الاختبارات والتحليلات الطبية

Multiple Myeloma Update 2024

• Multiple myeloma is a clonal plasma cell disorder, characterized by an abnormal increase of 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.
• The median age at diagnosis is about 65 years.

Disease Overview

• Unlike other malignancies that spread to bone, osteolytic lesions in multiple myeloma (MM) do not exhibit new bone formation. Bone disease is the major cause of morbidity.
• Other significant clinical manifestations include anemia, hypercalcemia, renal failure, and an increased risk of infections.
• Approximately 1% to 2% of patients have extramedullary disease (EMD) at initial diagnosis, while 8% develop it later.

Symptoms

• Common symptoms of MM include: hypercalcemia, renal dysfunction, anemia, and bone pain.

Monoclonal Gammopathy of Undetermined Significance (MGUS)

• Almost all MM patients develop from MGUS, a pre-malignant stage.
• MGUS is present in approximately 5% of the population above 50, and the prevalence is twice as high in blacks compared to whites.
• MGUS progresses to MM at a rate of 1% per year.
• Over 50% of individuals diagnosed with MGUS have the condition for more than 10 years before diagnosis.
• An intermediate, asymptomatic pre-malignant stage, referred to as smoldering multiple myeloma (SMM), can be clinically recognized in some patients.

Smoldering Multiple Myeloma (SMM)

• Approximately 0.5% of the general population aged 40 or over has SMM.
• SMM progresses to MM at a rate of 10% per year for the first 5 years after diagnosis, 3% per year for the next 5 years, and 1.5% per year thereafter.
• The progression rate is affected by disease burden and cytogenetic type.  Patients with certain translocations (t(4;14), del(17p), gain(1q)) have a higher risk of progression to symptomatic MM.

Diagnosis

• The diagnosis involves one or more myeloma-defining events (MDE) and evidence of either 10% or more clonal plasma cells in a bone marrow exam, or a biopsy-proven plasmacytoma.
• MDE includes established CRAB features (hypercalcemia, renal failure, anemia, or lytic bone lesions) and three specific biomarkers.

Biomarkers

• Clonal bone marrow plasma cells ≥60%
• Serum free light chain (FLC) ratio ≥100 (with involved FLC ≥100 mg/L and ≥ 200 mg of urinary monoclonal protein in 24 hrs)
• More than one focal lesion on an MRI

International Myeloma Working Group (IMWG) Criteria

• Both criteria must be fulfilled for a diagnosis: -Clonal bone marrow plasma cells (≥10%) or biopsy-proven extramedullary plasmacytoma.
• At least one myeloma-defining event (MDE):    * Hypercalcemia (serum calcium >2.75 mmol/L or >11mg/dl.    * Renal insufficiency (creatinine clearance <40 mL/min or serum creatinine > 177 μmol/L or >2mg/dl.)

Other Tests

• 24-hour urine collection for protein electrophoresis and immunofixation is recommended at least every 3-6 months to monitor urine M protein levels and detect potential renal complications.
• Serum free light chain (FLC) assay is helpful in patients without measurable M protein, if FLC ratio is abnormal and involved FLC level is ≥100 mg/L.

Additional Information

• The presence of ≥1 gm/dL M protein in serum or ≥200 mg/day in urine defines a measurable M protein level.
• Monitoring of M protein levels is done using SPEP and serum FLC assays, every month during therapy and every 3-4 months when off-treatment.

Imaging

• The extent of bone disease is best assessed using low-dose whole-body CT (WB-CT) or PET/CT imaging.
• MRI is helpful in identifying focal bone marrow lesions before true osteolytic disease appears, evaluating extramedullary disease or suspected cord compression.

Bone Marrow Study

• Bone marrow is typically hypercellular.
• The morphology of plasma cells (PCs) varies; from mature to immature, plasmoblastic, and pleomorphic forms, including multinucleated ones.
• Classical PCs are oval-shaped, with an eccentric nucleus and visible chromatin, an abundant basophilic cytoplasm with perinuclear clearing.
• MM can present with different cellular configurations; as Mott cells (multiple pale bluish-white, grape-like accumulations), refractive bodies, IgG flame cells or Gaucher-like cells and crystals.
• The number of plasma cells can vary. A few MM cases might show less than 10% PCs in a smear due to suboptimal bone marrow aspirate collection.
• It is vital to stain and analyze both bone marrow smears and imprints for an accurate evaluation of PC number. Occasionally, PCs may exhibit only bare nuclei.

Additional Plasma Cell Disorders Related to MM

• Non-IgM monoclonal gammopathy of undetermined significance (MGUS)
• Criteria: Serum monoclonal protein (non-IgM type)<3 gm/dl, clonal bone marrow plasma cells <10%, and absence of end-organ damage.
• Smoldering multiple myeloma (SMM)
  • Criteria: Serum monoclonal protein (IgG or IgA) ≥3 gm/dl or urinary monoclonal protein ≥500mg/24 hrs; or clonal bone marrow plasma cells(10-60%), and absence of myeloma defining events/amyloidosis.
• Plasma cell leukemia
  • Criteria: Meets multiple myeloma diagnostic criteria; and presence of ≥5% plasma cells in peripheral smear differential count.

Other Plasma Cell Disorders Related to MM:

• IgM monoclonal gammopathy of undetermined significance (MGUS)
• Criteria: Serum IgM monoclonal protein <3 gm/dl, bone marrow lymphoplasmacytic infiltration <10%, and no end-organ damage evidence.
• Light Chain MGUS
• All Criteria must be met - Abnormal FLC ratio (<0.26 or >1.65). - Increased involved light chain (Kappa/Lambda) FLC and FLC ratio. -No immunogloblin heavy chain expression
  • Absence of end-organ damage -Clonal bone marrow plasma cells <10%. -Urinary monoclonal protein <500 mg/24 hr

Solitary Plasmacytoma

• Biopsy-proven solitary lesion of bone or soft tissue with clonal plasma cells,
• Normal bone marrow without clonal plasma cells,
• Normal skeletal imaging (except for primary lesion) around spine and pelvis,
• Absence of end-organ damage (CRAB).

Solitary Plasmacytoma with Minimal Marrow Involvement

• Biopsy-proven solitary lesion of bone or soft tissue with clonal plasma cells.
• Clonal bone marrow plasma cells <10%.
• Normal skeletal imaging (except for primary lesion) around spine and pelvis
• Absence of end-organ damage (CRAB).

Molecular Cytogenetic Classification

• The molecular subtype of myeloma is an important prognostic factor. Table 1 details the different subtypes and the genes or chromosomes affected. (See Table 1 for specific sub-types).

Prognosis

• Overall survival is over 10 years for transplant-eligible myeloma patients. However, survival is lower for elderly patients (over 75). These figures might not accurately reflect current survival as they were reported prior to monoclonal antibody treatments and newer agents.

Risk Factors

• Standard risk: Trisomies or t(11;14), t(6;14)
• High risk:  t(4;14), t(14;16), t(14;20), del(17p), gain(1q), and del(1p).
• Double or triple hit myeloma:  Based on combination of risk factors in high-risk category.