Evidence Supporting Light Chain Cast Nephropathy As a Myeloma Defining Event

BACKGROUND In 2014, the International Myeloma Working Group (IMWG) revised the Renal involvement of the CRAB (hyperCalcemia, Renal, Anemia, Bone lesions) criteria for the diagnosis of multiple myeloma (MM) as an acute decline in kidney function represented by either a serum creatinine (Scr) > 2 mg/dl or an estimated glomerular filtration rate of < 40 ml/min/1.73 m2 secondary to light chain cast nephropathy (LCCN) biopsy proven or suspected. Since LCCN occurs only in patients with high serum free light chain (FLC) levels, a high tumor burden is presumed but how often it occurs with other myeloma defining events (MDE) is unknown.

METHODS Patients were selected from 2 cohorts. The first cohort came from a multicenter study on LCCN who were all diagnosed with MM between 2000 and 2018. Only newly diagnosed patients were included in this study. A second cohort was identified from the Mayo Clinic Kidney Biopsy database from 2003 to 2013. Inclusion criteria of this cohort were: the LCCN must be the dominate pathology on the kidney biopsy and it is secondary to a plasma cell proliferative disorder. Laboratory and radiologic data were collected to assess for CRAB criteria. Bone lesions were assessed by standard skeletal X-ray, MRI or CT/PET. Most had skeletal X-ray. The new SLiM CRAB criteria which have the addition 3 biomarkers: (S) >60% bone marrow plasma cells, (Li) an involved to uninvolved free light chain (FLC) ratio > 100 and (M) >1 bone lesion on MRI were also assessed.

RESULTS From the multicenter study, 28 patients were excluded for having relapsed MM and 27 were from Mayo who were included in the second cohort leaving 123 patients. In the Mayo cohort, 52 patients were identified who met criteria. Both cohorts were comparable in age, sex, bone marrow plasma cells and hemoglobin at diagnosis (Table 1). Interestingly, 3.3% of the multicenter cohort and 3.9% of the Mayo cohort did not meet the R criterion due to a presenting creatinine of ≤ 2.0 mg/dl. In the multicenter cohort 2/99 (2.0%) and 4/52 (7.7%) of the Mayo cohort had < 10% bone marrow plasma cells. The presenting involved FLC was higher in the multicenter group (p = 0.001). In the multicenter cohort, 99.1% met at least one of the SLiM criteria and 84.7% met one the C,A,B criteria. In the Mayo cohort, fewer patients met at least one of the SLiM criteria (86.5%, p < 0.001) but more patients met one or more of the C,A,B criteria (98.1%, p = 0.01). All but 1 patient from the multicenter cohort met one or more of the SliM C,A,B criteria. The most common SLiM criteria met in the multicenter cohort was Li while it was M in the Mayo cohort. The most common C,A,B criteria in the multicenter cohort was A while it was B in the Mayo cohort.

DISCUSSION This study provides the first evidence that nearly all patients who present with biopsy proven LCCN have at least one other MDE. Bone marrow burden was met in 98.0% of the multicenter cohort where all patients were diagnosed with MM, 92.3% of the Mayo cohort where the diagnosis of MM was not a prerequisite. More importantly, 84.7% and 98.1% of patients from the 2 cohorts respectively had another MDE besides LCCN confirming that LCCN is associated with high tumor burden. All but 1 patient would have been diagnosed with MM based on the SLiM CRAB criteria. In comparison to patients with other kidney lesions associated with monoclonal immunoglobulin, generally only 20-30% met the CRAB criteria for MM. This is why it is more appropriate to classify those patients as having monoclonal gammopathy of renal significance while patients with LCCN should be diagnosed with MM.

Leung:Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Bridoux:SANOFI: Research Funding, Speakers Bureau; ASTRA ZENECA: Consultancy, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: travel fees, Speakers Bureau. Dingli:Sanofi S.A.: Consultancy; Takeda Pharmaceuticals: Consultancy; Novartis: Consultancy; Janssen Pharmaceuticals: Consultancy; GlaxoSmithKline: Consultancy; Bristol Myers Squibb: Consultancy; Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals: Consultancy. Dispenzieri:Alynlam, Pfizer, Takeda, and BMS: Research Funding; Oncopeptides, and Sorrento: Other: Data monitoring safety committee; Janssen: Membership on an entity's Board of Directors or advisory committees. Gertz:Ionis/Akcea: Other: personal fees; Prothena: Other: personal fees; Sanofi: Other: personal fees; Janssen: Other: personal fees; Aptitude Healthgrants: Other: personal fees; Ashfield: Other: personal fees; Juno: Other: personal fees; Physicians Education Resource: Other: personal fees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: personal fees from Data Safety Monitoring Board; Johnson & Johnson: Other: personal fees; Celgene: Other: personal fees; Research to Practice: Other: personal fees; Sorrento: Other: personal fees; i3Health: Other: Development of educational materials for i3Health. Kapoor:Sanofi: Honoraria, Research Funding; X4 Pharmaceuticals: Honoraria; Regeneron: Research Funding; Amgen: Research Funding; Ichnos: Research Funding; Loxo: Research Funding; Karyopharma: Research Funding; BMS: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Research Funding; Casma: Honoraria; Pharmacyclics: Honoraria; Imedex: Honoraria; GSK: Honoraria; Cellectar: Honoraria; Oncopeptides: Honoraria. Kourelis:Novartis: Research Funding. Kumar:AbbVie,: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen,: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda,: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive,: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE,: Research Funding; MedImmune/Astra Zeneca,: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck,: Research Funding; Novartis,: Research Funding; Roche: Research Funding; Sanofi: Research Funding; Oncopeptides: Other: Independent review committee. Lacy:Celgene: Research Funding. Lin:Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Gamida Cell: Consultancy; Janssen: Consultancy, Research Funding; Novartis: Consultancy; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Legend: Consultancy; Sorrento: Consultancy; Vineti: Consultancy; Merck: Research Funding; Takeda: Research Funding. Motwani:GlaxoSmithKline: Consultancy, Honoraria; Wolters Kluwer: Ended employment in the past 24 months, Other: Salary as Deputy Editor of UpToDate. Muchtar:Janssen: Honoraria; Protego: Consultancy. Royal:Janssen: Honoraria; Vertex Pharmaceuticals: Consultancy. Venner:Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Research Funding; Amgen: Research Funding.