Hematology PB Smears and Plasma Cells

Multiple Myeloma - 2024 Update

• Multiple myeloma is a clonal plasma cell disorder, characterized by an abnormal increase in monoclonal immunoglobulins.
• It accounts for 1% of all cancers and approximately 10% of hematological malignancies.
• Slightly more common in men than women, and twice as common in African-Americans compared to Caucasians.
• Median age at diagnosis is approximately 65 years.

Disease Overview

• Unlike other malignancies that metastasize to bone, osteolytic lesions in MM don't exhibit new bone formation. Bone disease is the primary cause of morbidity.
• Other major clinical manifestations include anemia, hypercalcemia, renal failure, and an increased risk of infections.
• Extramedullary disease (EMD) occurs in approximately 1-2% of patients at initial diagnosis, and 8% develop EMD later.

Symptoms of Multiple Myeloma

• Hypercalcemia
• Renal dysfunction
• Anemia
• Bone pain

Monoclonal Gammopathy of Undetermined Significance (MGUS)

• Almost all myeloma patients originate from MGUS, a pre-malignant, asymptomatic stage.
• MGUS occurs in approximately 5% of the population over 50, and is two-fold higher in blacks versus whites.
• MGUS progresses to multiple myeloma at a rate of 1% per year. Over half of those diagnosed with MGUS have had the condition for more than 10 years before clinical diagnosis.
• An intermediate stage, called smoldering multiple myeloma (SMM), can exist between MGUS and active myeloma.

Smoldering Multiple Myeloma (SMM)

• SMM is prevalent in approximately 0.5% of the general population aged 40 or older.
• It progresses to multiple myeloma at an approximate rate of 10% in the first 5 years after diagnosis, then 3% in the next 5 years, and 1.5% per year thereafter.
• Cytogenetic abnormalities (e.g., t(4;14), del(17p), gain(1q)) are associated with a higher risk of progression to multiple myeloma.

Diagnosis

• Diagnosis necessitates the presence of one or more myeloma-defining events (MDE) in conjunction with evidence of at least 10% clonal plasma cells in a bone marrow examination or a biopsy-proven plasmacytoma.
• Myeloma-defining events (MDE): established CRAB features (hypercalcemia, renal failure, anemia, and/or lytic bone lesions), along with 3 specific biomarkers.
  • Clonal bone marrow plasma cells >60%
  • Serum free light chain (FLC) ratio >100 (with involved FLC level ≥100 mg/L and urinary monoclonal protein excretion ≥200 mg/24hrs)
  • More than one focal lesion on MRI
• All criteria must be met for diagnosis:
  • Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma
  • Any one or more of the following myeloma-defining events (MDE): hypercalcemia, renal insufficiency, etc.

Other Tests

• 24-hour urine collection for protein electrophoresis and immunofixation to monitor urine M protein levels and detect possible renal complications.
• Serum free light chain assay is valuable for patients lacking measurable M protein (with abnormal FLC ratio and involved FLC level ≥100 mg/L).

Biochemical Tests

• Monitoring M protein level in serum and urine (≥1 g/dL in serum or ≥200 mg/day in urine) and by serum FLC assay (monitored monthly during therapy and every 3-4 months when off-therapy).

Imaging Studies

• Low-dose whole-body CT or PET/CT scans are the preferred imaging methods for assessing bone disease.
• MRI is helpful to evaluate suspected SMM, extramedullary disease, or suspected cord compression.

Bone Marrow Study

• Typically hypercellular
• Morphology of plasma cells (PCs) varies
• Classical PCs are oval with an eccentric nucleus and abundant basophilic cytoplasm.
• In some cases, plasma cells may show atypical features (e.g., Mott cells, plasmacytoses).

Other Plasma Cell Disorders

• Includes Non-IgM MGUS, characterized by serum monoclonal protein <3g/dL, clonal bone marrow plasma cells <10%, and absence of CRAB features.
• Also includes smoldering myeloma, characterized by serum monoclonal protein (and/or monoclonal protein in urine) and/or clonal bone marrow plasma cells (10-60%) without evidence of CRAB .

Clinical Presentation/Diagnosis

• A few cases may have insufficient BM aspirate or focal distribution of myeloma in the marrow, resulting in less than 10% PCs.

Solitary Plasmacytoma

• Criteria require a biopsy-proven solitary lesion of bone or soft tissue, with evidence of clonal plasma cells and a normal bone marrow with no clonal plasma cells.
• No evidence of other myeloma defining events or amyloidosis . A normal skeletal survey and MRI (except for the primary solitary lesion) of the spine and pelvis.

Solitary Plasmacytoma with Minimal Marrow Involvement

• Meets the criteria for solitary plasmacytoma, but with less than 10% clonal bone marrow plasma cells.

Molecular Cytogenetic Classification (Table 1)

• Classifies multiple myeloma based on affected genes/chromosomes. This includes hyperdiploid myeloma, IgH translocated myeloma, and others.

Prognosis and Risk Stratification

• Overall survival in transplant-eligible patients is >10 years. However, for elderly ( >75 years) patients, median survival is approximately 5 years.
• Prognosis factors include the clinical stage of disease, cytogenetic abnormalities (e.g., t(4;14), del(17p), and gain (1q), host characteristics, and response to therapy.
• The Durie-Salmon staging system and the International Staging System (ISS) are used to assess tumor burden and predict prognosis.

Disease Biology

• Reflected by multiple myeloma subtype (table 1), the presence/absence of secondary cytogenetic abnormalities (del17p, gain1q, del1p), elevated lactate dehydrogenase, and the presence of plasma cell leukemia in peripheral blood smear.

Risk Groups of Multiple Myeloma

• Standard risk: trisomies, t(11;14), and t(6;14)
• High risk: t(4;14), t(14;16), t(14;20), del(17p), and gain(1q), del(1p)
• Double and Triple-Hit Multiple Myeloma: Combination of these high risk factors

References

• https://onlinelibrary.wiley.com/doi/full/10.1002/ajh.27422
• WHO Haematolymphoid Tumours (5th edition).