).➢Η μέση επιβίωση των ασθενών που παρουσιάστηκαν με στάδιο 4 έναντι σταδίου 5 ΝΑ ήταν παρόμοια (31 έναντι 38 μηνών,p=0,23 (Εικ. 5)
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✓ N=82 newly diagnosed MM patients with severe RI✓ Both NGAL and CysC were higher in patients requiring dialysis (median NGAL: 308 vs 153 ng/mL,
p<0.001, median CysC:4.99 vs 2.73 mg/L, p=0.001).✓ Renal response (Rrenal) was achieved in 60% of patients (including 50% major Rrenal) and 34%
of patients on dialysis became dialysis independent.✓ Median time to Rrenal was one month and median time to dialysis independence was 2 months.✓ Lower levels of NGAL (p=0.009) and CysC (p=0.014) were associated with higher probability of
major Rrenal among patients with severe RI but not on dialysis, while baseline eGFR was notassociated with higher probability for major Rrenal (p=0.346).
✓ By ROC analysis, in patients with severe RI but not on dialysis, NGAL <130 ng/ml was stronglyassociated with major Rrenal (86% vs 24% at 3 months, p<0.001; Figure 2).
✓ Regarding CysC, levels <2.6 mg/L were associated with higher probability and shorter time tomajor Rrenal (p=0.012).
✓ Both NGAL and CysC had no predictive value for patients under dialysis. None of them wasassociated with dialysis independence.
✓ In multivariate analysis performed in patients not on dialysis, that included age, NGAL, CysC andeGFR, only NGAL<130 ng/ml was significantly associated with major Rrenal (HR 5, 95% CI 2-18,p=0.01).
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• A renal response was observed in 16 (45.7%) of the 35 patients in the ITT group, with five (14.2%), four (11.4%) and seven (20%) achieving a Crrenal Prrenal and Mrrenalrespectively.
• The median time to a renal response was 28 days and the median time to best renal response was 157 days
Ludwig H et al Haematologica 2014