light chain cast nephropathy Efstathios Kastritis Plasma Cell - - PowerPoint PPT Presentation

Current criteria for renal response in light chain cast nephropathy

Efstathios Kastritis

Plasma 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/min 15-29 mL/min 15-29 mL/min 30-59 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

0,1 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

0,05 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 response to therapy: group 1, CrCl⩾40 at diagnosis; group 2, CrCl<40 at diagnosis but improved to ⩾40 after 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 CRrenal Vd: 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 2019 Bridoux 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

10 20 30 40 50 0.0 0.2 0.4 0.6 0.8 1.0 Months on CFZ % with event 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

10 20 30 40 50 0.0 0.2 0.4 0.6 0.8 1.0 Months on CFZ % with event 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

10 20 30 10 20 30

eGFR by MDRD eGFR by CKD-EPI

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 on dialysis 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 higher probability of major Rrenal among patients with severe RI but not on dialysis, while baseline 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 years Age > 75 years 72 (37-91) 68% 36% ISS-3 92% LDH > 300 U/L 17.5% High-Dose Dexa- based Bortezomib-based Thalidomide-based Lenalidomide-based 19% 38% 34% 9% eGFR < 30 ml/min 1.73 m2 eGFR < 15 ml/mon/1.73 m2 100% 49% Dialysis 13%

Renal response and survival

Median OS: 31,3 months

Median OS CKD 4: 38 months CKD 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 της θεραπείας) (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%

• f 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 not associated 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 strongly associated 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 to major Rrenal (p=0.012). ✓ Both NGAL and CysC had no predictive value for patients under dialysis. None of them was associated with dialysis independence. ✓ In multivariate analysis performed in patients not on dialysis, that included age, NGAL, CysC and eGFR, 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%)
• f the 35 patients in the ITT group, with five

(14.2%), four (11.4%) and seven (20%) achieving a Crrenal Prrenal and Mrrenal respectively.

• 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