Key Points
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Active prospective screening in patients with PCDs revealed that 11.3% of the families had at least 1 additional member affected.
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Forty-one (4.7% yield per family) first- and second-degree relatives were diagnosed with MG.
Visual Abstract
Abstract
Plasma cell dyscrasias (PCDs) exhibit familial aggregation, yet data quantifying this risk through active screening remain limited. Herein, we designed this study to identify and quantify the familial risk of PCDs by detailed family trees and screening all first- and second-degree relatives of affected patients. We approached 1084 consecutive patients with PCDs at a single center between 2017 and 2019, of whom 864 eligible index patients provided consent to first- and second-degree relative screening. Detailed pedigrees were created for all patients, and screening with serum protein electrophoresis, immunofixation, and free light chain assays was performed. Spouses were also screened as a control group. In total, 2481 family members were screened; median age was 63 years. At least 1 additional family member with a monoclonal gammopathy (MG) was detected in 98 (11.3%) of the 864 screened families. A positive history of PCD or other B-cell malignancy was present in 2.1% of the families. Notably, the screening process identified 41 new cases of MGs (4.7% yield per family). The incidence was 4.5% among siblings and second-degree relatives compared to 2.6% in the control group. In conclusion, this large prospective study confirms a familial predisposition to PCDs, revealing that >11% of the affected families have multiple members with MGs, corresponding to at least twice the risk of PCDs among members of affected families. These findings support the potential clinical value of active screening for relatives of patients with PCDs to facilitate early diagnosis, appropriate monitoring, and prompt intervention.
Introduction
Plasma cell dyscrasias (PCDs) are a heterogeneous group of disorders caused by the monoclonal proliferation of plasma or B cells in the bone marrow. The most common disorder is monoclonal gammopathy (MG) of undetermined significance (MGUS), which is an asymptomatic condition characterized by minimal marrow infiltration by clonal cells and the relevant secretion of monoclonal immunoglobulin. MGUS affects ∼3% of the general population aged >50 years, and the probability of progressing to symptomatic multiple myeloma (MM) is estimated to be 1% to 1.5% per year.1, 2, 3 Before progression to symptomatic disease, MGUS may evolve through an intervening stage, referred to as smoldering MM (SMM), which is characterized by an average risk of progression to MM of ∼10% annually. Patients with asymptomatic disease appear with more extensive bone marrow infiltration of >10% compared to MGUS, but with no symptoms or signs related to the underlying disease or end-organ damage.
Although an increased risk for the development of PCDs has been identified within family clusters, to date, only a limited number of potential genomic risk loci with undetermined significance have been described. Data from epidemiological studies have demonstrated evidence for familial aggregation, suggesting potential familial risk as a well-known risk factor for MM. It has been shown that first-degree relatives of patients with MM have ∼2 to 4 times higher risk of MM and MGUS. Most of these studies have used registries and wide databases to obtain and provide epidemiological data, in contrast to our study, in which active participation and systematic screening were used.4, 5, 6, 7, 8, 9 In addition, genome-wide association studies have also identified potential loci associated with genetic predisposition.10, 11, 12
Although several trials in the past failed to show significant benefit with early intervention, more recent clinical trials in this setting showed that patients with intermediate-risk or high-risk SMM may benefit from earlier treatment intervention.13, 14, 15 An ongoing large-scale screening study in Iceland evaluates the potential benefit of population screening and diagnostic interventions, but given the high prevalence of MGs, targeted screening in higher-risk populations may be of more clinical relevance and of sensible health resource use.
Therefore, in this study, we aimed to identify and quantify the familial risk of PCDs among the families of affected patients through detailed family trees and screening standard blood sampling for MG detection workup; we conducted a large prospective study with active recruitment within a large patient cohort diagnosed with PCDs in a single center, with concurrent active screening of their relatives and developed a detailed family pedigree to better identify the potential familial risk of the disease.
Methods
We prospectively approached 1084 consecutive patients diagnosed with PCDs (including MM, MGUS, SMM, Waldenström macroglobulinemia [WM], and immunoglobulin light chain [AL] amyloidosis) between January 2017 and January 2019 for enrollment in the study; all patients were followed up at the department of clinical therapeutics. Among them, 176 (16.2%) patients refused to participate in the study, whereas 44 (4.1%) were ineligible for further screening because of the absence of a living first- or second-degree relative. Consequently, 864 index patients were enrolled.
Each participating patient was informed in detail about the scope of the study and provided written informed consent. After the patient’s consent was obtained, a detailed family pedigree was created for each index patient using questionnaires and personal interviews, with a special focus on the family history of PCDs (including MGUS), B-cell lymphomas, or other hematologic or solid malignancies. All eligible first- and second-degree relatives were subsequently informed by each patient’s treating physician. First- and second-degree relatives aged >30 years were considered eligible for the study.
The family members of the index patient were then informed about the pertinent aspects of our investigation, and consenting eligible first- and second-degree relatives were evaluated for the presence of MG.
For the detection of MG, the participating family members provided blood samples for serum protein electrophoresis with immunofixation and serum free light chain (FLC) assay, in accordance with the IMWG criteria for PCDs.16,17
As a control group, the spouses of index patients were also offered to participate in the study.
All samples were processed at the same immunology laboratory of Alexandra General Hospital. In case of positive immunoelectrophoresis and/or abnormal FLC results, further standard workup was offered for the investigation of MG. The study was performed in accordance with the 1964 Declaration of Helsinki and was approved by the institutional review board of Alexandra University Hospital.
Continuous variables, such as patient age and follow-up duration, are summarized using medians with ranges or interquartile ranges. Categorical variables, including immunoglobulin isotypes and clinical diagnoses, are presented as absolute frequencies and percentages. The comparisons of categorical variables and screening detection rates between distinct cohorts were evaluated using the Pearson χ2 test or Fisher exact test, depending on the expected cell frequencies. To quantify familial risk and the magnitude of these associations, odds ratios (OR) along with their corresponding 95% confidence intervals (CI) were calculated. All tests were 2-sided, and a P value of <.05 was considered statistically significant. All statistical analyses were performed using RStudio version 2024.04.2+764 (Posit PBC).
Results
Overall, 1084 index patients were interviewed for their potential participation in the study. Among them, 752 had been diagnosed with symptomatic MM, 77 had SMM, 81 had MGUS, 93 had WM, and 81 were diagnosed with immunoglobulin light chain amyloidosis. Of those interviewed for participation, 176 (16.2%) index patients refused to participate in the study and provide consent for further contact with their families. In total, 137 patients were identified as having a known family history of PCDs before the study screening, whereas 125 families had at least 2 more affected members. In addition, 44 (4.1%) patients were ineligible for further screening because there were no first- or second-degree relatives alive or known.
Overall, 864 (79.7%) patients were eligible and provided consent to having their families contacted for interview for screening (Figure 1). The median number of screened first- or second-degree relatives and spouses per index patient was 3 (range, 1-10; interquartile range, 2-4). The median age of index patients was 65 years, whereas the median ages of offspring, siblings, and second-degree relatives and spouses were 37, 65, and 65 years, respectively (Figure 2). All patients, screened relatives, and spouses were White and of Greek ethnicity (Table 1). Overall, at least 1 additional member (beyond the index patient) with MG was detected in 98 families (11.3%). In 18 families (2.1%), there was a positive history of at least 1 additional first- or second-degree relative with a PCD or B-cell malignancy. Table 1 summarizes the characteristics of index patients and their screened relatives.
Figure 1.
Study flow diagram. AL amyloidosis, immunoglobulin light chain amyloidosis.
Figure 2.
Age distribution at screening across index patients, biological relatives, and spouses (controls).
Table 1.
Characteristics of index patients and screened relatives
| Variable | Measure |
|---|---|
| Index patients | |
| Number, n | 864 |
| Age, median (range), y | 65 (24-91) |
| Males, n (%) | 484 (56.0) |
| Race, n (%) | |
| White | 864 (100.0) |
| Ethnicity, n (%) | |
| Greek, n (%) | 864 (100.0) |
| MM, n (%) | 667 (77.1) |
| SMM, n (%) | 54 (6.3) |
| WM, n (%) | 54 (6.3) |
| AL amyloidosis, n (%) | 49 (5.7) |
| MGUS, n (%) | 40 (4.6) |
| Screened relatives | |
| Number, n | 2481 |
| Family members screened, median (range) | 3 (1-10) |
| Age, median (range), y | 63 (30-99) |
| Males, n (%) | 1220 (49.2) |
| Race, n (%) | |
| Caucasian | 2481 (100.0) |
| Ethnicity, n (%) | |
| Greek | 2481 (100.0) |
| Siblings and second-degree relatives, n (%) | 999 (40.3) |
| Age, median (range), y | 65 (30-97) |
| Offspring, n (%) | 666 (26.8) |
| Age, median (range), y | 37 (30-67) |
| Parents, n (%) | 513 (20.7) |
| Age, median (range), y | 81 (58-99) |
| Spouses, n (%) | 303 (12.2) |
| Age, median (range), y | 65 (31-95) |
For demographic purposes, second-degree relatives are pooled with siblings because of overlapping age distributions.
AL amyloidosis, immunoglobulin light chain amyloidosis.
The overall incidence of PCD among siblings and second-degree relatives was 4.5%, whereas it was 1.1% among offspring (Fisher P < .001; OR, 4.44; 95% CI, 1.99-9.90). As a control group, the incidence of PCDs among spouses (303 screened) was 2.6%, and all were identified during screening. Relatives (offspring, parents, siblings, and second-degree relatives) had double the odds of being identified with a PCD (5.4% vs 2.6%; OR, 2.11; 95% CI, 1.02-4.37) compared to spouses. Furthermore, when comparing siblings and second-degree relatives (median age, 65 years [range, 30-97]) to controls (spouses: median age, 65 years [range, 31-97]), the overall incidence of PCDs between these age-matched cohorts was 4.5% vs 2.6%. Although this difference did not reach statistical significance, a trend of increased odds of PCDs among siblings and second-degree relatives was observed compared with controls (χ2 P = .149; OR, 1.74; 95% CI, 0.81-3.73).
Overall, 41 new cases of MG (4.7% yield per family) were identified among biological relatives through the screening process associated with this study: 21 (51.2%) immunoglobulin G (IgG; median, 1232 mg/dL [range, 698-1747]), 17 (41.5%) IgM (median, 401 mg/dL [range, 73-1444]), and 3 (7.3%) IgA (median, 322 [range, 296-2638] mg/dL). The MGs identified encompassed 6 cases of WM (14.6%), 11 cases of IgM MGUS (26.8%), 20 cases of non-IgM MGUS (48.8%), 3 cases of SMM (7.3%), and 1 case of MM (2.5%; Figure 3). Among them, 6 cases were identified in families with an already-known family history of PCDs. Stratification of the positive cases revealed that non-IgM MGUS was the predominant diagnosis, particularly among siblings, with the vast majority of all PCDs detected in individuals aged ≥50 years (Figure 4).
Figure 3.
Characteristics of MGs identified through active screening.
Figure 4.
Characteristics of biological relatives with MGs identified through active screening.
After a median follow-up of 7.3 years, only 1 patient progressed to symptomatic disease (from SMM to MM), who then received first-line treatment and is currently on maintenance therapy while in remission. There were no deaths or disease progression events after first-line treatment among the 6 patients initially identified with symptomatic WM and the 1 patient with symptomatic MM.
Discussion
In this prospective study, we screened the first- and second-degree relatives of consecutive patients with PCDs to identify the familial incidence of MGs and investigate a potentially increased inherited risk. Overall, there was at least 1 additional member with MG in 11.3% of the 864 screened families, whereas there was at least 1 additional first- or second-degree relative with a previously known PCD or B-cell malignancy in 2.1% of the families. MGUS is a relatively common condition, affecting ∼3% of individuals aged >50 years, but the incidence is increased up to two- to fourfold in first-degree relatives; this is supported by our data.
Our study is not the first attempt to identify familial predisposition to PCDs by screening. A large population-based Swedish study of almost 4500 patients with MGUS and >14 500 corresponding first-degree relatives showed a threefold risk of developing MGUS and a fourfold risk of developing lymphoplasmacytic lymphoma/WM.8 In contrast to our prospective single-center study, this was a nationwide study using Swedish cancer registries that compared each affected patient with 4 random population-based controls matched by sex, year of birth, and country of residence.8 Both studies reported the same increase in the prevalence of MM and MGUS in first-degree relatives irrespective of immunoglobulin isotype, age at diagnosis, and sex of the first-degree relative. However, the Swedish study analyzed the incidence according to immunoglobulin isotype and found a 4-fold, 2.9-fold, and 20-fold increased risk of developing MGUS, MM, and WM/LPL in first-degree relatives of patients with IgG/IgA, respectively, and a 5-fold risk of developing chronic lymphocytic leukemia in first-degree relatives of patients with IgM MGUS.8 In our study, we report a lower incidence of PCDs among the offspring of affected patients (1.1%), which is probably associated with the lower median age of this population (37 years). The estimated risk reported among parents, siblings, and offspring in the Swedish study was also similar to that in our study.
Another recent population-based study of 7847 patients with MM and their first- and second-degree relatives confirmed an increased risk for MM in first-degree relatives but found no association among second-degree ones.18 Of note, there was no significant difference in the age of onset, serum levels of the monoclonal protein, type of involved immunoglobulin, and overall survival in relatives with MM or MGUS.18 The major difference compared to other studies is that our study is not population based but targeted with active prospective screening.
A large population-based screening study for MM precursors tried to investigate the potential benefits and harms of screening in patients with PCDs.2 The Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study randomized participants with detected monoclonal immunoglobulin (M protein) or pathological free immunoglobulin light chains (FLC) in the blood in 3 arms: no further workup, follow-up according to current guidelines, and intensive follow-up. In the iStopMM study, 4.4% of the participants had at least 1 positive value for monoclonal paraprotein, and 0.53% were diagnosed with SMM.2 Interestingly, approximately one-third of patients with SMM had an intermediate- or high-risk disease and were potential candidates for treatment.2 Similarly, the Predicting Progression of Developing Myeloma in a High-Risk Screened Population study is evaluating the prevalence of MGUS in high-risk patients of African descent or those with a family history of MM-related conditions.19 This nationwide study is using high-throughput quantitative mass spectrometry (MS) testing to detect MGs in 2439 individuals of Black ancestry and 3866 individuals with a family history of hematological malignancy or MM precursor state. Of note, screening with this method yielded a high prevalence of PCDs of >40% in all high-risk individuals aged ≥50 years compared to only 6% when evaluated by serum protein electrophoresis.19 In patients with a positive family history aged ≥50 years, MGUS prevalence was 13%, which is higher than the 3% prevalence reported for the general population in this age group. All the studies align with our study and highlight the increased incidence of MGs, especially in patients with a positive family history. However, in our study, we used immunofixation and not MS, minimizing the cost and overcoming the availability of MS. Other differences include the predominantly White study population and the active approach and screening adopted in our study. These findings provide a basis for health policy discussions on whether screening should be preferred over incidental detection of MGs.
Currently, asymptomatic myeloma is not treated but mainly monitored based on underlying prognostic characteristics. However, treatment with lenalidomide and dexamethasone in patients with high-risk SMM not only significantly delayed progression-free survival but also resulted in an overall survival benefit.15 Furthermore, the AQUILA study very recently received approval of daratumumab for the treatment of patients with high-risk SMM.20 Based on this, early detection and risk stratification, especially in case of increased genetic risk followed by prompt treatment initiation, are of extreme importance.21,22 We need further studies to determine whether the natural history of the screened population has improved compared to that of patients incidentally diagnosed with MGUS before screening becomes standard practice. In addition, the potential harm and psychological effect of the screening of these precursor conditions should be considered. However, a subanalysis of the iStopMM trial evaluating the potential benefits and harms of MGUS screening concluded that it was not associated with any demonstrable psychological harm.22 A total of 775 participants in arm 1 and 1838 participants in arms 2 and 3 answered Patient Health Questionnaire-9, General Anxiety Disorder-7, and Satisfaction With Life Scale questionnaires. Not only was psychological harm not detected, but a small positive psychological impact of MGUS diagnosis was also observed.23 These data address the potential concerns about the possible negative psychological impact of MGUS screening on the screened population.
The main strength of our study lies in its prospective design and the active screening of relatives, which provides stronger evidence compared to retrospective or registry-based approaches. The inclusion of 864 families, representing the largest single-institution cohort to date, enhances its robustness. Several methodological aspects are worth mentioning; family histories were carefully documented, all first- and second-degree relatives underwent serum protein electrophoresis with immunofixation, and spouses were included as controls. Further investigation with whole-genome sequencing and single nucleotide polymorphism analysis will provide further insights into our findings because recent molecular studies have provided direct evidence of genetic predisposition.9
However, this study also has some limitations. The population is derived from a single tertiary center, raising the possibility of referral and selection bias. The cohort consists entirely of White patients of Greek ancestry and therefore might reflect limited generalizability in diverse populations (eg, African American population, Asian population, etc). It is well established that the baseline prevalence of MGUS and MM is twofold to threefold higher and the age of onset significantly earlier, in individuals of African descent compared to those of European ancestry.24,25 Consequently, the 11.3% familial incidence rate and the age-specific screening yields reported in our population cohort likely represent an underestimation of the familial risk that would be observed in a racially diverse population or one with a high proportion of African American individuals. Furthermore, the genetic architecture driving familial PCD predispositions varies by ethnicity, and the patterns observed in our study may not directly reflect those in Northern European or African cohorts. Therefore, our familial risk estimates should be interpreted as specific to White populations, underscoring the need for parallel active screening studies in diverse ethnic groups to establish potential inclusive, race-specific screening guidelines. Furthermore, although our screening strategy aligns with standard clinical practice, the reliance on conventional electrophoresis and immunofixation rather than on highly sensitive approaches may have resulted in the underdetection of early or subclinical low-level MGs. The median number of relatives screened per family was modest, limiting the power to detect rare high-penetrance variants in future molecular analyses. In addition, we recognize that age is a major determinant of PCD risk; however, because in-depth demographic characteristics were not uniformly available across the total screened cohort, we could not adjust for age or conduct age-matched comparative analyses for relatives of patients with malignant PCDs. Moreover, although all relatives who screened positive for MG were provided with recommendations for systematic follow-up based on disease-specific guidelines, centralized long-term follow-up data are not available for this cohort. Because the screened relatives resided across various regions of Greece, regular monitoring at our single tertiary center was not feasible, and subsequent follow-up was transitioned to local health care providers. This geographical and logistical barrier underscores a significant challenge regarding the feasibility of implementing widespread active screening programs, highlighting the need for robust coordination between primary and secondary health care networks to ensure appropriate monitoring. Moreover, although we observed an increased prevalence of MGs in older relative cohorts, formal age-matched comparisons or standardized incidence analyses against general population registries were not feasible. Consequently, without further statistical validation, we cannot definitively conclude whether the detection rates in specific age groups significantly exceed expected baseline prevalences. Finally, the potential for participation bias cannot be excluded because relatives who were already aware of the index patient’s diagnosis may have been more motivated to consent to screening.
In conclusion, our study revealed that 11.3% of the patients had at least 1 additional affected member in their families, and 2.1% had a first- or second-degree relative already diagnosed with a PCD or B-cell malignancy. Genome-wide association studies in these high-risk patients could help us better define familial predisposition to PCDs and carefully monitor individuals at risk for the development of paraproteinemia.
A key question that needs to be addressed, combined with the emerging genetic data, is whether screening should be initiated in selected subpopulations to detect familial entities, especially for MM or WM. Currently, there are no guidelines for risk-adapted screening strategies, and close monitoring of asymptomatic patients is the main recommended strategy. However, there is growing evidence that potentially supports both the incorporation of active screening, particularly in first-degree relatives of affected patients, and the introduction of daratumumab monotherapy for patients with intermediate- to high-risk SMM. In this context, it is important to identify potential familial clustering and germ line predispositions to individualize diagnostic, monitoring, and therapeutic algorithms.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Acknowledgments
Authorship
Contribution: M.G., E.T., E.K., and M.A.D. contributed to conceptualization, methodology, and project administration; C.I.L., A.A., and C.F. performed the software analyses; D.F., E.T., E.K., and M.A.D. validated the data; E.K. performed the formal analysis; C.I.L. and E.K. curated the data; M.G. and A.A. wrote the original draft of the manuscript; D.F., E.T., E.K., and M.A.D. reviewed and edited the manuscript; C.F. performed the data visualization; E.T., E.K., and M.A.D. supervised the study; and all authors conducted the investigation.
Footnotes
M.G. and A.A. contributed equally to this study.
Data are available from the corresponding author, Maria Gavriatopoulou (mariagabria@gmail.com), on request.
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