Клиническое значение тестов FLC у пациентов без других признаков гематологического расстройства.

Introduction

Measurement of free light chain (FLC) levels in peripheral blood is typically reserved for patients already diagnosed with plasma cell dyscrasias (PCD) [ 1 , 2 ]. However, over the last decade, the employment of this test is continuously expanding and family physicians often incorporate it into the diagnostic assessments of nonspecific complains (e.g., unexplained fatigue/pain, mild anemia ect), even when the level of suspicion of PCD/lymphoproliferative diseases (LPD) is low. Consequently, there has been a growing occurrence of "incidental detection" of slightly abnormal FLC levels: increased FLC kappa (FLC-K), FLC lambda (FLC-L), and/or abnormal FLC ratio (FLC-R), often without any additional remarkably abnormal blood test that supports PCD. Data regarding the long-term clinical significance of this "minimal" finding in the lack of concomitant increased total protein level, and its importance as potential predictor for PCD/LPD diagnosis remained unclear. By screening healthy subjects [ 3 ] and populations at risk [ 4 ] (people of African ancestry and first-degree relatives of multiple myeloma (MM) patients) for PCD, the iStopMM [ 3 ] and the PROMISE [ 4 ] studies demonstrated a relatively high incidence of both monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) in screened subjects [ 5 , 6 ]. MGUS, and SMM were eventually identified in 18% and 1.08% of ≥ 70 years old healthy volunteers, respectively [ 5 , 6 ].

In contrast to these prospective studies that applied a combination of highly sensitive, MM-specific tests [ 3 – 6 ], our large real-world retrospective study, explored the clinical significance of an "abnormal" FLC test, detected in the absence of increased total protein level, in patients that were investigated in the community for non-specific complaints. Our study focused on PCD/LPD detection rate, and the potential impact of an abnormal FLC-R on overall survival (OS), aiming to provide primary care physicians enhanced diagnostic tools, especially when TP tests yield normal results, to detect MGUS, and potential SMM.

Methods

Study design and data source

This research is a non-interventional, retrospective observational cohort study. The cohort is based on anonymized data obtained from electronic medical records of members of Maccabi Healthcare Services (MHS), after receiving approval from the institution’s ethical committee (study MHS-0111-22). MHS is a nationwide health care, servicing a quarter of the population in Israel. The MHS electronic medical database contains longitudinal data on a stable population of 2.8 million people and possess several automatically formulated registries. Data for our study were automatically collected and included comprehensive laboratory results from a single central lab, physician visits, imaging, and extensive demographic information on each patient.

Study population

The study reviewed all consecutive patients without a known diagnosis of PCD/LPD, who underwent a FLC test due to nonspecific complains, between May 2007 (time of introduction of this test in MHS) and May 2023.

Inclusion criteria were: age ≥ 18 years, having a FLC test due to fatigue/weakness/other nonspecific complains, and being registered in MHS ≥ 12 months (m) prior to first FLC test (determined as the index date) and ≥ 6 m afterward. Patients diagnosed with PCD/LPD prior to, or < 6 m after the index date, were excluded. Patients with elevated total protein levels (TP > 8.3 g/dL) were also omitted, assuming that the FLC test was performed in high level of suspicion of PCD in these patients. Similarly, patients with an absolute lymphocyte count ≥ 5 × 10 9 /L were also excluded, considering that they already had LPD, though, not officially diagnosed yet.

Study variables and definitions

Patient characteristics at the index date, including demographics, pre-existing co-morbidities, and laboratory results, obtained at the time of the first FLC test: [hemoglobin (Hb), lymphocyte count, creatinine (CR), calcium (Ca), immunoglobulin (Ig) levels, serum protein electrophoresis (SPEP), immunofixation (IFE), and FLC levels], were all recorded. FLC levels were performed using the Binding Site assay [ 7 ].

Anemia was defined as Hb < 10 g/dL or a decrease in Hb level of ≥ 2 g/dL from baseline [ 8 ]. Acute renal failure (ARF), as elevated CR > 1.3 mg/dL within the last 6 m, hypercalcemia, as a Ca level > 10.4 mg/dL; and decreased albumin level, as albumin < 3.5 g/dL. Abnormal Ig levels were defined as IgG > 1600 or < 700 mg/dL, IgM > 230 or < 40 mg/dL and IgA > 520 or < 80 mg/dL.

The index FLC-test results were categorized as normal or abnormal, dependent on the FLC-R. An abnormal result, defined as FLC-R < 0.26 or FLC-R > 1.65, was further stratified into four categories: normal (0.26–1.65), slightly abnormal (slAb) (0.1–0.26 or 1.65–4), moderately abnormal (mAbn) (0.05–0.1 or 4–8), and significantly abnormal (sigAb) (Ratio < 0.05 or > 8).

Patients were followed for up to 5 years or until being officially diagnosed with PCD/LPD [including MGUS, MM, primary amyloidosis, plasmacytoma, chronic lymphocytic leukemia (CLL), B cell lymphoma], whichever occurred first. The first date of getting an official diagnosis of PCD/LPD was determined as an event.

The diagnosis of MGUS in those that eventually, were officially reported as having MGUS, relied on the International Myeloma Working Group (IMWG) criteria [ 9 ], referring either to conventional-MGUS or light-chain MGUS (LC-MGUS) [ 8 ]—increased level of the appropriate involved light chain with an abnormal FLC-R, in the absence of the expression of Ig heavy chain [ 8 ].

Statistical analyses

Descriptive statistics were presented as absolute numbers and percentages for categorical variables and mean/median and standard deviations for continuous variables. The Chi-squared test and Mann–Whitney test were used for comparisons of proportions and medians across groups, respectively.

Kaplan–Meier method was used to generate survival curves, presented as cumulative diagnosis of PCD/LPD within 5-years and overall survival. Log-rank test was performed to assess differences in the survival curve between groups. Univariate and multivariate Cox proportional hazards regression models were used to obtain hazard ratios and adjusted hazard ratios, respectively, for 5-year PCD/LPD diagnosis and overall mortality compared to the normal FLC-R population. All tests were two-tailed, and 0.05 level was used for significance. All analyses were conducted using The R statistical computing software [ 10 ].

Results

Patient characteristics

In total, 11,241 patients with no prior diagnosis of PCD/LPD underwent FLC tests during the study period. Of those, 2,186 were excluded (Fig. 1s), being diagnosed with PCD/LPD or dying of unrelated causes within the first 6 m after the index date ( n = 2,153 and n = 33 respectively), having a concomitant increase in total protein level ( n = 368), or elevated lymphocyte count (though not officially diagnosed with LPD ( n = 236).

A total of 8,661 patients, all fulfilling the study criteria, were included. Four thousand fifty-five (46.8%) patients were males, and the median age was 67 years (range 18–100). Most patients had no anemia, nor ARF [ n = 519 (6%), n = 353 (4.9%), respectively]. In total, 2,215 (25.6%) had an abnormal FLC-R result and 1,208 (14%) had increased levels of IgG/IgA/IgM. FLC-R levels among the abnormal cohort were slAb in 2,090 (94.36%), mAbn in 65 (2.93%) and sigAb in 60 (2.71%). Characteristics of patients, included in the entire cohort and dependent on the FLC-R are presented in Tables 1 and 1s. The presence of M-protein was more prevalent in the abnormal FLC-R cohort compared to the normal FLC-R cohort [255(12.2%) vs. 424 (6.6%), p < 0.001], and was higher in patients with higher FLC-R; approaching 9.5% ( n = 198) in patients with slAb FLC-R and 47% ( n = 28) in patients with a sigAb FLC-R.

Diagnoses of PCD/LPD

During a median follow-up period of 52 m (6–60 m), 943 patients were officially diagnosed with a PCD, including 816 that were diagnosed with MGUS, 83 with MM, 41 with primary amyloidosis and 3 with plasmacytoma. Out of the patients that were initially diagnosed with MGUS, 46 (5.6%) were diagnosed with MM during the follow-up period (in addition to the 83 mentioned earlier). Furthermore, 48 patients were diagnosed with a LPD, mostly indolent lymphomas. The abnormal FLC-R group included 408 diagnosed patients, accounting for 18.42% of this subgroup, compared to 583 (9.04%) in the normal FLC-R group. These results translated to a twofold higher rate of PCD/LPD diagnosis, approaching 3.3 (95%CI 3.1–4.1) per 1,000 patients per month, in patients with an abnormal FLC-R compared to 1.59 (95%CI 1.4–1.9) per 1,000 patients per month, in the patients with a normal FLC-R. Patients with an abnormal FLC-R and a detectable M-protein had the greatest risk for being diagnosed with PCD/LPD, approaching 19.27 (95%CI 16.7–26.7) per 1,000 patients per month (Fig. 2 s). Among the 6,446 subjects that presented with normal FLC-R, 40 patients (0.6%) were eventually diagnosed with MM and 476 (7.4%) with MGUS. The median difference in the involved and uninvolved free light chains (dFLC) in these particular patients were 5.9 mg/L and 5.1 mg/L, respectively, significantly higher than measured in patients with normal FLC-R that have not developed PCD (4.6 mg/L, p < 0.001, p < 0.001). Moreover, it was significantly greater in those that developed MM compared with those that were diagnosed with MGUS ( p = 0.03).

Out of 353 patients presenting with ARF, 37 (10.5%) were eventually diagnosed with PCD (30 with MGUS, 4 MM and 3 with amyloidosis), 18 (46.8%) with an abnormal FLC-R. There was no statistical significance difference in the incidence of PCD among patients with ARF, presenting with normal versus an abnormal FLC-R ( p = 0.2).

The median time to diagnosis of PCD/LPD was 19 m (6–60 m); with 18 m (6–60), 19 m (6–60 m) and 28 m (6–59 m) for diagnosing MGUS, MM and LPD, respectively. Patients with a higher FLC-R had a shorter time to PCD/LPD diagnosis; 16.5 m (6–59) for patients with slAb FLC-R, 15 m (6–58) for patients with mAbn FLC-R and 11 m (6–57) for patients with sigAb FLC-R.

Factors associated with increased risk for PCD/LPD diagnosis

Based on multivariate Cox regression (Table 2 ), relying on univariate analysis Table 2s) FLC-R sub-groups of slightly, moderately, and significantly abnormal, were all associated with an increased risk for being diagnosed with PCD/LPD (HR = 1.8, CI95%:1.53–2.12, p < 0.001; HR = 6.3, CI95%:4.16–9.53, p < 0.001; and HR = 10.4, CI95%:7.0–15.35 p < 0.001, respectively). Age emerged as a significant risk factor for PCD/LPD, with age group of 51–75 years exhibiting a HR of 1.57 (CI95% 1.19–2.1, p = 0.001) and age group > 75 years having a HR of 1.8 (CI95%: 1.32–2.4, p < 0.001) (compared to the age group under 51 years). Osteoporosis was identified as the lone significant comorbidity, with an HR of 1.4 (CI95%:1.16–1.64, p < 0.001). Furthermore, both elevated levels of IgM (HR: 1.71, CI95%:1.37–2.1, p < 0.001) and IgA (HR: 1.8, CI95%:1.34–2.46, p < 0.001), as well as decreased levels of IgM (HR 1.3, CI95%:1.03–1.68, p = 0.02), were determined to be significantly associated with PCD/LPD diagnosis. Furthermore, a separate multivariate model specifically examining the significance of a concomitant increase in Ig level and abnormal FLC-R confirmed their co-existence as strongly associated with PCD/LPD [HR of 3.03 (CI95%:2.4–3.8, p < 0.001)].

Analysis for factors specifically associated with MM and separately, with LPD, defined mAbn and sigAb FLC-R, decreased IgG levels, elevated IgA levels, HTN and CHF to be associated with increased risk for MM, amyloidosis or plasmacytoma (Tables 3s,4s), whereas a sigAb FLC-R and an increased IgM levels were linked with LPD (Tables 5s,6s).

Overall survival

Within a median follow-up time of 61 m (range 6–189), 1,218 (14%) patients have died, including 172 (2%) that had already been diagnosed with PCD/LPD at the time of death [MGUS-119 (9.8%), MM-27 (2.2%), CLL-6 (0.5%), lymphoma patients-3 (0.25%)]. The mortality rate in the abnormal FLC-R group was higher than observed in the normal FLC-R; 18.8% versus 12.4% ( p < 0.001) and the median time to death was shorter [45 m (range 6–153) compared with 54 m (range 6–169) ( p < 0.001)]. The cumulative OS for the entire cohort was 62.3%; 51.1% for patients with an abnormal FLC-R compared to 65.3% for those that had a normal FLC-R at the index day ( p < 0.001).

Univariate Cox regression analysis (Table 7s) found that an abnormal FLC-R was linked with a shorter OS (HR = 1.76, CI95%:1.56–1.98, p < 0.001), with a HR of 1.75 (CI95%:1.55–1.97, p < 0.001) for patients with a sliAb FLC-R and HR of 1.97 (CI95%:1.36–2.85, p < 0.001) for patients with moderately or significantly abnormal FLC-R.

Multivariate Cox regression (Table 3 ) found that older age had the strongest association with shorter survival [age > 75 years, HR = 17.52 (CI95%:8.5–36.14, p < 0.001), 51–75 years, HR = 5.95 (CI95%:2.92–12.13, p < 0.001)]. Male gender (HR = 1.5, CI95%:1.21–1.76, p < 0.001), anemia (HR = 2.54, CI95%:1.94–3.33, p < 0.001), a decreased albumin level HR 3.13 (CI95%:2.31–4.25, p < 0.001), increased IgG level HR of 1.42 (CI95%:1.07–1.88, p = 0.01), CHF (HR = 2.5, CI95%:1.75–3.56, p < 0.001) HTN (HR = 1.5, CI95%:1.19–1.89) and COPD (HR = 1.86, CI95%:1.46–2.4, p < 0.001) were all linked with shorter survival.

Discussion

FLC test is known to be part of the evaluation of PCD [ 8 , 11 ]. However, family physicians are also using this test when investigating nonspecific symptoms, looking for an "occult" PCD/LPD that would explain patients complains. This strategy may result in an incidental detection of MGUS/SMM, unrelated to patient's complains [ 12 ]. Recent retrospective studies, though not confirmed yet in prospective studies, suggest that early detection of MGUS/MM might improve quality of life for those progressing to MM, preventing skeletal and renal complications [ 13 , 14 ] and prolonging overall survival [ 13 , 15 , 16 ]. However, most MM patients are not being diagnosed in their MGUS/SMM stage, but present with full-blown disease [ 17 , 18 ], indicating that the opportunity for early diagnosis, prior to clinical complications have often been missed. FLC levels (particularly the FLC-K level), can fluctuate due to autoimmunity [ 19 , 20 ], and are also influenced by age and renal function. While new criteria for defining clinically significant abnormal FLC levels have been recently proposed [ 21 ], these criteria have not yet been validated or routinely implemented in clinical practice.

By reviewing the routine laboratory workflow in a community setting and analyzing patient outcomes according to the results of "typical MM-related tests", particularly FLC test, we aimed to identify individuals at risk for being diagnosed with PCD/LPD, based on these tests. Our focus was on the significance of unexpectedly abnormal FLC results in patients with nonspecific complains and with non–elevated TP levels nor elevated lymphocyte count, that could have supported the detection of the PCD/LPD.

As expected, the proportion of patients in our cohort that expressed an abnormal FLC-R increased with age, most probably reflecting the higher incidence of MGUS associated with aging [ 9 , 22 ]. In most patients, the abnormal FLC-R was not accompanied with simultaneous detection of M-protein (attributed to our inclusion criteria, excluding patients with increased TP from our cohort), yet many of them were not officially classified by their family physicians as having LC-MGUS during the follow-up period. These patients probably have not been followed according to current recommendations for MGUS [ 9 , 23 , 24 ]. In a recent study, reviewing 3,328 patients that underwent SPEP due to a clinical suspicion for monoclonal gammopathy, an alert prompting physicians to add a FLC test, led to increased diagnoses of monoclonal gammopathies [ 25 ]. In line with that, we found that even a slightly increased FLC-R was associated with a 1.8-fold increase in the risk of PCD/LPD, whereas the higher FLC-R levels were associated with an even greater risk. Nevertheless, 52% and 31% of those that presented with a moderately and significantly abnormal FLC-R, were still not officially defined by their physicians as having PCD during a 5-year follow-up period, reflecting a misdiagnosis of MGUS in those that failed to express the classical "red flags" for diagnosing PCD such as increased TP or Ig levels [ 26 ].

A better acquaintance of the meaning of an abnormal FLC-R would encourage family physicians to perform the entire set of MM-related tests and diagnose patients with conventional or LC-MGUS, thereby, promoting the adoption of close follow-up policy and the capturing of progression to MM prior to organ damage. Indeed, patients "progressing" to MM after being followed for MGUS/SMM were found to have superior outcomes in terms of organ damage, and probably overall survival [ 27 ].

Progression from MGUS to MM was reported in 5.6% and was more predominant in patients that were classified as having a conventional MGUS; results which are in consensus with previous studies that demonstrated a greater risk for progression to MM and a shorter time to MM development in patients with conventional versus LC-MGUS [ 28 ]. Consistent with existing literature, Increased levels of IgG and IgA were linked with a higher risk of developing MM [ 29 ] whereas elevated levels of IgM were associated with increased risk for LPD [ 30 ]. Older age, and osteoporosis, were found to be associated with increased risk for PCD, confirming previous studies that reported these linkages [ 31 , 32 ].

Although our proposed model is still insufficient for determining the exact risk of an individual patient for being diagnosed with PCD/LPD, it can still define those that are unlikely to develop these complications, being highly specific. While the development of a predictive model remains a goal for future research, it requires the application of machine learning tools and subsequent validations in larger cohorts, referring to the findings we have provided in our study.

As mentioned formerly, early detection of MM, being achievable by diagnosing MGUS, was proposed to prolong overall survival [ 13 , 15 , 16 ]. However, according to our results, an abnormal FLC-R was not significantly associated with shorter overall survival, though it raised the risk of being diagnosed with PCD, particularly MM. Diagnosis of MM was associated with reduced overall survival, suggesting that with a longer follow-up period, the detection of an abnormal FLC-R may be associated with shorter OS. The introduction of new, highly effective, well-tolerated anti-MM therapies, would facilitate, in the future, an earlier employment of anti–MM treatment in patients with intermediate/high risk smoldering myeloma [ 33 ], highlighting the importance of early detection, in the pre-active phase of MM.

As previously noted by other investigators, the dFLC was significantly greater in patients that were diagnosed with MM [ 34 , 35 ], and according to our results might indicate a higher risk for developing PCD in patients with a normal FLC-R.

However, new and more sensitive tests for detecting monoclonality, such as mass spectrometric analysis and FLC Modified Serum Protein Immunofixation Electrophoresis [ 36 , 37 ], are likely to promote the detection of MGUS even earlier.

Our study has several limitations. Being a retrospective study, it might have been affected by a selection bias whereas physicians have employed different criteria for performing FLC testing. Additionally, we did not always have a complete set of tests for each patient, including "MM-essential" tests that were missed. However, our study mirrors "real-life" situation, where primary care providers may use the test in broader indications then specified and may not request to perform the entire MM tests. Moreover, in many laboratories, immunofixation is frequently omitted (even if ordered), if no clear M spike is being detected [ 38 ], suggesting that the incidence of PCD in our population might be even greater. Another notable issue is that a significant portion of patients who were diagnosed with MGUS during the study period have already had MGUS, or even SMM when they underwent the first FLC test, though, not officially diagnosed as having MGUS at that time. Lastly, the follow-up period of our study was relatively short, precluding a reliable assessment of the long-term impact of having abnormal FLC-R on long-term survival.

In conclusion, our data suggest that the use of FLC tests, along with other MM screening tests, in patients presenting with nonspecific symptoms and subtle indicators for PCD/LPD, may enhance the detection of MGUS and potentially improve OS. However, further studies are necessary to validate these finding and to establish the clinical significance of these tests in routine practice.

Although the European Myeloma Network does not recommend screening for MGUS outside of clinical research [ 26 ], and the International Myeloma Working Group has yet to formalize recommendations [ 9 ], our real-life study supports ongoing prospective studies, demonstrating a relatively high incidence of detection of occult PCD.

Our retrospective study emphasizes the independent clinical significance of elevated FLC levels and abnormal FLC-R in healthcare seeking adults, being meaningfully associated with PCD/LPD diagnosis, even in patients with no increase in their TP levels. This can be used as a simple risk assessment model that would incorporate all independent factors found to be associated with increased risk for PCD/LPD, thereby enabling physicians, especially in the community, to screen their patients, monitor their blood tests and promote an early detection of PCD when required.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 216 kb)

Author contributions

D.S and I.A contributed to the study design. A.R.B and I.A supervised the study. A.R.B was responsible for statistical methodology. G.M, H.A, and D.S were involved in data retrieval. D.S, A.R.B, I.A, Y.C and G.M participated in data analysis. D.S, A.R.B, I.A, Y.C, H.P, and G.M collectively contributed to writing the manuscript. All authors have read and approved the final version of the manuscript for submission.

Funding

The study was funded by an internal grant that supports student's research.

Data availability

No datasets were generated or analyzed during the current study.

Declarations

Conflict of Interest

The authors declare that they have no conflicts of interest related to this research study. No funding organization or external party influenced the design, conduct, interpretation, or reporting of the findings presented in this manuscript.

Footnotes

65th ASH meeting and exposition December 9-12, 2023.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Anat Reiner-Benaim and Irit Avivi contributed equally to this study.

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Associated Data

Supplementary Materials

Supplementary file1 (DOCX 216 kb)

Data Availability Statement

No datasets were generated or analyzed during the current study.