|Year : 2017 | Volume
| Issue : 5 | Page : 424-429
Spectrum of monoclonal light-chain gammopathy in a tertiary care hospital
Mir Sadaqat Hassan Zafar1, Swasti Sinha2, Shyam Aggarwal3, Manorama Bhargava2
1 Department of Clinical Hematology, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India
2 Department of Hematology, Sir Ganga Ram Hospital, New Delhi, India
3 Department of Medical Oncology, Sir Ganga Ram Hospital, New Delhi, India
|Date of Submission||26-Feb-2017|
|Date of Acceptance||06-Jul-2017|
|Date of Web Publication||14-Nov-2017|
Mir Sadaqat Hassan Zafar
Department of Clinical Hematology, Room No. 509, 5th Floor, Sheri-I-Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir
Source of Support: None, Conflict of Interest: None
Background: Monoclonal light chain gammopathies are uncommon subsets of plasma cell disorders which usually present as diagnostic challenge. Materials and Methods: Twenty cases of monoclonal light-chain gammopathy were identified after screening 150 plasma cell disorders at a tertiary care referral center of North India and were analyzed for clinical profile and treatment outcomes. Results: Out of 20 cases of monoclonal light-chain gammopathy, 65% (13/20) were light-chain multiple myeloma (LCMM) type, 20% (4/20) were light-chain deposition disease (LCDD) type, and 15% (3/20) had primary amyloidosis (AL). Renal failure (65% of cases) was the most common presentation. All the patients with LCDD presented with renal failure (4/4) while as 61% of LCMM (8/13) and 33% of AL (1/3) presented with renal failure. Five patients presented with anemia and all were LCMM type. Two patients presented with lytic bone lesions (LCMM type) and one patient presented with plasmacytoma (LCMM). Overall response rate after 4 cycles of induction therapy was 92.3% in LCMM group, 100% in LCDD group, and 33.33% in AL group (excluding one patient who expired before the start of treatment). LCMM showed 23% partial remission (PR), 30.77% very good PR, 38.46% complete response (CR), and 5% no response (NR). LCDD showed PR 75% and CR 25%. AL showed PR 33.33% and NR 5%. Conclusions: Renal failure is a common presentation of monoclonal light chain gammopathies, and it should alert the treating physician for the underlying uncommon plasma cell disorder.
Keywords: Acute renal failure, monoclonal light chain gammopathy, plasma cell disorder
|How to cite this article:|
Hassan Zafar MS, Sinha S, Aggarwal S, Bhargava M. Spectrum of monoclonal light-chain gammopathy in a tertiary care hospital. Med J DY Patil Univ 2017;10:424-9
| Introduction|| |
Plasma cell disorders encompass a broad spectrum of diseases ranging from the benign monoclonal gammopathy of undetermined significance to the life-threatening conditions of multiple myeloma, light-chain deposition disease (LCDD), and light-chain amyloidosis (AL). Monoclonal light-chain gammopathies constitute a relatively uncommon subset of plasma cell neoplasms characterized by exclusive secretion of single, homogeneous light-chain immunoglobulins but no associated heavy chain or complete immunoglobulins. They include cases of light-chain multiple myeloma (LCMM), LCDD, and primary AL. Although the occurrence of LCMM is not unusual, the other two forms of light-chain gammopathies are rarer.,
LCMM involves secretion of light chains (κ or λ) only and comprises 15% multiple myeloma cases. Prognostically, LCMM has worse outcome, is shown by few studies only. However, the treatment options are similar as that of any other multiple myeloma case.
LCDD is commonly diagnosed monoclonal immunoglobulin deposition disease (MIDD). A single clone of plasma cells is responsible for the overproduction of either kappa or rarely lambda light chains. Even in the absence of detectable serum or urine monoclonal immunoglobulin, a monoclonal population of bone marrow plasma cells can be demonstrated through immunofluorescence, and an altered serum-free light chain ratio is usually seen.,,
LCDD is characterized by the deposition of non-amyloid monotypic immunoglobulin light chains, especially in the kidney, resulting in renal dysfunction. LCDD typically presents with hypertension, microhematuria, and proteinuria, and in the absence of therapy, the clinical course is one of inexorably progressive chronic kidney disease, leading to a requirement for renal replacement therapy.,,
Primary systemic light-chain AL is a clonal plasma cell disorder characterized by decreased number of monoclonal plasma cells in the bone marrow compared to myeloma; however, misfolded fibrillar protein produced by these plasma cells has an affinity for visceral organs. There is predominantly lambda light chain involvement. Notably, it involves kidney, heart, liver, nerve, or gastrointestinal tract leading to their dysfunction. It can also complicate multiple myeloma, Waldenström's macroglobulinemia, monoclonal gammopathy of undetermined significance, or lymphoma. Hence, the survival is poor due to end-organ damage by the amyloid protein.
As there is a paucity of data from Indian literature about the clinical profile of monoclonal light chain disorders, we performed subanalyses of 150 cases of confirmed plasma cell neoplasms to collect baseline data for future reference.
| Materials and Methods|| |
Various cases of plasma cell disorders evaluated and treated in the Departments of Hematology and Medical Oncology of a tertiary care hospital were taken for analysis. It was a retrospective study, in which cases were analyzed for demographic data, clinical presentation, and all the baseline investigations including complete blood count, complete blood chemistry, serum and urine protein electrophoresis, serum and urine immunofixation, bone marrow examination, serum β2 microglobulin, and free light chain assay if available. Renal or other site biopsies with immunofluorescence or Congo red staining and echocardiography were checked in relevant cases. Cases fulfilling the criteria for monoclonal light-chain gammopathy, i.e., LCMM, LCDD, and systemic AL were further assessed.,,
LCMM was diagnosed by documenting clonal bone marrow plasma cells ≥10% or biopsy proven plasmacytoma, presence of serum and/or urinary monoclonal protein, evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder (specifically hypercalcemia-serum calcium >11.5 mg/dL, renal insufficiency-serum creatinine >173 micromoles/l (or >2 mg/dL), anemia-hemoglobin value of >2 g/dL below the lower limit of normal or a hemoglobin value <10 g/d or bone lesions-lytic lesions, severe osteopenia or pathologic fractures) with no immunoglobulin heavy chain expression on immunofixation.
Systemic AL was diagnosed by the presence of an amyloid-related systemic syndrome (such as renal, liver, heart, gastrointestinal tract, or peripheral nerve involvement), positive amyloid staining by Congo red in any tissue (e.g., fat aspirate, bone marrow, or organ biopsy), and evidence of a monoclonal plasma cell proliferative disorder (serum or urine M protein, abnormal free light chain ratio, or clonal plasma cells in the bone marrow). Approximately 2%–3% of patients with AL will not meet the requirement for evidence of a monoclonal plasma cell disorder listed above.
Primary AL is particularly difficult to diagnose because no single imaging, blood, or urine test is diagnostic for this disorder. The diagnosis should be suspected in any patient with nondiabetic nephrotic syndrome; nonischemic cardiomyopathy with hypertrophy on echocardiography, hepatomegaly or increased alkaline phosphatase value with no imaging abnormalities of the liver, chronic inflammatory demyelinating polyneuropathy with a monoclonal protein, or the presence of a monoclonal gammopathy in a patient with unexplained fatigue, edema, weight loss, or paresthesias. The presence of proteinuria in a patient with a monoclonal gammopathy may be mistaken for multiple myeloma with cast nephropathy. If specific diagnostic evaluation for AL is not performed, patients with sensory neuropathy may instead undergo treatment for a chronic inflammatory demyelinating polyneuropathy with a monoclonal protein. The high frequency of lambda light-chain proteinemia is a hallmark of AL. Biopsy of the iliac crest bone marrow combined with abdominal subcutaneous fat aspiration will identify amyloid deposits in 85% of patients with AL. If both the fat and the bone marrow stain negative for amyloid, there is still a 15% chance of AL, and the appropriate organs should be biopsied when there is high index of suspicion.,
LCDD was diagnosed by documenting deposition of monotypic, noncongophilic immunoglobulin light chains, especially in the kidney and presence of serum and/or urinary monoclonal protein.
Patients with suspicion of LCDD should be subjected to the screening panel for patients with plasma cell disorders. The introduction of quantitative serum assays for free light chain, however, has increased the sensitivity of laboratory testing strategies for identifying monoclonal gammopathies; this increased diagnostic sensitivity is readily apparent in the monoclonal light chain diseases. By combining serum protein electrophoresis, free light chain assay and immunofixation, and urine protein electrophoresis/immunofixation, the sensitivity for LCDD goes up to 83.3% and decreases to 77.8% if we omit the use of urine for electrophoresis/immunofixation. Excluding free-light chain assay decreases the sensitivity for LCDD detection to 77.8%. Patients with extensive proteinuria, rapidly progressive renal failure, and organ dysfunction such as congestive heart failure or liver should be suspected to have LCDD. Because sensitive techniques as mentioned earlier can miss monoclonal component detection in approximately 10%–15%, kidney biopsy is important to guide an adequate and prompt diagnosis of LCDD. The confirmation of LCDD diagnosis is made by the immunohistologic analysis of tissue from an affected organ, which is not congophilic in nature. Light-chain restriction analysis on the tissue will confirm whether the light or heavy chain is monoclonal.,
After a detailed screening of 150 confirmed plasma cell disorders, 20 cases of monoclonal light chain gammopathy were taken for subanalyses. Response assessment was used as per the IMWG guidelines and international symposium on amyloid and AL.,
Complete response (CR): negative immunofixation on the serum and urine and disappearance of any soft-tissue plasmacytomas with <5% plasma cells in bone marrow.
Very good partial response (VGPR): serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level <100 mg per 24 h.
Partial response (PR): ≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ≥90% or to <200 mg per 24 h. If the serum and urine M-protein are unmeasurable, ≥50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria. If serum and urine M-protein is unmeasurable, and serum free light assay is also unmeasurable, ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥30%.
| Results|| |
Out of 150 cases of plasma cell disorders, 20 cases of monoclonal light-chain gammopathy (13.33%) were identified. The 20 cases of monoclonal light-chain gammopathy (age 38–70 years) comprised LCMM (65%), LCDD (20%), and AL (15%) groups [Table 1].
Seventy percent of cases were male, and 30% cases were female. Thirteen patients (eight LC MM, four LCDD, and one AL) presented with acute renal failure (65% of cases) with the lowest serum creatinine documented as 2.8 mg/dl and highest serum creatinine documented as 8.2 mg/dl.
Five patients presented with anemia and all were LCMM type. Two patients presented with lytic bone lesions (LCMM type) and one patient presented with plasmacytoma (LCMM). Twelve cases (eight LCMM, two LCDD and two AL) were of kappa light-chain type (60%) while eight (five LCMM, two LCDD, and one AL) were lambda light-chain type (40%). Out of the three primary AL patients, one presented with acute abdominal pain and subsequently found to have splenic rupture that expired before the start of treatment; the other patient presented with chronic diarrhea and polyneuropathy with rectal biopsy proven amyloid component, and the third one presented with renal failure with renal biopsy-proven amyloid deposition [Figure 1] and [Figure 2].
Thus, LCMM was the most common entity seen. The most common clinical presentation was an acute renal failure, and the most common light chain involved was kappa type [Table 2].
|Table 2: Clinical presentation and treatment of 20 monoclonal light chain gammopathy cases|
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Bortezomib and dexamethasone were used as induction therapy in 14 patients (eight LCMM, four LCDD, and two AL), CyBorD (cyclophosphamide, bortezomib, and dexamethasone) in 4 patients (four LCMM), and one patient (LCMM) received VTD (bortezomib, thalidomide, and dexamethasone). LCMM showed partial response (23%), very good partial response (30.77%), CR (38.46%), and no response (NR) of 5%. LCDD showed a partial response (75%) and CR (25%). AL showed a partial response (33.33%) and NR (5%). Overall response rate after 4 cycles of treatment was 92.3% in LCMM group, 100% in LCDD group and 33.33% in AL group (excluding the patient who expired before the start of treatment) [Table 3].
| Discussion|| |
Free light chains (κ and λ) are by-products of immunoglobulin synthesis and in normal subjects are released into circulation in small quantities. In plasma cell disorders, they are produced in quantities thousands of times of normal, leading to accumulation in serum and kidney thus causing renal damage. Monoclonal light-chain gammopathy is a rarer subset of plasma cell disorders including LCMM, LCDD, and AL. Although the diagnosis of LCMM is straight forward, the other two pose diagnostic challenges in clinical practice.,
The clinical course of monoclonal light-chain gammopathies is usually more aggressive with higher incidence of renal failure. Patients with AL and plasma cell myeloma have a shorter survival than those with AL or myeloma alone. The median survival for patients with primary AL is approximately 2 years from diagnosis. The median overall survival for patients with LCDD is approximately 4 years. However, survival shortens if it is associated with multiple myeloma or extrarenal light-chain deposition.
In our study analysis, 20 cases of monoclonal light chain gammopathy were identified, i.e., LC MM (13/20), LCDD (4/20), and AL (3/20) groups. Thus, LCMM was the most common entity seen. This corresponds to the usual predominance of LCMM and LCDD types.,
Renal failure (65% of cases) was the most common presentation with the lowest serum creatinine documented as 2.8 mg/dl and highest serum creatinine documented as 8.2 mg/dl. All the patients with LCDD presented with renal failure (4/4) while as 61% of LCMM (8/13) and 33% of AL (1/3) presented with renal failure. Anemia, lytic bone lesions, and plasmacytoma were seen in LCMM only. Out of the three primary AL patients, one presented with acute abdominal pain and subsequently found to have splenic rupture that expired before the start of treatment; the other patient presented with chronic diarrhea and polyneuropathy and the third one presented with renal failure. Twelve cases were of kappa light-chain type (60%) while eight were lambda light-chain type (40%). Kappa light-chain type was predominant in LCMM while as lambda light-chain type in AL.
Nasr et al. reported a single-institution experience of 64 cases, in which 51 had LCDD, 7 had heavy chain deposition disease, and 6 had light and heavy chain deposition disease. During a median of 25 months of follow-up in 56 patients, 32 (57%) had stable/improved renal function, 2 (4%) had worsening renal function, and 22 (39%) progressed to ESRD. The mean renal and patient survivals were 64 and 90 months, respectively.
Stratta et al. evaluated 289 elderly patients with multiple myeloma (n = 115) and monoclonal gammopathy of undetermined significance (n = 174). Renal pathology documented MIDD in 12/30 cases (40%): six cases of AL, two of LCDD, one of heavy chain disease, and three of cast nephropathy, as well as four cases of glomerulonephritis, eight of arteriolosclerosis, and six of normal picture. Renal impairment was the only significant risk factor for patient death.
Renal dysfunction has been associated with shorter survival or early death in plasma cell disorders. However, recent subanalyses of patients with impaired renal function from two phase 2 studies showed that renal dysfunction did not appear to have a negative impact on response rates, toxicity, or treatment discontinuation in patients with relapsed and/or refractory multiple myeloma receiving bortezomib therapy.
Studies indicate that bortezomib is effective and safe in patients with renal impairment and that it can improve renal function. Ludwig et al. reported the reversal of light-chain-induced acute renal failure with bortezomib-based therapy in 5 out of 8 MM patients.
In another recent retrospective analysis, bortezomib-based regimens were given to 117 multiple myeloma patients with renal impairment, including 14 patients who required dialysis. At least, a PR-renal was documented in 83 out of 113 evaluable patients (73%), including 27% of the CR-renal or near CR-renal patients.
Nineteen patients were treated with four cycles of chemotherapy before assessing the response. Bortezomib/dexamethasone, CyBorD, or VTD protocols were used. Out of 8 cases of LCMM, 6 cases had complete normalization of serum creatinine, one patient had 50% reduction, and one patient showed NR. Out of 4 cases of LCDD, 2 patients had complete normalization of serum creatinine while as one patient showed 50% reduction and one patient showed NR. One patient of AL that attained partial hematologic response but 50% reduction in serum creatinine initially, lost the renal response toward the end of therapy.
Recently, the use of bortezomib in small series of patients with LCDD has been reported. These data together suggest that induction chemotherapy may help ameliorating the renal dysfunction seen in LCDD and perhaps would lead to a more feasible approach with HDM and ASCT with a better outcome. The role of induction chemotherapy in LCDD should be investigated in a prospective manner.,
LCMM showed partial (23%), very good partial response (30.77%), CR (38.46%), and NR of 5%. LCDD showed partial response (75%) and CR (25%). AL showed partial response (33.33%) and NR (5%). Overall response rate after 4 cycles of treatment was 92.3% in LCMM group, 100% in LCDD group, and 33.33% in AL group. The two nonresponding patients were one each from LCMM and AL. Thus, contrary, previous reports, LCMM and LCDD did not show poor response to induction.
Sayed et al. studied prospectively fifty-three patients with biopsy-proven LCDD and patients were followed for a median of 6.2 years. There was a strong association between hematologic response to chemotherapy and renal outcome, with a mean improvement in glomerular filtration rate (GFR) of 6.1 ml/min/year among those achieving a complete or very good partial hematologic response with chemotherapy, most of whom remained dialysis independent, compared with a mean GFR loss of 6.5 ml/min/year among those achieving only a partial or no hematologic response, most of whom developed end-stage renal disease. Seven patients received a renal transplant, and among those whose underlying clonal disorder was in sustained remission, there was no recurrence of LCDD up to 9.7 years later. This study highlighted the need to diagnose and treat LCDD early and to target at least a hematologic VGPR with chemotherapy, even among patients with advanced renal dysfunction, to delay progression to end-stage renal disease and prevent recurrence of LCDD in the renal allografts of those who subsequently receive a kidney transplant.
Patient survival and tolerance of high-dose chemotherapy appear to be substantially better in LCDD than in systemic AL. Although renal AL amyloid deposition can be slowed or halted by chemotherapy, which successfully suppresses light-chain production with accompanying prolongation of renal survival, overall prognosis in AL is markedly poorer than in LCDD.
| Conclusions|| |
Renal dysfunction is a common presentation of monoclonal light chain gammopathies, and it should alert the treating physician for the uncommon underlying plasma cell disorders. The diagnosis of monoclonal light-chain gammopathies require high index of suspicion as they are unusual in routine clinical practice. Bortezomib-based therapies if started early, produce favorable responses both hematological and organ specific. However, if the diagnosis is delayed or cases are undiagnosed, morbidity and mortality remain high. This study adds to the scarce data in literature and forms the baseline for future reference. It has a limitation of smaller sample size which can be improved by a future prospective observational study with larger sample size.
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Conflicts of interest
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]