Defect in Automated Antigen Excess Detection Discovered after Reviewing Serum Free Light Chain Results in Context with Clinical Findings.

Serum κ and λ free light chains can be markedly elevated in monoclonal gammopathies; consequently, serum free light chain (sFLC) immunoassays are susceptible to inaccuracies caused by antigen excess. As a result, diagnostics manufacturers have attempted to automate antigen excess detection. A 75-year-old African-American woman had laboratory findings consistent with severe anemia, acute kidney injury, and moderate hypercalcemia. Serum and urine protein electrophoresis and sFLC testing were ordered. The sFLC results initially showed mildly elevated free λ light chains and normal free κ. The pathologist noted that sFLC results were discrepant with the bone marrow biopsy, electrophoresis, and immunofixation results. After manual dilution of the serum, repeat sFLC testing revealed significantly higher λ sFLC results. Antigen excess causing falsely low sFLC quantitation may not be detected by immunoassay instruments as intended. Correlation with clinical history, serum and urine protein electrophoresis results, and other laboratory findings is essential when interpreting sFLC results.

Urine immunofixation electrophoresis and serum free light chain analyses benefit diagnosis of multiple myeloma in orthopedic patients with normal serum total proteins, creatinine, calcium, and hemoglobin.

BACKGROUND: A substantial number of patients with multiple myeloma (MM) who have bone destruction are initially admitted into the orthopedic service at the hospital. However, routine laboratory testing usually fails to identify these patients, thus delaying optimal therapy. Therefore, there is a clear medical need for early diagnosis of MM in these patients. METHODS: Between 2019 and 2021, 42 patients receiving treatment for orthopedic conditions had normal hemoglobin (Hb), total protein (TP), albumin (ALB), creatinine (CREA), and blood calcium (Ca) levels before their surgical procedure(s) but were subsequently pathologically confirmed to have MM, based on their presenting orthopedic symptoms. During the same period, 52 patients with orthopedic conditions were pathologically excluded from the diagnosis of MM and were recruited into our control group. Serum free light chain (sFLC) testing was performed in 94 consecutive patients in the orthopedic service using Siemens N Latex FLC kits. The levels of Hb, TP, ALB, CREA, and Ca were also measured. All 42 patients with MM were divided into group A (n = 25: κ proliferation) and group B (n = 17: λ proliferation) by the pathology department. RESULTS: There were no significant differences in levels of Hb, TP, ALB, CREA, and Ca between group A and group B and the control group. However, the sFLC κ/λ ratio of group A and B was also significantly different from that of the control group (P < .001). The results of serum immunofixation electrophoresis (IFE) testing demonstrated negative results in 14 cases (58.3%) in group A and 4 cases (25.0%) in group B. CONCLUSIONS: Some patients with orthopedic conditions who do not have typical MM laboratory results, such as those with abnormal Hb, TP, ALB, CREA, and Ca levels before their operation(s), actually have MM. MM should be highly suspected in patients with unexplained bone lesions and with an abnormal sFLC κ/λ ratio. Further tissue or bone marrow biopsy is needed in these patients even if serum and urine IFE results are negative and light chain ratio is normal.

Monoclonal gammopathy of unknown significance in kidney transplanted patients: novel insights into long-term outcomes.

BACKGROUND: Because of increased access to kidney transplantation in elderly subjects, the prevalence of monoclonal gammopathies of unknown significance (MGUS) in kidney transplantation (KT) is growing. However, little is known about the consequences of MGUS on long-term outcomes. METHODS: We identified 70 recipients with MGUS present at transplantation (KTMG) and 114 patients with MGUS occurring after KT (DNMG), among 3059 patients who underwent a KT in two French kidney transplantation centers. We compared outcomes of KTMG with those of matched controls. RESULTS: Baseline characteristics were similar except for an older age in KTMG compared with the DNMG group (62 vs 57 years, P = .03). Transient MGUS occurred more frequently in DNMG patients (45% vs 24%, P = .007). When compared with matched controls without MGUS, KTMG patients showed higher frequency and earlier post-transplant solid cancers (15% vs 5%, P = .04) and a trend for more bacterial infections (63% vs 48%, P = .08), without difference regarding patient and graft survival, rejection episodes or hematological complications. KTMG patients with an abnormal kappa/lambda ratio and/or severe hypogammaglobulinemia at the time of KT experienced shorter overall survival. CONCLUSIONS: MGUS detection at the time of KT is neither associated with a higher occurrence of graft rejection, nor adversely affects graft or overall survival. MGUS should not contraindicate KT. However, MGUS at the time of KT may be associated with higher risk of early neoplastic and infectious complications and warrants prolonged surveillance. Measurement of serum free light chain should be performed before transplant to refine the risk evaluation of KTMG patients and propose personalized follow-up and immunosuppression.

Monoclonal Gammopathy of Undetermined Significance in Patients With Transthyretin Amyloidosis (ATTR): Analysis Using the iStopMM Criteria.

INTRODUCTION: To identify the prevalence of monoclonal gammopathy of undetermined significance (MGUS) in patients with transthyretin amyloid (ATTR). We used the iStopMM study revised reference ranges for serum free light-chain (sFLC) corrected for eGFR to identify ATTR patients with light-chain MGUS (LC-MGUS). Characteristics and frequencies of the ATTR cohort with underlying MGUS was compared to a cohort of MGUS patients without ATTR. PATIENTS AND METHODS: A retrospective analysis of ATTR and MGUS patients evaluated at our center between January 2014 to December 2021. A total of 149, predominantly male (87.5%) ATTR patients with a median age of 82 were included. This cohort was compared to 228 MGUS patients. RESULTS: Of the 149 ATTR patients, 27 (18.1%) had coexisting MGUS. Among ATTR patients with MGUS, 12/27 (44%) had LC-MGUS based on sFLC abnormalities assessed using the iStopMM reference ranges. Of the MGUS only cohort, 44/228 (19.3%) met criteria for LC-MGUS. Utilizing the iStopMM reference ranges, 6 ATTR patients did not meet criteria for abnormal sFLCs, uncovering a 20% false-positive rate. CONCLUSION: We noted higher rates of MGUS, particularly LC-MGUS, among ATTR patients when compared to our MGUS only cohort. The high prevalence remained after utilizing the iStopMM sFLC corrected for eGFR reference ranges. Additionally, 6 ATTR patients with renal-dysfunction would have met MGUS criteria if not evaluated using the iStopMM revised measures. These findings emphasize careful interpretation of sFLC abnormalities and encourage providers to keep ATTR on the differential when work-up uncovers sFLC aberrations.

Use of Clinical Decision Support to Improve the Laboratory Evaluation of Monoclonal Gammopathies.

OBJECTIVES: There is considerable variation in ordering practices for the initial laboratory evaluation of monoclonal gammopathies (MGs) despite clear society guidelines to include serum free light chain (sFLC) testing. We assessed the ability of a clinical decision support (CDS) alert to improve guideline compliance and analyzed its clinical impact. METHODS: We designed and deployed a targeted CDS alert to educate and prompt providers to order an sFLC assay when ordering serum protein electrophoresis (SPEP) testing. RESULTS: The alert was highly effective at increasing the co-ordering of SPEP and sFLC testing. Preimplementation, 62.8% of all SPEP evaluations included sFLC testing, while nearly 90% of evaluations included an sFLC assay postimplementation. In patients with no prior sFLC testing, analysis of sFLC orders prompted by the alert led to the determination that 28.9% (800/2,769) of these patients had an abnormal κ/λ ratio. In 452 of these patients, the sFLC assay provided the only laboratory evidence of a monoclonal protein. Moreover, within this population, there were numerous instances of new diagnoses of multiple myeloma and other MGs. CONCLUSIONS: The CDS alert increased compliance with society guidelines and improved the diagnostic evaluation of patients with suspected MGs.

Can urine studies be replaced by serum free light chains measurements to assign responses in multiple myeloma patients?

Serum and urine protein electrophoresis and immunofixation are the preferred techniques for monitoring monoclonal proteins and evaluating treatment response in multiple myeloma (MM) patients with measurable disease. However, urine studies are subjected to limitations that may lead to inaccuracies or prevent guidelines compliance. We retrospectively studied if the substitution of urine studies by measuring serum free light chains (sFLCs) results in a comparable disease monitoring, both in intact immunoglobulin (II) and light chain (LC) MM patients. In our cohort, equal or higher percentages of disease were identified by sFLCs at baseline and maximum response as compared to urine studies. Achieving very good partial response or better (≥VGPR) according to the response criteria proposed by the French group (evaluating sFLCs instead of urine) and the IMWG response criteria were associated to a 62% and 63% reduced risk of progression, respectively. A similar prognostic value for reaching ≥VGPR was also observed among LCMM patients when the French group and the IMWG response criteria were applied. Overall, these results support the replacement of urine studies by the sFLCs assay in IIMM. In LCMM, sFLCs could be used for monitoring and urine studies could be performed only to confirm complete remissions and progressions.

The role of serum-free light chain ratios in the prediction of poor prognosis in multiple myeloma patients: a systematic review and meta-analysis.

BACKGROUND: The association between the serum free light chain (sFLC) ratio and the prognosis of multiple myeloma (MM) patients is controversial. AIM: The purpose of this study is to explore the relationship between the sFLC ratio and the prognosis of MM patients through meta-analysis. METHODS: Online public databases were searched to find relevant studies. The retrieval time is limited from the establishment of the database to July 2021. The overall survival (OS) and progression-free survival (PFS) rates were compared. The results were described using hazard ratio (HR) and a 95% confidence interval (CI). Qualitative studies were also included. RESULTS: A total of 9 studies involving 2864 participants were included. A pooled analysis based on four studies including newly-diagnosed MM patients, demonstrated that an abnormal sFLC ratio was associated with poor outcomes of OS (HR = 1.82, 95% CI: 1.15-2.90) and PFS (HR = 1.87, 95% CI: 1.20-2.90). Three qualitative studies showed that an abnormal sFLC ratio was related with poor outcomes of OS (studies all included newly diagnosed MM patients) and PFS (two studies included newly-diagnosed MM patients and one study included non-newly-diagnosed MM patients). Two studies stated that the sFLC ratio is not associated with OS (both studies included non-newly-diagnosed MM patients) and one study reported that the sFLC ratio is not associated with PFS (study included non-newly-diagnosed MM patients). CONCLUSION: sFLC ratio could be used to predict adverse outcomes in newly-diagnosed MM patients, but is not suitable for non-newly-diagnosed MM patients.

Valor diagnóstico de la electroforesis de proteínas y cadenas ligeras libres en suero en el mieloma múltiple / Diagnostic value of serum protein electrophoresis and free light chains in the multiple myeloma's diagnosis

RESUMEN Fundamento: La electroforesis de proteínas y las cadenas ligeras libres en suero son técnicas utilizadas en el diagnóstico del mieloma múltiple. Sin embargo, la utilidad diagnóstica de ambas pruebas puede variar según el método empleado y condiciones reales del medio donde se realicen. Objetivo: Determinar el valor diagnóstico de la electroforesis de proteínas y de las cadenas ligeras libres en suero en el mieloma múltiple. Metodología: Se realizó un estudio retrospectivo de los parámetros electroforesis de proteínas en suero y cadenas ligeras libres en suero a 43 pacientes con diagnóstico de mieloma múltiple por evaluación de la médula ósea. La electroforesis de proteínas se realizó por el método convencional de separación de proteínas sobre papel de acetato de celulosa y para las cadenas ligeras libres se aplicó un ensayo inmunoturbidimétrico en el que se usó un analizador químico (Cobas 311). Se calcularon 7 parámetros que evaluaron la exactitud diagnóstica. Resultados: Todos los parámetros que evaluaron la exactitud diagnóstica estuvieron dentro de los intervalos de confianza en ambas pruebas. Conclusiones: La electroforesis de proteínas y las cadenas ligeras libres en suero son ensayos de gran utilidad en el diagnóstico del mieloma múltiple y se deben utilizar en conjunto para la mayor captación posible de casos.

ABSTRACT Background: Protein electrophoresis and serum free light chains are techniques used in the diagnosis of multiple myeloma. However, the diagnostic utility of both tests may vary according to the method used and the actual conditions of the environment where they are performed. Objective: To determine the diagnostic value of protein electrophoresis and serum free light chains in multiple myeloma. Methodology: A retrospective study of serum protein electrophoresis parameters and serum free light chains was conducted in 43 patients diagnosed with multiple myeloma by bone marrow evaluation. Protein electrophoresis was completed by the conventional method of protein separation on cellulose acetate paper and for free light chains an immunoturbidimetric assay was applied in which a chemical analyzer (Cobas 311) was used. Seven parameters were calculated to evaluate diagnostic accuracy. Results: All parameters assessing diagnostic accuracy were within confidence intervals in both tests. Conclusions: Protein electrophoresis and serum free light chains are very useful assays in the diagnosis of multiple myeloma and should be used in conjunction for the highest possible approval of cases.

Light Chain-Predominant Multiple Myeloma Subgroup: Impaired Renal Function Correlates with Decreased Survival.

OBJECTIVE: Patients with light chain-predominant multiple myeloma have been shown to exhibit shorter survival. Retrospective comparison of clinical and laboratory data was undertaken to ascertain the likely cause(s) of this observation. METHODS: Records of patients with multiple myeloma seen at 1 institution revealed 316 patients with conventional and 71 patients with light chain-predominant multiple myelomas with secretion of intact immunoglobulins. Laboratory and clinical findings in the 2 groups were compared. RESULTS: Patients with light chain-predominant multiple myeloma had a significantly higher death rate, a higher rate of chronic dialysis, a lower estimated glomerular filtration rate and serum albumin, a significantly higher urine protein concentration, and a significantly higher prevalence of hypertension and blood transfusion requirements. Other clinical and laboratory parameters surveyed were not significantly different between the 2 groups. CONCLUSION: The shorter survival of patients with light chain-predominant multiple myeloma is clearly associated with renal damage caused by excess free immunoglobulin light chains. Renal damage may be ameliorated by early aggressive treatment with chemotherapy, plasmapheresis, and dialysis; a multi-institutional prospective controlled trial would be needed to test this hypothesis.

Role of Serum Free Light Chain Assay in Relapsed/Refractory Multiple Myeloma. A Real-Life Unicentric Retrospective Study.

BACKGROUND: In the era of novel drugs a growing number of multiple myeloma (MM) patients are treated until disease progression. Serum free light chain (sFLC) assay is recommended for disease monitoring in oligo-secretory and micromolecular MM. METHODS: In this real-life survey, a total of 130 relapsed/refractory MM patients treated at our center with at least three lines were investigated as a retrospective cohort. RESULTS: The median age at diagnosis was 64 years and more than half of patients were male. A total of 24 patients (18%) had oligo-secretory/micromolecular disease at diagnosis. More than 20% of 106 normo-secretory patients had oligo-secretory/micromolecular escape. In order to evaluate potential role of sFLC assay before ("pre") and after ("post") every treatment line, involved serum free light chain values (iFLC) less than 138 mg/mL and serum free light chain ratios (FLCr) <25 were identified by using ROC curve analysis. The analysis of the entire cohort throughout four treatment lines demonstrated a statistically significant negative impact on progression-free survival (PFS) for both involved pre-sFLC and its ratio (respectively p = 0.0086 and p = 0.0065). Furthermore, both post-iFLC and post-FLCr greater than the pre-established values had a negative impact on PFS of the study cohort; respectively, p = 0.014 and p = 0.0079. Odds ratio analysis evidenced that patients with both involved post-sFLC greater than 138 mg/mL and post-FLCr above 25 at disease relapse had a higher probability of having clinical relapse (respectively p = 0.026 and p = 0.006). CONCLUSIONS: Alterations of sFLC values, namely iFLC and FLCr, both prior to treatment initiation and in the course of therapy at every treatment line, could be of aid in relapse evaluation and treatment outcome. We therefore suggest close periodical monitoring of sFLC assay, independently from secretory status.

Biomarkers in AL Amyloidosis.

Systemic AL amyloidosis is a rare complex hematological disorder caused by clonal plasma cells which produce amyloidogenic immunoglobulins. Outcome and prognosis is the combinatory result of the extent and pattern of organ involvement secondary to amyloid fibril deposition and the biology and burden of the underlying plasma cell clone. Prognosis, as assessed by overall survival, and early outcomes is determined by degree of cardiac dysfunction and current staging systems are based on biomarkers that reflect the degree of cardiac damage. The risk of progression to end-stage renal disease requiring dialysis is assessed by renal staging systems. Longer-term survival and response to treatment is affected by markers of the underlying plasma cell clone; the genetic background of the clonal disease as evaluated by interphase fluorescence in situ hybridization in particular has predictive value and may guide treatment selection. Free light chain assessment forms the basis of hematological response criteria and minimal residual disease as assessed by sensitive methods is gradually being incorporated into clinical practice. However, sensitive biomarkers that could aid in the early diagnosis and that could reflect all aspects of organ damage and disease biology are needed and efforts to identify them are continuous.

Multiple myeloma: Detection of free monoclonal light chains by modified immunofixation electrophoresis with antisera against free light chains.

INTRODUCTION: Neoplastic monoclonal gammopathies are frequently associated with production of excess free monoclonal light chains. A sensitive method for detecting free monoclonal light chains in serum could provide a marker for residual/minimal residual disease and as an adjunct to serum protein electrophoresis to serve as a screening method for monoclonal gammopathies. METHODS: Conventional serum immunofixation electrophoresis was modified by applying undiluted serum samples, and staining for serum free light chains with antisera specific to free light chains. Washing/blotting of gels was enhanced to remove residual proteins that did not bind to the antibodies including intact monoclonal immunoglobulins. Results from this modified immunofixation electrophoresis were compared with results from commercially available MASS-FIX/MALDI assay. RESULTS: Monoclonal free kappa light chains could be detected to a concentration of about 1.78 mg/L and monoclonal free lambda light chains to a concentration of about 1.15 mg/L without the need for special equipment. Comparison of these thresholds with parallel results from a commercially available MASS-FIX/MALDI assay revealed the modified electrophoretic method to be more sensitive in the context of free monoclonal light chains. CONCLUSIONS: Modified serum immunofixation electrophoresis has been shown to detect low levels of monoclonal free light chains at a sensitivity suitable for the method to be used in detecting minimal residual disease, and potentially in a screening assay for monoclonal gammopathies. The disparity in the results with commercially available MASS-FIX/MALDI assay is postulated to be due to limited repertoire of reactivity of nanobodies of camelid origin.

Light Chain Multiple Myeloma: High Serum Free Light Chain Concentrations Portend Renal Damage and Poorer Survival.

BACKGROUND: Monoclonal immunoglobulins provide an indication of the tumor burden in patients with plasma cell neoplasms. Higher concentrations of serum free light chains in light chain predominant multiple myeloma have been shown to correlate with a poorer outcome. We examined the correlations of serum free light chain concentrations in light chain myelomas with survival, estimated glomerular filtration rate (eGFR) and other clinical and pathological parameters. METHODS: Records of patients with light chain multiple myelomas were reviewed. Highest concentration of serum free light chains for each patient were plotted to ascertain an inflection/change point. Survival, eGFR, and other clinical and pathological parameters were compared between the low and high light chain concentration groups. RESULTS: Plotting serum free light chain concentrations revealed an inflection point at a concentration of 455 mg/L apportioning patients in to 2 subgroups: 39 patients with low light chain concentrations and 26 patients with high concentrations. The high concentration group had more unfavorable pathology in bone marrow examination in terms of higher neoplastic plasma cell burden and high-risk cytogenetics. The survival rate and eGFR in the high concentration group were significantly worse than in the low concentration group. CONCLUSIONS: As noted for light chain predominant multiple myeloma, high serum free light chain concentration in light chain multiple myelomas are associated with higher renal disease burden and shorter survival. Monitoring of serum free light chain concentrations and customizing treatments to address this parameter are warranted.

Treatment response measurements and survival outcomes in a cohort of newly diagnosed AL amyloidosis.

INTRODUCTION: The assessment of AL amyloidosis response is based on serum free light chains (sFLC) levels, and serum and urine monoclonal protein investigations. Recently, difference between involved and uninvolved free light chains (dFLC), involved free light chain (iFLC) and complete response (CR) has been reported as independent predictor of survival and a refinement of the hematological response criteria has been proposed by several groups. METHODS: In the current study, all consecutive newly diagnosed symptomatic AL amyloidosis patients were evaluated. The primary objective of the study was to assess hematological and organ response after first line of treatment. RESULTS: A cohort of 76 cases with upfront treatment was used for this analysis. After a median of 3 months post-therapy, hematological response was seen in 88% of cases including CR in 26.3%, VGPR in 38.2% and PR in 23.7%. Median OS was longer in patients with dFLC < 10 mg/L at 3 months, iFLC <20 mg/L at 1 and 3 months, and those achieving CR. Multivariate analysis showed presence of CR as the most important independent prognostic factors for survival. CONCLUSIONS: Our study suggests that maximal sFLC response and CR are potential endpoints to define clinical outcomes. Large collaborative studies are required to validate and optimize response criteria.

Serum and urine free light chains measurements in patients with systemic sclerosis: novel biomarkers for disease activity.

Circulating free light chains (FLCs), considered biomarkers of B cell activity, are frequently elevated in patients affected by systemic inflammatory autoimmune diseases. As the systemic sclerosis (SSc) clinical course can be variable, this study is aimed at evaluating FLCs levels in affected individuals as biomarkers of disease activity. We assessed FLC levels in serum and urine of 72 SSc patients and 30 healthy controls (HC). Results were analyzed in comparison with overall clinical and laboratory findings, disease activity index (DAI) and disease severity scale (DSS). SSc patients displayed increased levels of κ and λ FLC in serum significantly higher than HC (p = 0.0001) alongside the mean values of free κ/λ ratio and κ + λ sum (p = 0.0001). SSc patients showed increased free κ in urine with a κ/λ higher than HC (p = 0.0001). SSc patients with increased κ + λ in serum showed that erythro-sedimentation rate (p = 0.034), C-reactive protein (p = 0.003), DAI (p = 0.024) and DSS (p = 0.015) were higher if compared to SSc patients with normal levels of FLC. A positive linear correlation was found between serum levels of free κ and DAI (r = 0.29, p = 0.014). In addition, SSc patients with increased free κ in urine had higher DAI (p = 0.048) than SSc patients with normal κ levels. Our results strengthen the role of serum FLC as useful biomarker in clinical practice to early diagnosis and monitor disease activity, showing for the first time that also urine FLC levels correlated with disease activity in SSc patients.

[Clinical presentation and prognosis in patients with light-chain amyloidosis with an ultra-high level of serum free light-chain].

Objective: To investigate the clinical features and outcomes of patients with light-chain (AL) amyloidosis with an ultra-high level of serum free light-chain (FLC) . Methods: Five hundred and ninety-five patients with AL amyloidosis were retrospectively reviewed between January 2009 and January 2020 at Peking Union Medical College Hospital. We analyzed the clinical features and prognosis of patients with ultra-high FLC levels [difference between involved and uninvolved light chains (dFLC) >500 mg/L; n=124] and those without ultra-high FLC levels (dFLC≤500 mg/L; n=471) . Results: Patients with ultra-high FLC presented with more frequent cardiac involvement (82.3% vs 70.1%, P=0.007) , and a higher percentage of patients with 2004 Mayo Ⅲ stage (41.8% vs 33.8%, P=0.029) , but less frequent renal involvement than patients without an ultra-high FLC (59.7% vs 71.8%, P=0.009) . Patients with an ultra-high FLC achieved a lower proportion of hematologic (72.4% vs 82.3%, P=0.048) and cardiac response (37.3% vs 54.7%, P=0.016) and had shorter overall survival (13.0 months vs not reached, P<0.001) and a higher early death rate within 3 months (28.2% vs 11.3%, P<0.001) than those without an ultra-high FLC. Ultra-high FLC independently predicted worse prognosis in patients with AL amyloidosis (HR=2.279, 95%CI 1.685-3.083, P<0.001) . Conclusions: Patients with an initially ultra-high FLC represented a subgroup with more common cardiac involvement, more advanced cardiac stages, and extremely poor prognosis.

Analysis of Multiple Bands on Serum Protein Immunofixation Electrophoresis: Challenge in Interpretation of Clonality in a Patient with Light Chain-Predominant Multiple Myeloma.

Sera from patients with multiple myeloma usually display a single monoclonal immunoglobulin band on serum protein immunofixation electrophoresis. Multiple bands may be seen if the myeloma is bi- or triclonal or if the monoclonal immunoglobulin has rheumatoid factor activity. We describe a patient with light chain-predominant IgA lambda myeloma; the patient's serum displayed 2 spatially distinct bands reacting for alpha heavy and lambda light chains. The methods used to establish monoclonality are addressed.

(F)utility of urine Bence Jones proteins for "routine" screening for plasma cell dyscrasia.

Testing urine for Bence Jones Protein (BJP) had been a time old procedure used for screening and monitoring of monoclonal disorders since its description. However, has poor sensitivity and despite advances in diagnostic methods of monoclonal disorders it is being continued to be requested in individuals for evaluation of myeloma or plasma cell disorders. Effective utilization and minimizing untimely or unnecessary investigations is important in the evaluation and management of any medical condition. Though, we are hard-wired during our education with some "trigger" or "peculiar" words that make us jump to actions too quickly, without comprehending the actual problem. Supporting evidence is presented to avoid reflexive use of multiple tests and utilize tests that improve utilization, reduce waste, and uphold the Choosing Wisely principles in providing optimal care to the patients.