Extramedullary Disease in Myeloma

Multiple Myeloma Update - 2024

• Multiple myeloma is a clonal plasma cell disorder characterized by an abnormal increase in monoclonal immunoglobulins.
• It accounts for approximately 1% of all cancers and 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 about 65 years.

Disease Overview

• Unlike other malignancies that metastasize to bone, osteolytic lesions in MM do not 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.
• Approximately 1% to 2% of patients have extramedullary disease (EMD) at initial diagnosis, and 8% develop EMD during the disease course.
• Common symptoms include hypercalcemia, renal dysfunction, anemia, and bone pain .

Symptoms of Multiple Myeloma

• Hypercalcemia
• Renal dysfunction
• Anemia
• Bone pain

Monoclonal Gammopathy of Undetermined Significance (MGUS)

• Nearly all MM patients originate from asymptomatic pre-malignant MGUS.
• MGUS is found in about 5% of the population over 50, with a higher prevalence in Black individuals compared to Whites.
• MGUS progresses to MM or related malignancy at a rate of approximately 1% per year.
• Over 50% of individuals diagnosed with MGUS have had the condition for over 10 years before clinical diagnosis.
• Some patients develop an intermediate asymptomatic (but more advanced pre-malignant) stage called smoldering MM.

Smoldering Multiple Myeloma (SMM)

• SMM is prevalent in approximately 0.5% of the general population aged 40 or older and progresses to MM at a rate of approximately 10% per year for the first five years following diagnosis, 3% per year for the next five years, and 1.5% per year thereafter.
• Factors influencing progression rate include disease burden and underlying cytogenetic type. Patients with specific translocations (e.g., t(4;14), del(17p), gain(1q)) have a higher risk of progression to MM.

Diagnosis of Multiple Myeloma

• Diagnosis requires the presence of one or more myeloma-defining events (MDE) plus evidence of at least 10% clonal bone marrow plasma cells or a biopsy-proven plasmacytoma.

• MDE includes features like CRAB (hypercalcemia, renal failure, anemia and lytic bone lesions) and three specific biomarkers.

• Biomarkers for diagnosis may include:

  • clonal bone marrow plasma cells ≥60%
  • serum free light chain (FLC) ratio ≥100
  • more than one focal lesion on MRI

• Additional International Myeloma Working Group (IMWG) diagnostic criteria include:

  • Clonal bone marrow plasma cells ≥10% or biopsy-proven bony/extramedullary plasmacytoma.
  • Presence of any one or more myeloma-defining events. These events include evidence that end-organ damage is attributable to the plasma cell proliferative disorder. Examples of such events include hypercalcemia (serum calcium > 2.5 mmol/L or > 11 mg/dL) and renal insufficiency (creatinine clearance <40 mL/min or serum creatinine >177 µmol/L or > 2 mg/dL).

Complete Blood Count (CBC) and Peripheral Blood Smear

• Normochromic normocytic anemia
• Variable WBC count and differential
• Normal or low platelet count
• Rouleaux formation (characteristic feature related to M protein quantity/type)
• Circulating plasma cells may be present in low numbers

Bone Marrow Study

• Usually hypercellular
• Morphology of plasma cells (PCs) varies from mature to immature, plasmablastic, and pleomorphic (including multinucleated and multilobulated forms).
• Classical PCs are typically oval-shaped with eccentric nuclei and well-defined or clock-face chromatin, without a nucleolus.
• Abundant basophilic cytoplasm with perinuclear hof

Additional Diagnostic Tools

• Bone marrow plasmacytosis

• Immature PC forms usually have more dispersed nuclear chromatin, high N/C ratio, and prominent nucleoli.

• Plasma cells and findings like Mott, Morula, refractive, and flame cell might be observed.

• Aspirates or touch imprints, in some cases may show less than 10% plasma cells if suboptimal bone marrow biopsy was collected. A trephine biopsy examination may provide more reliable PC numbers.

• Bone marrow PCs might be seen in clusters around arterioles, interstitial clusters, focal nodules, or even diffuse sheets, sometimes even filling bone marrow.

Different morphologies might range from PC morphology to lymphoid, immunoblastic, spindle/oval to signet ring cells. Normal hemopoiesis is usually preserved except for diffuse involvement; scattered osteoclasts and fibrosis may be observed in some cases.

• Imaging such as low-dose WB-CT or PET-CT for assessment of bone disease, MRI for assessing SMM, suspected cord compression or detailed imaging of areas.

Other Plasma Cell Disorders Related to MM

• Non-IgM monoclonal gammopathy of undetermined significance (MGUS): characterized by less than 3 gms/dl monoclonal protein, less than 10% plasma cells in bone marrow, without end-organ damage

Smoldering Multiple Myeloma

• Serum monoclonal protein (IgG or IgA) ≥3 g/dL, or urinary monoclonal protein ≥500 mg/24 h OR clonal bone marrow plasma cells of 10-60%
• No myeloma defining events or amyloidosis.

Plasma Cell Leukemia

• Meets full criteria for multiple myeloma, but with more than 5% plasma cells in peripheral blood.

IgM MGUS

• Serum IgM-monoclonal protein < 3g/dL.
• Bone marrow lymphoplasmacytic infiltration <10%
• No evidence of associated anemia, constitutional symptoms, hyperviscosity, lymphadenopathy or hepatosplenomegaly

Light Chain MGUS

• Abnormal FLC ratio (< 0.26 or > 1.65)
• Increased level for the involved light chain
• No immunoglobulin heavy chain expression on immunosfixation
• Absence of end-organ damage related to the PC proliferative disorder
• Clonal bone marrow plasma cells ≤10%
• Urinary monoclonal protein ≤ 500 mg per 24 hours

Solitary Plasmacytoma

• Biopsy-proven solitary lesion (bone/soft tissue) with evidence of clonal plasma cells.
• Normal bone marrow
• No evidence of end-organ damage (CRAB)
• Normal skeletal survey and MRI/CT spine/pelvis

Solitary Plasmacytoma with Minimal Marrow Involvement

• Biopsy proven solitary lesion (bone/soft tissue) with evident clonal plasma cells.
• Clonal bone marrow plasma cells ≤10%.
• Normal skeletal survey/MRI/CT spine/pelvis (except primary lesion).
• Absence of end-organ damage (CRAB)

Molecular Cytogenetic Classification of Multiple Myeloma

• Table 1 details primary molecular cytogenetic classification.

Prognosis and Risk Stratification

• Overall survival for transplant-eligible myeloma patients is more than 10 years.

• Elderly (≥75 yrs) patients show a lower, approximately 5-year median OS, which likely underestimate present-day survival.

• Monoclonal antibodies and other recent advancements may affect survival estimates.

• Accurate prognosis involves considering host characteristics, tumor burden (stage), cytogenetic abnormalities, and therapeutic response.

• Tumor assessment traditionally employs Durie-Salmon Staging and International Staging System (ISS)

Disease Biology

• Multiple myeloma biology is best judged by molecular subtype and also the presence or absence of secondary cytogenetic abnormalities (such as del(17p) gain(1q), or del(1p)).
• Elevated serum lactate dehydrogenase is another marker of potential risk.
• Plasma cell leukemia (presence of plasma cells in the blood) is an additional marker.

Risk Groups of Multiple Myeloma

• Standard risk: Trisomies t(11;14) ,t(6:14)
• High risk: t (4:14), t(14:16), t(14:20), del(17p) , gain(1q)
• Double-hit/triple-hit myeloma (based on combinations of high risk factors)

References

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