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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.
• The median age at diagnosis is 65 years.

Disease Overview

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

Symptoms

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

Monoclonal Gammopathy of Undetermined Significance (MGUS)

• Almost all multiple myeloma cases evolve from MGUS, an asymptomatic pre-malignant stage.
• MGUS is present in approximately 5% of the population above the age of 50, with a two-fold higher prevalence in Black individuals.
• MGUS progresses to multiple myeloma at a rate of 1% per year.
• Over 50% of those diagnosed with MGUS have had it for over 10 years prior to clinical diagnosis.
• A related intermediate asymptomatic pre-malignant stage is termed smoldering multiple myeloma (SMM).

Smoldering Multiple Myeloma (SMM)

• SMM is prevalent in about 0.5% of the general population aged 40 and above.
• It progresses to multiple myeloma at a rate of approximately 10% per year for the first 5 years, 3% for the next 5 years, and 1.5% annually thereafter.
• Progression rates are influenced by disease burden and cytogenetic factors (like t(4;14), del(17p), and gain(1q)).

Diagnosis

• Diagnosis of multiple myeloma requires one or more myeloma-defining events (MDE) along with evidence of 10% or more clonal plasma cells in bone marrow or a biopsy-proven plasmacytoma.
• Established CRAB features (hypercalcemia, renal failure, anemia, or lytic bone lesions) or three specific biomarkers: 1. clonal bone marrow plasma cells ≥60%, 2. serum free light chain (FLC) ratio ≥100 (with involved FLC level ≥100 mg/L and urinary monoclonal protein excretion of ≥200 mg per 24 hours), 3. more than one focal lesion on MRI.
• Both clinical criteria must be fulfilled: 1. clonal bone marrow plasma cells ≥10% or biopsy-proven bony/extramedullary plasmacytoma, 2. at least one of the following MDEs: hypercalcemia (serum Ca >2.75mmol/L or >11mg/dl), renal insufficiency (creatinine clearance <40 ml/minute/serum creatinine >177 µmol/L or >2 mg/dl).

Additional Diagnostic Criteria

• Anemia (hemoglobin value <10g/dl or >2g/dl below lower limit of normal),
• Bone lesions (one or more osteolytic lesions on radiography, CT, or PET-CT),
• Clonal bone marrow plasma cells ≥60%
• Ratio of involved/uninvolved serum free light chain(FLC) ≥100 (with involved FLC level ≥100 mg/L)

• 1 focal lesions on MRI (size ≥5mm in at least one location).

Potential Symptoms

• Recurrent infections, constipation, loss of appetite, nausea, increased thirst, tiredness, paleness, increased fractures, and bone pain.

Complete Blood Count and Peripheral Blood Smear

• Normochromic and normocytic anemia.
• Variable white blood cell count and differential.
• Normal or low platelet count.
• Rouleaux formation is typically seen.
• Circulating plasma cells can sometimes be observed, but usually in small numbers.

Bone Marrow Study

• Usually hypercellular bone marrow (BM).
• Plasma cell (PC) morphology varies from mature to immature, plasmablastic, and pleomorphic (including multinucleated and multilobulated forms).
• Classical PCs are oval-shaped with eccentric nuclei and well-defined/clock-face chromatin without nucleoli.
• Abundant basophilic cytoplasm with perinuclear "hot" appearance.
• Bone marrow plasmacytosis can be a feature in multiple myeloma cases.
• Immature cells show dispersed chromatin, high N/C ratio, and prominent nucleoli.
• Myeloma cell cytoplasm often shows abundant endoplasmic reticulum and occasionally contains condensed/crystalized cytoplasmic immunoglobulin, creating a variety of distinct morphological features.

Other Diagnostic tests

• SPEP strip with M band in gamma region.
• Serum immunofixation electrophoresis.
• 24-hour urine collection for protein electrophoresis and immunofixation.
• Serum free light chain assay useful for patients lacking a measurable M protein and abnormal FLC ratio (>100 mg/L and ≥100).

Biochemical Tests

• Serum calcium (Ca), renal function tests (RFT), liver function tests (LFT), erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), albumin, and B2M levels are important.

Imaging Studies

• Low-dose whole-body CT, PET/CT scans are superior for evaluating bone disease.
• MRI is beneficial for patients suspected of having SMM or extramedullary disease, suspected cord compression, or specific symptomatic area assessment.
• Conventional skeletal survey can also be used if advanced imaging is not available.
• Serum CrossLaps can help assess bone turnover in relation to bisphosphonate therapy.

Diagnostic Criteria for Plasma Cell Leukemias

• Meet diagnostic criteria for multiple myeloma.
• Presence of 5% or more plasma cells in a peripheral blood smear white blood cell count differential.

Other Plasma Cell Disorders Related to Multiple Myeloma

• Non-IgM monoclonal gammopathy of undetermined significance (MGUS) criteria:

1. Serum monoclonal protein (non-IgM type) <3 gm/dL.
2. Bone marrow clonal plasma cells <10%.
3. Absence of end-organ damage (no CRAB features)

Additional Related Diagnoses

• Smoldering multiple myeloma criteria:

1. Serum/urinary monoclonal protein (IgG/IgA) ≥3 gm/dl or ≥500 mg/24h and clonal bone marrow plasma cells (10-60%).
2. Absence of myeloma defining events or amyloidosis.

Solitary Plasmacytoma

• Biopsy-proven solitary bone or soft tissue lesion with evidence of clonal plasma cells.
• Normal bone marrow.
• Normal spine and/or pelvis skeletal survey and MRI (excluding the primary lesion region).
• Absence of end-organ damage (no CRAB features).

Solitary Plasmacytoma with Minimal Marrow Involvement

• Same criteria as solitary plasmacytoma, but with less than 10% clonal plasma cells in the bone marrow.

Molecular Cytogenetic Classification of Multiple Myeloma

• Presents a table describing the subtypes (Hyperdiploid myeloma, IgH translocated myeloma, etc) with their associated genes/chromosomes affected and their approximate percentage of myeloma patients. (Note: Table 1 is not accessible as a part of the image provided).

Prognosis, and Risk Stratification

• Overall survival is over 10 years for transplant-eligible multiple myeloma patients.
• In elderly patients (over 75 years), it's approximately 5 years. This estimate likely underestimates current survival rates due to more recent monoclonal antibodies and other therapeutic advancements within the last five years.
• Factors like host characteristics, tumor burden, biology (cytogenetic abnormalities), and therapy response influence prognosis.
• Traditional staging systems used include Durie-Salmon Staging (DSS) and International Staging System (ISS).

Disease Biology

• Multiple myeloma's biology is best evaluated based on:

1. Molecular subtype (as found in Table 1),
2. Presence/absence of secondary cytogenetic abnormalities (e.g., del(17p), gain(1q), or del(1p)),
3. Elevated serum lactate dehydrogenase level,
4. Evidence of circulating plasma cells in a routine peripheral blood smear (plasma cell leukemia, if present.

Risk Groups in Multiple Myeloma

• Lists the different risk groups for Multiple Myeloma based on associated gene mutations with their appropriate risk level.

References

• A reference is provided but it is not accessible as a part of the image provided.