Prevalence of Monoclonal Gammopathy of Clinical Significance (MGCS) Among Patients with Monoclonal Gammopathies: Report from a Referral Center

Monoclonal gammopathies (MG) may be associated with a variety of syndromes due to the properties of the monoclonal protein, ectopic production of cytokines or other mechanisms. These syndromes may involve the kidneys, peripheral nerve, skin, eyes or other non-organ confined systemic syndromes. These disorders are usually associated with a nonmalignant or premalignant B-cell or plasma cell clone that does not fulfill the typical criteria of symptomatic myeloma or Waldenström's macroglobulinemia. These heterogeneous syndromes have attracted increasing attention and have been termed as "Monoclonal Gammopathy of Clinical Significance" (MGCS), however, their diagnosis remains challenging, requiring a high degree of suspicion or invasive target organ biopsies. Because of the difficulties in their recognition, it is not known how common these syndromes are among patients with monoclonal gammopathies. On the other hand, MG is a frequent finding: a recent prospective study in Iceland reported a prevalence of ~5% among subjects over the age of 40. Thus, the prevalence of MGCS may be significantly underestimated due to the heterogeneous phenotype, the difficulties in establishing the diagnosis and low degree of suspicion.

In order to provide an estimate of the prevalence of MGCS among patients with known MG, we analyzed the database of a plasma cell dyscrasia referral center, in Athens, Greece. This is a prospectively maintained database which includes all patients with monoclonal gammopathies who are referred to our center for evaluation or treatment. Since AL amyloidosis is associated with a more aggressive clinical phenotype and requires prompt initiation of therapy, we evaluated these patients separately in our analysis. Because of an increasing interest in MGCS after 2010, and subsequent rising awareness and diagnostic sensitivity, we excluded earlier referrals and focused only on patients who were referred after 1/1/2010.

The analysis included all patients who were referred for evaluation because of MG with or without concomitant symptoms or laboratory abnormalities. From 1/1/2010 to 31/12/2021, 3138 patients were referred for evaluation. The final diagnosis was MGUS or asymptomatic myeloma or asymptomatic WM in 1437 patients, symptomatic MM in 1145 patients, AL amyloidosis in 320 patients, symptomatic WM in 108 patients and a MGCS-related syndrome was diagnosed in 128 patients (4.1%). Among those with MGCS, the majority had either MGRS (n=51) or IgM-related neuropathy (n=58); other specific diagnoses included POEMS syndrome, Schnitzler's syndrome, necrobiotic xanthogranuloma or scleromyxedema, and other rare syndromes (TEMPI syndrome, IgM retinopathy, Clarkson's syndrome).

Peripheral neuropathy with a concomitant MG was the most common co-existing condition among non-AL amyloidosis patients: 73% had IgM and 37% a non-IgM MG. A causal relationship between MG and neuropathy was established for 42% of those with non-IgM neuropathy (mainly due to POEMS syndrome). The median age of the MGCS patients was 64, not significantly different in clinical terms from that of patients with SMM/MGUS, AL amyloidosis, symptomatic MM and symptomatic WM (which was 65, 65, 67 and 70 years respectively). The baseline level of monoclonal immunoglobulin among MGCS patients was low (median 0.4 gr/dl) and significantly lower than in patients with MGUS/SMM/aWM (median 1.04 gr/dl). The median BM infiltration by clonal cells in patients with MGCS was 10%, and was 7% in the MGUS/SMM group, 15% in patients with AL amyloidosis, 50% in patients with symptomatic MM and 40% for patients with symptomatic WM. Most patients with MGCS received anticlonal therapy; other non-clone targeting therapies were used in patients with Schnitzler's syndrome and Clarkson's disease. A significant proportion of patients with IgM-related neuropathy received only supportive therapy.

In conclusion, MGCS was found in ~4% of patients with MG in a plasma cell dyscrasia referral center. The establishment of MGCS diagnosis requires high degree of clinical suspicion due to their rarity and highly heterogeneous clinical presentation. Despite the bias associated with the analysis from a referral center, given the frequency of MG in the general population, there is probably a significant number of patients with MGCS who remain underdiagnosed and may suffer from complications associated with an otherwise non-malignant plasma cell dyscrasia.

Kastritis:GSK: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Genesis: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Honoraria. Gavriatopoulou:GSK: Consultancy, Honoraria; Sanofi: Honoraria; Janssen Cilag: Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Genesis Pharma: Honoraria; Karyopharm: Consultancy, Honoraria. Terpos:Genesis: Honoraria, Research Funding; BMS: Honoraria; Sanofi: Honoraria, Research Funding; Amgen: Honoraria, Other: Travel expenses, Research Funding; Novartis: Honoraria; EUSA Pharma: Honoraria, Other: Travel expenses; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; GSK: Honoraria, Research Funding. Dimopoulos:BMS: Honoraria; Amgen: Honoraria; Beigene: Honoraria; Takeda: Honoraria; Janssen: Honoraria.