Urinary Light Chain Excretion Research Articles

Abstract 587: Improvement in renal function in patients with multiple myeloma and impaired renal function receiving novel agent induction therapies

Abstract BACKGROUND: Renal impairment (RI) is a common complication in patients with multiple myeloma (MM). Effective myeloma treatment can lead to reduction in urinary light-chain excretion and reversibility of RI. Our pooled analysis assessed the magnitude of improvement in renal function (RF) in patients with newly diagnosed (ND) or relapsed and/or refractory (RR) MM treated with novel agent induction therapies, including 3 immunomodulators, 3 proteasome inhibitors, 1 histone deacetylase inhibitor, 1 XP01 inhibitor and 2 monoclonal antibodies. METHODS: Seventeen registrational trials with 34 treatment arms that collected time profiles of RF during treatment with novel agent induction therapies in 3569 patients with NDMM and 7786 patients with RRMM at baseline were identified from various new drug applications submitted to the US FDA. Change in estimated glomerular filtration rate (eGFR, as estimated by Modification of Diet in Renal Disease formula) compared to baseline was summarized for each therapy. RESULTS: Increase in eGFR was observed in patients with MM and each category of RI (mild [eGFR 60 - <90 mL/min/1.73 m2], moderate [eGFR 30 - <60 mL/min/1.73 m2] or severe [eGFR 15 - <30 mL/min/1.73 m2]) at baseline who received induction therapies. The time to greatest improvement in eGFR was approximately 3 to 6 months post-treatment. The average improvement in eGFR between Month 3 and 6 post-treatment, as compared to baseline, is summarized in Table 1 for each therapy. Further analysis showed that patients with clinical objective responses (partial response or better) tended to have greater improvement in eGFR than non-responders, especially in patients with NDMM. Table 1:Improvement in eGFR in patients with MM and RI during the treatment of novel agent induction therapies between Month 3 and 6 as compared to baseline.PatientsTherapyMean (SD) increase in eGFR (mL/min/1.73 m2)% of patients with improvement in eGFR by at least 1 categoryRRMM (N=7786)Monotherapy A8.8 (15.3)33%Monotherapy B-1.5 (10.4)10%Monotherapy C5.9 (13.9)25%Combination D7.7 (15.4)30%Combination E8.9 (17.2)30%Combination F8.1 (14.9)33%Combination G7.6 (14.6)28%Combination H9.5 (16.1)34%Combination I6.5 (14.0)28%Combination J7.4 (14.6)27%Combination K7.6 (14.8)28%Combination L6.4 (12.0)17%Combination M3.1 (14.5)13%Combination N11.2 (17.1)38%NDMM (N-3569)Combination D7.8 (16.4)32%Combination J7.6 (16.0)29%Combination O6.0 (15.2)28%Combination P10.1 (16.7)38%Combination Q10.4 (17.5)37%Combination R11.5 (17.7)38% CONCLUSIONS: During the treatment with novel agent induction therapies for MM, frequent assessment of RF is needed in patients with RI to guide the proper dosing regimen. Citation Format: Liang Li, Shuai Hu, Hao Zhu, Yaning Wang, Lian Ma, Brian P. Booth, Nam Atiqur Rahman, Janice Schwartz, Gideon Blumenthal, Qi Liu. Improvement in renal function in patients with multiple myeloma and impaired renal function receiving novel agent induction therapies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 587.

POI18 Increased urinary free immunoglobulin light chain excretion in patients with multiple sclerosis

BackgroundPlasma and B cells have been implicated in multiple sclerosis (MS). The presence of intrathecal oligoclonal IgG and free light chains (FLCs) is a feature of MS and rituximab has...

Dysproteinemia-related nephropathy associated with crystal-storing histiocytosis

CASE PRESENTATION A 41-year-old white man presented with a 6-month history of worsening neck pain accompanied by 20Ib weight loss. He was initially referred to an orthopedic surgeon and work-up including magnetic resonance imaging revealed shoulder bursitis for which he received a steroid injection. However, neck pain continued and laboratory tests revealed anemia and renal insufficiency, leading to his referral to an internist. The patient had no significant past medical history or family history of renal disease and he was not taking any medications. Physical examination revealed temporal wasting but was otherwise unremarkable. Laboratory investigations revealed the following: blood urea nitrogen 32 mg/dl (normal 7-25 mg/dl), serum creatinine 4.2 mg/dl (normal 0.5-1.4 mg/dl), serum calcium 9.8 mg/dl (normal 8.5-10.4 mg/dl), phosphorous 4.3 mg/dl (normal 2.5-4.5 mg/dl), sodium 143mmol/l (normal 135-146 mmol/l), potassium 3.6mmol/l (normal 3.5-5.3 mmol/l), chloride 109 mmol/l (normal 98-110 mmol/l), bicarbonate 17 mmol/l (normal 21-33 mmol/l), glucose 95 (normal 65-139 mg/dl), lactate dehydrogenase 505 (normal 105-333 IU/I), white blood cell count 9800/μl, hemoglobin 9.7 g/dl, hematocrit 28.3%, and platelet count 316000/μl. Erythrocyte sedimentation rate was markedly elevated (>100mm/h). Total serum protein was 8.8 g/dl (normal 6.0-8.3 g/dl), serum albumin was 4.2 g/dl (normal 3.5-4.9 g/dl), and β2-microglobulin was elevated (10.7 mg/l, normal < 1.85 mg/l). Quantitative serum immunoglobulins (Ig) revealed elevated IgD (842 mg/dl, normal 0-14 mg/dl) and decreased levels of IgG (450 mg/dl, normal 694-1618 mg/dl), IgA (32 mg/dl, normal 81-463 mg/dl), and IgM (9.9 mg/dl, normal 48-271 mg/ dl). Serum protein electrophoresis revealed a monoclonal spike (0.82 g/dl) with IgD kappa (κ) specificity, elevated free K light chains (81 200 mg/l, normal range 3.3-19.4 mg/l), and normal level of lambda (λ) light chains (10.6 mg/l, normal range 5.7-26.3 mg/l). Urinalysis revealed 100mg/dl glucose; these findings, together with the normal serum glucose, normal serum phosphate, and low serum bicarbonate levels, suggested partial Fanconi's syndrome. Urinalysis also revealed 1 + protein; however, 24-h urine collection contained 20.2 g protein of which 13.975 g (69.2%) consisted of free K light chains. Bone marrow examination revealed diffuse infiltration by IgD K-positive plasma cells, accounting for 50% of overall cellularity, consistent with multiple myeloma. Based on the finding of significant urinary light chain excretion, the patient's multiple myeloma was stage III-B. A skeletal survey revealed no bony lesions, and magnetic resonance imaging of the axial skeleton revealed marrow abnormalities consistent with myeloma but no osseous lesions. Given the new onset of renal insufficiency and partial Fanconi's syndrome with massive urinary light chain excretion, a renal biopsy was performed to determine the pattern of dysproteinemia-related renal disease.

Guidelines on the diagnosis and management of multiple myeloma 2005

In 2001, guidelines for the diagnosis and management of myeloma were published by the Guidelines Working Group of the UK Myeloma Forum (UKMF) on behalf of the British Committee for Standards in Haematology (BCSH) (UK Myeloma Forum; British Committee for Standards in Haematology, 2001). That same year, the second edition of guidelines prepared by the Nordic Myeloma Study Group (NMSG) in 1995 was issued (in the Scandinavian languages; http:// www.myeloma-nordic.org). As both sets of guidelines were intended to be evidence based, it was reassuring to note that the recommendations were similar. Subsequently, informal contact between members of the two groups led to the decision to prepare these common, updated guidelines. These revised and updated guidelines include new sections on imaging and the management of skeletal disease, cover new developments in disease classification and staging and the use of new therapeutic approaches, such as thalidomide, bortezomib and reduced-intensity allogeneic transplantation. The guidelines are presented in specific sections as follows:

Free immunoglobulin light-chain serum levels in the follow-up of patients with monoclonal gammopathies: correlation with 24-hr urinary light-chain excretion.

In patients with light-chain myeloma or primary AL-amyloidosis, 24-hr light-chain excretion in the urine is considered an essential marker of the tumor mass. However, 24-hr urine collection and analysis may be cumbersome and prone to inaccuracy. Recently, a sensitive immunonephelometric assay for immunoglobulin free light chains (FLC) in the serum was developed. We sought to determine whether the serum level of monoclonal FLC could be used as an indicator of urinary excretion and disease evolution. Seven patients with light-chain myeloma and AL-amyloidosis were studied, all of which had a monoclonal FLC that could be detected in the urine using standard methods. In four of these patients, follow-up revealed a remarkable correlation between FLC serum levels and daily urinary excretions. The ratio of serum level to urinary light-chain excretion, although stable in a given patient, was extremely variable between patients. In the three remaining cases featuring hardly measurable amounts of light chain in the urine, the serum FLC assay proved sensitive enough for correlation with clinical events. Thus, immunonephelometric measurement of serum FLCs is a reliable method for the follow-up of patients with light-chain secreting monoclonal gammopathies.

Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant.

Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant.

Urinary N-acetyl-β- d-glucosaminidase as an indicator of tubular damage in multiple myeloma

In 34 patients with multiple myeloma we have studied urinary N-acetyl-β- d-glucosaminidase (NAG) as an index of tubular injury and related it to urinary light chain excretion and serum creatinine. Our results confirm the association of light chain proteinuria with both tubular damage and global renal impairment, but show that not all light chains are nephrotoxic. Tubular damage occurs independently of global renal impairment. Clinically, urinary NAG appears to be a useful index of early tubular damage in multiple myeloma.

Interferon therapy in multiple myeloma: Failure of human fibroblast interferon administration to affect the course of light chain disease

Fibroblast interferon at a dosage of 28 × 10 6 U/wk failed to influence disease progression in a preterminal case of therapy-resistant light chain myeloma. In a second case, that had not previously been treated, a first course of fibroblast interferon ( 30 × 10 6 U/wk ) associated with corticosteroids remained without effect. In this patient subsequent leukocyte interferon treatment was associated with a decrease in urinary light chain excretion and normalization of calcaemia, all other parameters remaining unaltered. A third patient with light chain disease was resistant to chemotherapy ab origine. None of the disease parameters responded to either fibroblast or leukocyte interferon therapy ( 21 × 10 6 U/wk ). During therapy a downward trend occurred in the relative number of lymphocytes characterizable as B and T cells. Mitogenic reactivity remained unchanged except for a downward trend, during fibroblast interferon therapy, in reactivity to PHA and Con A after 6 days culturing. Spontaneous (background) mitogenesis upon culture showed an upward trend.

Immunofluorescent studies of the myeloma kidney with special reference to light chain disease

Renal tissue from nine patients with multiple myeloma and five subjects with renal failure secondary to other diseases was studied. Direct immunofluorescent staining procedures were employed for immunoglobulins, free kappa (κ)or lambda (λ) light chain components, fibrinogen, B 1C complement component and albumin. The most striking immunofluorescence was noted in tubular casts in patients with multiple myeloma. Antigenic determinants of many plasma protein constituents, including albumin, fibrinogen, IgG, as well as kappa and lambda Bence Jones proteins were identified in myeloma kidney casts. Similarly, diverse staining was notable also in casts examined from control patients with other types of renal failure. No specific glomerular fluorescence was noted among the myeloma patients studied. Predominant staining for kappa or lambda light chain components correlated with urinary light chain excretion data. In two instances of patients with lambda or kappa light chain disease, tubular cell localization of material reacting with specific anti-light chain conjugates was demonstrable as droplets within renal tubular cells. Tubular epithelial cell atrophy, rather than tubular casts per se, showed a direct relationship to clinical evidence of renal insufficiency.