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

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?

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

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

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)

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 (?)

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

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

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

Renal response is associated with deep hematologic response: is hematologic response

adequate to predict renal response ?

Ludwig H et al J Clin Oncol 2010

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

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

Impact of renal function improvement (renal response) to OS

Dimopoulos MA et al J Clin Oncol 2009

Renal response in VISTA trial

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

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

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)

MM-013 PomDex Renal response

Dimopoulos MA et al J Clin Oncol

Renal response and survival

All patients Excluding early deaths

N=116 patients with baseline eGFR < 30 ml/min

Renal response criteria in patients requiring dialysis

Hutchison CA et al Lancet Haematol 2019Bridoux F et al JAMA 2017

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

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

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).

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

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

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

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

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)

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

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?

✓ 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

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?

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

Back up slides

Endpoints

• Is survival a valid end point for renal response criteria ?

• Should other endpoints be examined ?

– Serum creatinine / eGFR levels

– Markers of renal damage

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%

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)

✓ 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).

• 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