Multiple Myeloma: Diagnostic Characteristics and Basic Management

Multiple myeloma is a type of hematological neoplasm of the bone marrow. It arises from the clonal proliferation of defective plasma cells and the damaging effects on multiple organ systems from the deposition of monoclonal paraproteins.

Plasma cells are differentiated B lymphocytes that secrete antibodies. These immunoglobulins are generated through gene recombination, making B cells innately prone to genetic errors as they differentiate into plasma cells. It causes the overproduction and secretion of monoclonal immunoglobulin, called M protein or paraprotein, which can be detected by serum protein electrophoresis. 

Manifestations of the disease arise due to infiltration of the bone marrow with malignant plasma cells, as well as extraosseous deposits called plasmacytomas. The presentation of end-organ failure is often referred to as “CRAB.”

C : Hypercalcemia (serum calcium >2.75 mmol/L or >0.25 mmol/L above the upper limit of normal) occurs when there is increased osteoclast activity leading to osteolytic lesions. Signs include thirst, tiredness, confusion, arrhythmias, or muscle spasms. Treatment may include intravenous hydration and bisphosphonate therapy. These drugs inhibit osteoclast activity and prevent pathological fractures and pain, but the effect on overall survival has not been determined. There is an increased risk of osteonecrosis of the jaw with bisphosphonate therapy and regular dental check-ups are recommended.

A : Renal failure (serum creatinine >177 μmol/L or creatinine clearance <40 ml/min) results from both the precipitation of light chain casts in the distal tubule causing obstruction and the direct toxic effect on the proximal renal tubules. . The non-specialist can facilitate recovery from renal dysfunction with hydration and treatment of hypercalcemia and hyperuricemia. Poor recovery from renal dysfunction is associated with initial severe renal failure and proteinuria.

A : Anemia (hemoglobin <100 g/L or 20 g/L below the lower limit of normal) and pancytopenia may occur as a consequence of extensive bone marrow infiltration that reduces red blood cell production. Blood product support is often required and erythropoietin injections may be considered if renal failure is also present.

B : bone disease : pathological fractures can be located in areas where the bone marrow is most active in adults, namely the skull, spine, pelvis, rib cage, and long bones. In more severe cases, MM may present with spinal cord compression secondary to vertebral collapse or extraosseous plasmacytoma.

Therefore, clinicians should review the warning signs of spinal cord compression and have a low threshold for urgent neurosurgical and imaging review for potential decompression options. A clinical oncology review should also be sought to consider radiotherapy. Profound sensory or motor weakness are warning signs; new-onset fecal incontinence (due to loss of sensation of rectal fullness); new-onset urinary incontinence (loss of bladder fullness); and perianal anesthesia.

After the description of the typical signs and symptoms, the non-specialist should know what studies to request when suspecting a new diagnosis of MM.

- Screening tests : complete blood count (anemia/pancytopenia), urea and creatinine (renal dysfunction), calcium and immunoglobulins (serum protein electrophoresis) and serum free light chain assay (kappa and lambda)). It should be noted that the presence of a high paraprotein (>30 g/L), often with immune paresis and/or a skewed kappa/lambda ratio imbalance, is highly suggestive of a diagnosis of myeloma.

-Peripheral blood smear may show rouleaux and occasionally circulating myeloma cells, indicative of “plasma cell leukemia.” B2 microglobulin may also be ordered to determine tumor burden. Virologic screening (including HIV antigen, hepatitis serology, cytomegalovirus PCR, and Epstein-Barr virus antibodies) should be performed .

-The traditional “skeletal study” has been replaced by imaging such as computed tomography (CT), positron emission CT or magnetic resonance imaging (MRI) of the whole body. Focal imaging (such as MRI of the spine or pelvis) or plain long bone x-rays may be used to look at areas of interest in more detail.

-Bone marrow aspirate and trephination biopsy should be performed to confirm the diagnosis and stratify the patient’s risk based on the percentage of plasma cell infiltration, flow cytometry to determine plasma cell phenotype, and fluorescence. in situ hybridization analysis (FISH) for chromosomal translocations and copy number abnormalities.

MM requires evidence of end-stage organ failure or other myeloma-defining events. If CRAB is not present, then the diagnosis is smoldering multiple myeloma (SMM) if plasma cell infiltration is above 10%, or monoclonal gammopathy of undetermined significance (MGUS) if below 10%. MGUS can progress to myeloma at a rate of 1% of patients per year, but otherwise neither it nor SMM require treatment, although they do require monitoring.

It is important to note that a paraproteinemia is not specific to myeloma-related disease.

Other important differences include Waldenström macroglobulinemia, chronic lymphocytic leukemia, cryoglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, myeloma protein and skin changes), and amyloid light chain (AL) amyloidosis.

Each patient should be reviewed at a multidisciplinary team (MDT) meeting before starting treatment. The MDT includes haematologists, nurse practitioners, microbiologists, radiologists, occupational therapists, physiotherapists, dieticians and psychologists. The patient’s performance status and opinion should be incorporated into an appropriate treatment approach, as should their eligibility for stem cell transplantation.

Myeloma is currently considered a treatable but incurable condition and newly diagnosed patients should receive regular monitoring throughout treatment with the involvement of a clinical nurse specialist.

The objective is to obtain biochemical and clinical remission of the disease.

First-line treatment in patients with confirmed myeloma usually includes proteasome inhibitors (such as bortezomib) or immunomodulatory drugs (such as thalidomide). Side effects of both medications can include peripheral neuropathy. These drugs are generally used in combination with high-dose corticosteroids (dexamethasone) and dose adjustments are required depending on the side effect profile that occurs. Immunomodulatory drugs (such as thalidomide) have an increased risk of venous thromboembolism, so patients should receive an appropriate anticoagulant in addition to a pregnancy prevention program.

Monoclonal antibody therapies (such as the anti-CD38 monoclonal antibody daratumumab) are also now available, but they can also interfere with blood type; The need for supportive blood products should be anticipated to compensate for delays in supply. In eligible patients, usually younger than 70 years, autologous stem cell transplantation is recommended to consolidate the response to first-line treatment, followed by single-agent maintenance therapy (lenalidomide).