Chapter 2 – Diagnosis and staging

Contributors: Carlos Fernández de Larrea and Joan Bladé

2 – Classification

Monoclonal gammopathies are currently classified into two major groups: malignant and benign (Table 2.4).

In most cases, if not all, MM evolves from a premalignant stage of clonal proliferation called monoclonal gammopathy of undetermined significance (MGUS) [5]. Thus, asymptomatic gammopathies are mainly MGUS and the so-called asymptomatic or smoldering MM (SMM), classified into these two categories according to tumor burden (Table 2.5) [6,7].

Table 2.4 Classification of monoclonal gammopathies.

HIV, human immunodeficiency virus; POEMs, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes.

Table 2.5 Classification of asymptomatic gammopathies.

*Except in patients with true non- secretory multiple myeloma. **For idiopathic Bence Jones (smoldering myeloma) proteinuria all criteria must be met: urinary monoclonal protein on urine protein electrophoresis ≥ 500 mg/24 h and/or clonal bone marrow plasma cells ≥10%, no immunoglobulin heavy-chain expression on immunofixation and absence of end-organ damage. IgA/G/M, immunoglobulin A/G/M; MGUS, monoclonal gammopathy of undetermined significance. All rights reserved. Rajkumar et al [2]. Adapted from © American Society of Hematology, 2011. All rights reserved. Korde et al [7].

Progression to MM and related disease is constant during MGUS evolution (1% per year), being the actuarial and actual probability of malignant transformation at 20 years from diagnosis of 25% and 11%, respectively [8]. IgM MGUS has a predilection for developing into Waldenström’s macroglobulinemia or other lymphoproliferative disorders; other isotypes progress mainly to MM [9]. However, in SMM the risk of progression is higher in the first 5 years of follow-up (10% per year), changing to a MGUS-like progression profile beyond the first 5 years from diagnosis [10]. Recent models have demonstrated the progression and overall survival benefits of treating high-risk SMM patients compared to the current standard practice of observation [11]. Several risk models are now established to aid initial risk stratification of these patients, with the two most widely used being the Mayo Clinic criteria and the PETHEMA Spanish group classifications (see Table 2.6). The IMWG recommend that if reliable biomarkers are identified that represent an 80% probability of progression to MM within 2 years, these patients should be regarded as having MM and offered treatment [2].

Plasma cell leukemia (PCL) is a rare and aggressive variant of myeloma characterized by the presence of circulating plasma cells. Present diagnostic criteria include more than 20% and/or an absolute count greater than 2×109/L circulating plasma cells. The clinical picture is characterized by an aggressive clinical presentation with high tumor burden, extramedullary involvement, marked bone marrow infiltration by immature plasma cells, increased incidence of light-chain only (Bence Jones) type and high lactate dehydrogenase (LDH) serum levels [14].

Table 2.6 Risk of progression of smoldering multiple myeloma patients according to the Mayo Clinic and Spanish PETHEMA models.

BMPC, bone marrow plasma cells; FLC, free light chain; MFC, multiparameter flow cytometry; MM, multiple myeloma; TTP, time to progression. All rights reserved. Pérez-Persona et al [12] and Kyle et al [13].