FLC test is known to be part of the evaluation of PCD.[9, 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 studies suggest that early detection of MGUS/SMM 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.
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 ageing.[8, 19] 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.[8, 20, 21] 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.[22] 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.[23]
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.[24]
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 vs LC-MGUS.[25] Consistent with existing literature, Increased levels of IgG and IgA were linked with a higher risk of developing MM[26] whereas elevated levels of IgM were associated with increased risk for LPD.[27] Older age, and osteoporosis, were found to be associated with increased risk for PCD, confirming previous studies that reported these linkages.[28, 29]
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,[30] highlighting the importance of early detection, in the pre-active phase of MM.
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,[31] suggesting that the incidence of PCD in our population might be even greater. Additionally, a 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 support the employment of FLC tests, as well as other MM- screening tests in patients presenting with nonspecific symptoms and subtle additional indicators for PCD/LPD, suggesting that its employment would increase detection of MGUS and eventually improve OS.
Although the European Myeloma Network does not recommend screening for MGUS outside of clinical research,[23] and the International Myeloma Working Group has yet to formalize recommendations,[8] our real-life study support 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.