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 • 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 bortezomib 1-4 Alexanian R, et al Arch Intern Med 1990;150: 1693-5. 1. Blade J, et al Arch Intern Med 1998; 158:1889-93. 2. 3. Knudsen LM, et al Eur J Haematol 2000;65:175-81. 4. Kastritis E, et al Haematologica 2006
Current renal response criteria in MM Response BASELINE eGFR* Best CrCl RESPONSE (mL/min/1.73 m 2 ) 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 N=116 patients with baseline eGFR < 30 ml/min 0,5 0,4 0,3 0,2 0,1 0 sCR CR VGPR PR NR Major Renal Response No Major Renal Response
Myeloma response and Renal responses N=116 patients with baseline eGFR < 30 ml/min 0,45 0,4 0,35 0,3 NRR 0,25 MRrenal 0,2 PRrenal 0,15 CRrenal 0,1 0,05 0 CR VGPR PR NR
Impact of renal function improvement (renal response) to OS Renal response in VISTA trial Dimopoulos MA et al J Clin Oncol 2009
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 Patients with <2 months of F/Up De Vries JC et al LEUKEMIA & LYMPHOMA, 2017 were omitted
ENDEAVOR: renal responses 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) Dimopoulos MA et al Blood 2019
MM-013 PomDex Renal response Dimopoulos MA et al J Clin Oncol
Renal response and survival N=116 patients with baseline eGFR < 30 ml/min Excluding early deaths All patients
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 1.0 --- Progressive disease 1 1 1 2 --- CFZ related Renal complication (Any) 0.8 0.6 % with event N=114 RRMM patients treated with CFZ 0.4 0.2 N= 33 with eGFR < 50 ml/min 0.0 0 10 20 30 40 50 19/114 developed renal complications Months on CFZ probably related to CFZ 1.0 --- Progressive disease 1 1 --- TMA 1 2 18/33 improved eGFR to >60 ml/min 1 3 --- Proteinuria 0.8 1 4 --- ARF 0.6 % with event 0.4 0.2 0.0 Kastritis E et al ASH 2018 0 10 20 30 40 50 Months on CFZ
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 50% 45% 41,50% 45% Major Renal 40% (PR+CR) 35% RenalCR 30% 25% 20% RenalPR 15% 10% RenalMR 5% 0% IMWG renal response Simplified criteria
Renal response by current and simplified criteria and survival Εικ .6 --- CR+PR renal --- Renal Response --- MR renal --- No renal response --- No renal response p =0.351 p =0.370
Does it make any difference which equation we use? IMWG Renal Response criteria based on eGFR calculated by MDRD or CKD-EPI 40% 34% 30% 33% 32% 31% CRrenal 20% PRrenal MRrenal 10% 7,5% 7,5% 0% MDRD CKD-EPI
Comparison of CKD staging of RI based on eGFR calculated by MDRD or CKD-EPI 30 eGFR by CKD-EPI 20 10 0 0 10 20 30 eGFR by MDRD
Renal Response according to simplified renal response criteria based on eGFR calculated by MDRD or CKD-EPI Renal response 80% 60% 40% 45% 45% 20% 0% MDRD CKD-EPI 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 m 2 )
Evaluation of different therapies for renal response by different criteria 80% IMWG-MDRD IMWG-CKD-EPI 60% 63% Simplified 58% 53% 40% Εικ .3 Εικ .4 37% 35% 35% 32% 26% 26% 20% 0% High-Dose Dexa Bortezomib IMiDs
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?
Biomarkers to predict Renal response ✓ 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. N=50 patients with eGFR < 30 ✓ 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). 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 m 2 ) N=105 patients Age (Median/range) 72 (37-91) Age > 65 years 68% Age > 75 years 36% ISS-3 92% LDH > 300 U/L 17.5% High-Dose Dexa- based 19% Bortezomib-based 38% Thalidomide-based 34% Lenalidomide-based 9% eGFR < 30 ml/min 1.73 m2 100% eGFR < 15 ml/mon/1.73 m2 49% Dialysis 13%
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