Multiple Myeloma

See Also

Epidemiology

Elderly (median age 70 years old)
1. Those <65 years old with Multiple Myeloma represent only 15% of cases
Incidence: 28,850 new cases per year in United States (2015)
Deaths: 11,000 per year
Twice as common in black persons
More common in men
Family History confers 2-4 fold increased risk (Autosomal Dominant trait)
Associated conditions
Associated with certain occupational exposures
1. Farming Pesticides
2. Petroleum workers
3. Woodworkers
4. Leather workers
5. Ionizing radiation

Pathophysiology

Malignant proliferation of Plasma Cells
1. Overproduce monoclonal Protein
2. Abnormal Immunoglobulin (IgG, IgM, IgA are most common)
3. May also involve light chains (either kappa or lambda)
Plasmacytoma may also form solitary plasma cell tumor
On spectrum of plasma cell malignancy
1. Spontaneous (de novo) onset in 80% of cases
2. Monoclonal Gammopathy of Undetermined Significance (MGUS) in 20% of cases
  1. Progression to Multiple Myeloma at rate of 1% per year
3. Smoldering Multiple Myeloma (SMM)
  1. Progression to Multiple Myeloma at rate of 10% per year for first five years (then decreases)
4. Clinical Multiple Myeloma
5. Plasma Cell Leukemia
Risk Factors for progression from MGUS or SMM to Multiple Myeloma
1. Non-IgG subtype
2. High levels of monoclonal Protein
3. Abnormal free light chain ratio
4. Gene alterations

Symptoms

Asymptomatic in 34% of cases (present with abnormal labs: Anemia, Proteinuria, Hypercalcemia)
Back pain or bone pain (58%)
Fatigue (32%)
Pathologic Fracture (up to 34-40% of cases)
Anorexia and weight loss (24%)
Paresthesias (5%)
1. Wrist Pain (Carpal Tunnel related Neuropathy)
Other presenting symptoms
1. Nausea or Vomiting
2. Spinal Cord Compression (5%)
3. Hyperviscosity Syndrome related symptoms

Signs
Bone Findings

Osteolytic lesions
Pathologic Fractures
Palpable swellings on accessible bones
Location
1. Sternum
2. Skull
3. Ribs
4. Vertebrae (May result in Spinal Cord Compression)

Differential Diagnosis
General

Primary or metastatic cancer
Benign bone lesions
Vertebral Compression Fracture (Osteoporosis)

Differential Diagnosis
Plasma Cell Peripheral Disorder

Common
1. Monoclonal Gammopathy of Undetermined Significance (MGUS)
Uncommon
1. Waldenstrom Macroglobulinemia
2. Amyloidosis
3. B-Cell Non-Hodgkin Lymphoma
Rare
1. Plasmacytoma
2. Plasma Cell Leukemia

Labs
Initial

Comprehensive Metabolic Panel (including Serum Calcium, Serum Albumin and Protein, Renal Function tests, Electrolytes)
1. Hypercalcemia
  1. Serum Calcium >10.1 mg/dl (present in 28%, Serum Calcium >11 mg/dl in 13% of patients)
2. Renal Insufficiency
  1. Serum Creatinine >1.3 mg/dl (present in 48%, Creatinine >2 mg/dl in 23% of patients)
Complete Blood Count with Platelets
1. Normochromic Normocytic Anemia
  1. Hemoglobin <12 grams/dl (present in 65-73% of patients)
  2. Anemia is nearly always present at one point for every patient
Other initial tests to consider
1. Thyroid Stimulating Hormone (TSH)
2. Acute phase reactants (ESR, C-RP)
3. Serum Vitamin B12
4. Urinalysis
  1. Proteinuria (bence jones Proteins)
5. Peripheral Smear
  1. Myeloma Cells
  2. Rouleaux of Red Blood Cells

Labs
Confirmatory

Serum Protein Electrophoresis and Urine Protein electrophoresis for Monoclonal Peak
1. M Protein in either serum or urine: 97% of patients
2. Serum M Protein by electophoresis (82%) or immunofixation (93%)
3. Urine M Protein by electrophoresis: 75%
Immunofixation electrophoresis of serum and urine
Serum quantitative Immunoglobulins
24 Hour Urine Protein
Beta-2 microglobulin
Lactate Dehydrogenase (LDH)
Serum free light chain

Labs
Diagnosis - typically done in oncology

Bone Marrow Biopsy and aspirate (with cytogenetics, FISH, immunohistochemistry)
1. Typically performed by oncology

Imaging

Skeletal Survey (including Skull XRay)
1. Recommended imaging for primary providers
2. Classic "punched out" lytic lesions (66% of patients)
3. Pathologic Fractures (26% of patients)
PET/CT or whole body MRI
1. Typically obtained in oncology
Bone Densitometry or DEXA (consider)
1. Osteoporosis (23% of patients)

Diagnosis
Multiple Myeloma

Clonal Bone Marrow plasma cells >10% or biopsy proven bony or extramedullary Plasmacytoma AND
Myeloma defining event (one or more, absence suggests smoldering Multiple Myeloma)
1. Hypercalcemia
  1. Serum Calcium >11 mg/dl (or >1 mg/dl above upper range of normal)
2. Renal Insufficiency
  1. Serum Creatinine >2 mg/dl (or GFR <40 ml/min)
3. Anemia
  1. Hemoglobin <10 g/dl (or more than 2 g/dl below the lower limit of normal)
4. Osteolytic Bone lesions
  1. Osteolytic lesions (one or more) on XRay, CT or PET/CT

Staging

Systems
1. International Staging (ISS)
  1. Standard staging system used most commonly (as of 2017)
2. Revised International Staging (R-ISS)
  1. Better predictor of progression and survival than ISS (which it will likely replace)
3. Durie-Salmon Staging
Stage I
1. International Staging (ISS)
  1. Serum B2 Microglobulin <3.5 mg/L and Serum Albumin >= 3.5 g/dl
2. Revised International Staging (R-ISS)
  1. ISS Stage I AND
  2. Normal Lactate Dehydrogenase (LDH)
  3. No high risk Chromosomes (e.g. del(17p), t(4;14), t(14:16))
3. Durie-Salmon Staging
  1. Hemoglobin >10 g/dl
  2. Serum Calcium <12 mg/dl
  3. No bone disease or Plasmacytoma
  4. Serum paraprotein <5g/dl (IgG) or <3 g/dl (IgA)
  5. Urinary light chain excretion <4 g per 24 hours
Stage 2
1. International Staging
  1. Serum B2 Microglobulin 3.5 to 5.5 mg/L
2. Revised International Staging (R-ISS)
  1. Not R-ISS stage I or III
3. Durie-Salmon Staging
  1. Not DSS stage I or III
Stage 3
1. International Staging
  1. Serum B2 Microglobulin >=5.5 mg/L
2. Revised International Staging (R-ISS)
  1. ISS Stage III AND
  2. Increased Lactate Dehydrogenase (LDH) OR
  3. High risk Chromosomes (e.g. del(17p), t(4;14), t(14:16))
3. Durie-Salmon Staging
  1. Hemoglobin <8.5 g/dl
  2. Serum Calcium >12 mg/dl
  3. Skeletal Survey with >2 lytic lesions
  4. Serum paraprotein >7 g/dl (IgG) or >5 g/dl (IgA)
  5. Urinary light chain excretion >12 g per 24 hours

Management
Combination Therapy

See oncology references for current management protocols
Indication
1. Symptomatic Multiple Myeloma
Protocol 1: Otherwise physically healthy patients (previously limited to age <65 years)
1. First: High dose myeloablative Chemotherapy
  1. CDT: Cyclophosphamide AND Thalidomide AND Dexamethasone OR
  2. VCd: Bortezomib AND Cyclophosphamide AND Dexamethasone
2. Next: Autologous Stem Cell Transplant (ASCT) with high dose Melphalan
Protocol 2: Serious comorbidity (unable to tolerate marrow ablation and ASCT)
1. Thalidomide AND Alkylating Agent (Melphalan, Cyclophosphamide or Chlorambucil) AND Prednisolone OR
2. Bortezomib AND Doxorubicin AND Dexamethasone OR
3. Bortezomib AND Thalidomide AND Dexamethasone (VTd)
Other Medications
1. Lenalidomide and Dexamethasone based protocols
  1. Bortezomib (VRd)
  2. Daratumumab (DRd)
  3. Carfilzomib (KRd)
2. Proteasome Inhibitors (monoclonal antibodies) - Newer Chemotherapy agents
  1. Bortezomib (Velcade)
  2. Carfilzomib (Kyprolis)
3. Corticosteroids (Dexamethasone)
  1. Administered concurrently with Chemotherapy to reduce light chain renal load (Kidney injury risk)
Efficacy
1. ASCT increases median survival 12 months, and results in longterm survival 10% in some cases
2. Palliative (Not curative)
3. Relapse is common

Management
Adjunctive

Bisphosphonates (IV Zoledronic acid or Pamidronate)
1. All treated patients (regardless of bony lesions) to prevent Vertebral Fractures and other bony complications
2. Vitamin D Supplementation should also be given, and consider Calcium Supplementation with caution
3. Terpos (2013) J Clin Oncol 31(18): 2347-57 [PubMed]
Venous Thromboembolism prophylaxis
1. Reduces VTE Risk from 12-26% to 5-8% in Multiple Myeloma
2. Indications
  1. Active treatment of Multiple Myeloma (esp. immunomodulatory agents)
  2. Continue for first 4-6 months after diagnosis (or until disease controlled)
3. Options
  1. Low Molecular Weight Heparin (e.g. Lovenox)
  2. Warfarin (Coumadin) and target INR 2-3
  3. As an alternative, Aspirin alone may be considered for patients at very low risk
4. References
  1. Falanga (2012) Curr Opin Oncol 24:702-10 [PubMed]
Prophylactic Antibiotics
1. First 3 months of treatment (some cases)
  1. Trimethoprim-sulfamethoxazole (Septra, Bactrim) OR
  2. Fluoroquinolone
2. Recurrent pneumococcal infections
  1. Penicillin
3. Proteasome Inhibitor therapy
  1. Antivirals (prevent Varicella Zoster Virus reactivation)
Immunizations (at least 2 weeks before or 1 month after ASCT)
Anemia management
1. Erythropoiesis-stimulating agents (risk of thrombosis)
2. Red Blood Cell Transfusion for Hemoglobin <7 g/dl
Radiotherapy
1. Localized conditions (e.g. severe bone pain, pathologic Fractures, local tumors)
Pain management
1. Analgesics
2. Neuropathy medications
3. Physical Activity
4. Radiotherapy (localized severe bone pain)

Management
Monitoring

Complication monitoring (see below)
1. Weight loss
2. Fatigue
3. Bone pain
4. Peripheral Neuropathy
5. Venous Thromboembolism
6. Infection
7. Chemotherapy adverse effects and toxicity (e.g. Pancytopenia)
MGUS and SMM monitoring
1. Scheduled monitoring of paraproteins and serum light chains

Complications

Immune Suppression
1. Infection presenting complaint in 25% of patients
2. Start empiric Antibiotics for febrile illness
3. See prevention below for Immunizations
Hypercalcemia
1. Initial Management: Normal Saline Infusion with Corticosteroids
2. Additional management in Refractory Cases: Furosemide, Bisphosphonates
Renal Failure
1. Acute Kidney Injury is multifactorial (free light chains at proximal tubules, Hypercalcemia, Dehydration, nephrotoxicity)
2. Treat Acute Kidney Injury with crystalloid (e.g. NS, at least 3 L/day)
3. Dexamethasone is often given prophylactically with Chemotherapy to reduce light chain renal load
4. Dialysis as indicated
Neuropathy (Nerve infiltration by amyloid)
Anemia
1. Results from Bone Marrow invasion
2. Consider differential diagnosis for Anemia
3. Often improves with Multiple Myeloma treatment
4. Consider Erythropoietin or transfusion
Invasive bone lesions (80-90%)
1. Pathologic Fractures
2. Bone pain
3. Osteoporosis
4. Hypercalcemia
Vertebral Fractures
1. See Vertebral Fracture
2. Intravenous Bisphosphonates (Pamidronate, Zoledronic acid)
  1. Continue indefinately
  2. Reduces fracture Incidence and pain
3. Surgical Intervention: Percutaneous Vertebroplasty or Kyphoplasty
  1. Indicated in refractory cases
4. Radiation Therapy
  1. Indicated for Spinal Cord Compression
Hyperviscosity Syndrome
1. Findings: Fatigue, Headache, Visual disturbance, Retinopathy
2. Treat with plasma exchange, antimyeloma Chemotherapy

Monitoring

Symptomatic improvement
Decrease in M Component

Prognosis

Invariably fatal but relates to staging
1. Stage I: 62 Month median survival
2. Stage 3: 29 Month median survival
Treated patients live asymptomatically for years
1. Five year survival was 45% in 2007 (compared with 30% in 1990)
2. Median overall survival approaches 8 years with modern management (including monoclonal antibodies)
Mortality from cause unrelated to Myeloma: 25%

Resources

Multiple Myeloma Research Web Server
1. http://myeloma.med.cornell.edu
Cleveland Clinic Multiple Myeloma and Amyloidosis
1. http://www.clevelandclinic.org/myeloma

References