Multiple Myeloma: OLD AGE

• Multiple myeloma is a malignant proliferation of a single clone of plasma cells in the bone marrow.
• This leads to excessive production of monoclonal immunoglobulin (M protein) and extensive skeletal destruction.

Clinical Picture

• The clinical picture of multiple myeloma can be remembered by the acronym "OLD AGE".
• Skeletal: Bone pains and pathological fractures are common.
• Renal: Acute kidney injury (AKI) and chronic kidney disease (CKD) can occur.
• Blood: Anemia and bleeding tendencies are present.
• Infections: Recurrent infections, especially with Streptococcus pneumoniae and gram-negative organisms.
• Neurological: Spinal cord compression leading to focal paraplegia can occur.
• General: Fatigue, generalized weakness, and weight loss are common symptoms.
• Hypercalcemia is often observed.

Investigations

• Skeletal: CT and X-ray show multiple osteolytic lesions, especially in the skull.
• Renal: Impaired renal function and Bence-Jones proteinuria (M protein) may be observed.
• Blood: Anemia and hypercalcemia are common.
• Electrophoresis and Immunofixation: Serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) detect M protein (Bence-Jones protein).
• Immunofixation identifies the immunoglobulin class of the M protein (commonly IgG, then IgA).
• Bone Marrow Aspiration and Biopsy: Shows BM plasmacytosis with sheets or clusters of plasma cells (>10% infiltration).

Treatment

• Chemotherapy: Melphalan, thalidomide, and prednisone are used.
• Immunotherapy: Monoclonal antibodies like elotuzumab and daratumumab are employed.
• New therapy: Selinexor, a nuclear export inhibitor, inhibits the transport of oncogenic proteins.
• Radiotherapy and bone marrow transplantation (BMT) are also treatment options.
• Multiple myeloma should be considered if an older patient develops a pathological fracture.
• An older patient with bone pain, anemia, renal failure, and hypercalcemia should be evaluated for multiple myeloma.
• The classic diagnostic triad for multiple myeloma consists of bone marrow plasmacytosis (>10% infiltration), osteolytic bone lesions, and M proteins in blood or urine.

Introduction to Multiple Myeloma

• Multiple myeloma is a clonal plasma cell proliferative disorder.
• It is characterized by an abnormal increase of monoclonal paraprotein.
• This increase leads to specific end-organ damage.

Epidemiology

• It is most frequently diagnosed in 65-74 year olds.
• African Americans are twice as likely to be diagnosed with multiple myeloma.
• Men are 1.5 times more likely to be diagnosed with multiple myeloma.

Pathogenesis

• Myeloma cells lead to the production of monoclonal protein causing hyperviscosity and neuropathy and coagulation defects due to amyloid deposition.
• Myeloma cells also cause decreased immunoglobulins and neutropenia leading to infections.
• They can cause bone marrow infiltration and subsequent bone destruction.
• This leads to hypercalcemia, renal failure, and anemia.

Disease Characteristics

• As plasma cell clones become more aggressive, the number of BM plasma cells and circulating myeloma protein increase.
• This leads to end-organ damage, such as anemia, renal insufficiency, hypercalcemia, and increased risk of infections.
• Bone lesions are osteolytic and can be seen on skeletal radiography.
• Extramedullary disease involves other organs like the skin and liver.

Clinical Presentation

• Anemia is due to bone marrow infiltration and renal failure (decreased EPO level).
• Bone pain results from increased osteoclast activity causing lytic bone lesions and pathological fractures.
• Plasmacytoma (collection of plasma cells outside the bone marrow) contributes to bone pain.
• Hypercalcemia is due to increased bone destruction.
• Renal failure is due to hypercalcemia, drug-induced causes (NSAIDs), and plasma cell infiltration in the kidney.
• Spinal cord compression can be due to plasmacytoma or pathological fractures.
• Recurrent infections are due to hypogammaglobulinemia.
• Hyperviscosity occurs due to high levels of plasma cells.

Alternate Diagnosis

• Hypercalcemia can be caused by hyperparathyroidism, thyrotoxicosis, or drugs.
• Renal failure can be caused by diabetic nephropathy or hypertension.
• Anemia can be caused by anemia of chronic illness or nutritional deficiency.
• Bone pain can be caused by osteoporosis or primary bone cancer.

Clinical Features

• Hypercalcemia is present in 13% at diagnosis.
• Increased osteoclastic bone resorption and increased renal tubular calcium reabsorption are the causes.
• Renal failure is present in 19% at diagnosis.
• Light chain cast nephropathy, hypercalcemia, monoclonal immunoglobulin deposition disease, plasma cell infiltration of the kidneys, concurrent amyloidosis, and drug-induced causes are renal failure etiologies.
• Anemia is present in 35% at diagnosis.
• Bone marrow infiltration by plasma cells, cytokine-mediated suppression of erythropoiesis, and renal failure contribute to anemia.
• Bone pain is present in 58% at diagnosis.
• Increased osteoclast activity causing lytic bone lesions, osteoporosis, and pathological fractures are causes of bone pain.
• Plasmacytomas affecting the bone also contribute to bone pain.

Other Features

• Spinal cord compression occurs in 5% of patients due to plasmacytomas or pathological fractures.
• Recurrent infections are due to hypogammaglobulinemia and leukopenia.
• Hyperviscosity symptoms are due to high levels of circulating paraprotein.

How to Diagnose

• Complete blood count shows normocytic normochromic anemia.
• Blood chemistry includes renal and liver function tests, ESR, LDH, and serum calcium.
• Quantitative immunoglobulin assay measures Ig G, Ig A, Ig M levels.
• Serum protein electrophoresis detects paraproteins (M proteins) in the blood.
• Serum free light chain assay and serum B2 microglobulin are performed.
• A urine test is conducted.
• Bone marrow evaluation is required at diagnosis, to evaluate response, and at the time of relapse.
• Radiology with X-rays, PET, MRI, CT scans, which may not be performed in all cases, can help to detect complications associated with multiple myeloma and determine if cancer has spread.

Diagnostic Criteria for MM

• ≥ 10% BM plasma cells or biopsy-proven bony or extramedullary plasmacytoma and ≥ 1 MDE (CRAB or biomarkers of malignancy)
• Biomarkers of malignancy include >1 focal lesion (25 mm in size), ≥60% plasma cells on BM examination and Serum involved/uninvolved FLC ratio ≥100 (involved FLC must be ≥100 mg/L)

CRAB Criteria

• Hypercalcemia: Serum calcium >0.25 mmol/L higher than the upper limits of normal, or >2.75 mmol/L
• Renal Insufficiency: Serum creatinine >177 µmol/L or <0.67 mL/s creatinine clearance
• Anemia: Hemoglobin <100 g/L or hemoglobin >20 g/L below the lower limit of normal
• Bone lesions: ≥1 osteolytic lesion on skeletal radiography, CT, or PET-CT
• Factors affecting treatment options include age, cost, comorbidities, disease complications (renal failure) and risk stratification.

Treatment of Multiple Myeloma

• Supportive care includes hydration and diuretics for hypercalcemia.
• Blood transfusion and erythropoietin are done for symptomatic anemia and adequate hydration, and treating hypercalcemia and avoid nephrotoxic drugs are done for renal impairment.
• Bisphosphonates for bone lytic lesions, analgesia for bone pain, antibiotics for infections, and plasmapheresis for hyperviscosity are done.
• Specific treatment includes chemotherapy (alkylating agents), targeted therapy (immunomodulatory drugs), monoclonal antibodies (anti-CD38), and autologous stem cell transplantation.

Lecture Notes - Epidemiology

• Elderly (mean age 65-70 years).
• Men > Women.
• Family History = 4-fold increased risk.

Prognostic Investigations

• Serum albumin: hypoalbuminaemia correlates with poor prognosis.
• LDH: tumor burden (prognostic).
• B2 microglobulin: tumor burden.
• C-reactive protein (CRP): tumor aggression.

Staging

• Criteria are based on Sr B2-M and Sr albumin levels.

Poor Prognostic Factors

• Age > 60 years.
• Anemia.
• Low serum albumin.
• High B2 microglobulin.
• Raised LDH.
• Poor general condition.
• Poor cytogenetics.
• Poor response to therapy.

Treatment - Supportive

• Bone pain: Analgesics and Stabilization by surgical fixation.
• Pathological fracture: Radiotherapy and Bisphosphonate.
• Anemia: Packed RBC's transfusion, Erythropoietin, and Supportive care.

Treatment

• Infection: IVIG, Antibiotics and antifungal.
• Hypercalcemia: Adequate hydration, Calcitonin, Corticosteroids, Bisphosphonate.
• Renal impairment: Adequate hydration & avoid nephrotoxic drugs. Treatment of hypercalcemia, hyperuricemia and infections.
• Hyper viscosity: Plasmapheresis + chemotherapy.

Treatment - Specific

• Melphalan /steroid: for elderly patients unfit for chemotherapy.
• Immunomodulators: Thalidomide.
• Proteasome inhibitors: Bortezomib.
• Monoclonal antibodies: anti CD38 (daratumumab).
• Auto stem cell transplant.
• VAD is no longer the gold-standard induction regimen.

Multiple Myeloma Diagnostic Criteria

• Clonal bone marrow plasma cells or plasmacytoma.
• Presence of serum and/or urinary monoclonal protein (except in patients with true non-secretory multiple myeloma).
• Evidence of end-organ damage attributed to the plasma cell disorder.

CRAB

• Hypercalcemia: ≥ 11 mg/L or upper limit of normal
• Renal Insufficiency: creatinine (> 2 mg/dl)
• Anemia: with Hb value of > 2 g/dl below the lower limit of normal or Hb value <10 g/dl.
• Bone lesions: lytic lesions, severe osteopenia or pathologic fractures.