Multiple Myeloma- Causes, Symptoms, Diagnosis, Treatment and Ongoing care

Basics

Description

Multiple myeloma (MM) is a plasma cell malignancy characterized by lytic bone lesions, paraproteinemia, anemia, renal insufficiency, hypercalcemia, and infectious diathesis.Monoclonal gammopathy of undetermined significance (MGUS) is a common disorder with limited monoclonal plasma cell proliferation that can lead to MM.Synonyms: Plasma cell myeloma; Plasma cell leukemia

Epidemiology

Predominant age: Average age 66 years old (1)Predominant gender: Male > Female (slightly) (1)lack people are almost 2 × more commonly affected than white people (1).

Incidence

3–4 new cases/100,000 annually (2)

Prevalence

In 2007, there were 61,642 cases in the US (3).

Risk Factors

Most cases have no known risks associated.Increased incidence of exposure to herbicides, insecticides, petroleum, heavy metals, plastics, radiationMyeloma increases in incidence with age.MGUS progression to MM is 0.5–1% year.

Genetics

Rare family clusters

General Prevention

None known

Pathophysiology

Clonal bone marrow proliferation with mature B cells (2)Genetic damage in developing B-lymphocytes at time of isotype switching, transforming normal plasma cells into malignant cells, arising from single clone (4)Chromosomal alterations include 13q14 deletions, 17p13 deletions, and 11q abnormalities. Most common translocations are t(11;14)(q13;q32) and t(4;14)(p16;q32). Overexpression of myc or ras and mutations in p53 and Rb-1 also have been described (2).Malignant cells multiply in bone marrow, crowding normal bone marrow cells and producing large quantities of monoclonal immunoglobulin (M) protein (4).Malignant cells stimulate osteoclasts that cause bone resorption and inhibit osteoblasts that form new bone, causing lytic bone lesions (4).

Etiology

Unknown

Commonly Associated Conditions

Secondary amyloidosis commonly due to MM

Diagnosis

History

34% of patients are asymptomatic at the time of presentation.Bone pain (58%) in back, long bones, skull, ribs, and pelvis due to bone mass or pathologic fracture (26–34%)Peripheral neuropathy: Carpal tunnel syndrome most commonSymptoms of hypercalcemia: Anorexia, nausea, somnolence, and polydipsiaInfection, especially with encapsulated organisms: Fever is rare at presentation.Weight loss, malaise, weakness

Physical Exam

DehydrationSkin findings of amyloidosis: Waxy papules, nodules, or plaques that may be evident in the eyelids, retroauricular region, neck, or inguinal and anogenital regions; petechiae and ecchymosis; “pinch purpura”Hyperviscosity syndrome in 7%: Retinal hemorrhages, prolonged bleeding, neurologic changesTender bones and masses

Diagnostic Tests & Interpretation

Lab

Criteria for diagnosis: The diagnosis of MM requires all of the following (1):

A bone marrow aspirate or biopsy showing that at least 10% of the cells are clonal plasma cells or the presence of a plasmacytomaM protein in the blood or urineEvidence of damage to the body as a result of the plasma cell growth, such as destructive bone lesions, kidney failure, anemia, or hypercalcemia

Initial lab tests

Complete blood count (CBC) with differential and platelet counts to evaluate anemia, other cytopenias; anemia in 73% (1)Blood urea nitrogen (BUN), creatinine: Increased levels indicate renal involvement (2).Serum electrolytes, serum albumin, serum calcium: Hypercalcemia with levels >11 mg/dL in 13% (1)Serum lactate dehydrogenase (LDH), ß2-microglobulin: Increased levels indicated increased tumor burden (2).Quantitive serum analysis of immunoglobulin levels: IgG, IgA, IgM (2)Serum protein electrophoresis (SPEP), serum immunofixation electrophoresis (SIFE): M protein level elevated; assessing changes in the level of M protein helps to track progression of myeloma and response to treatment (2); 82% localized band on serum protein electrophoresis, 93% monoclonal protein on immunoelectrophoresis (1)Erythrocyte sedimentation rate: ElevatedUrinanalysis: 24-h urine for protein, urine protein electrophoresis (UPEP), urine immunofixation electrophoresis (UIFE); 20% positive urine protein (2)

Follow-Up & Special Considerations

Bone marrow aspirate and biopsy for histology, immunohistochemistry, plasma cell labeling index, cytogenetics, fluorescence in situ hybridization (FISH): May detect chromosomal abnormalities (2)Serum-free light chains in selected patients (2)Plasma cell labeling index may be helpful to identify the fraction of the myeloma cell population that is proliferating (2).

Imaging

Initial approach

Skeletal survey: 26–34% of patients present with lytic bone lesions on x-ray.MRI for any back pain or earliest signs/symptoms of spinal cord compression

Follow-Up & Special Considerations

CT scan is more sensitive than plain radiography for small long bone lesions; can differentiate malignant from benign vertebral compression fractures in patients who are not MRI candidatesPositron-emission tomographic (PET) scans with CT scans are used for staging and follow-up: Active myeloma is positive (2).Bisphosphonates are considered as therapy; a baseline bone densitometry may be indicated (2).

Diagnostic Procedures/Surgery

Staging:

International staging system for myeloma: Stage I: Albumin =3.5 g/dL and ß2-microglobulin <3.5 µg/mLStage II: Neither stage I nor stage IIIStage III: ß2-microglobulin =5.5 µg/mLMayo Clinic Criteria for high-risk multiple myeloma (1): Cytogenetics: Deletion of chromosome 13, hypodiploidyFISH: t(4;14), t(14;16), 17p-Plasma cell labeling index >3%

Pathological Findings

Marrow plasmacytosis >30%, >10% immature; Russell bodies

Differential Diagnosis

MGUS: Monoclonal protein <3 g/dL; marrow plasma cells <10%; absence of end-organ damage: Prevalence 5.3% if >70 years of ageProgress to MM 0.5–1%/yearIncreased risk of progression if IgA or IgM, higher percentage of marrow plasma cellsMetastatic cancer to boneWaldenström macroglobulinemia: IgM monoclonal gammopathy with >10% marrow lymphoplasmacytic infiltrateSystemic AL amyloidosis: Amyloid-related syndrome with positive amyloid stain plus monoclonal plasma cell disorderPOEMS syndrome: Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes

Treatment

Treatment varies depending on how active disease is and the stage of MM.Treatment for inactive, smoldering MM at this time is supportive only. Patients should be monitored at 3-month intervals. These patients do not have evidence of end-organ damage. However, clinical trials are ongoing to determine whether newer agents are able to delay progression (1).Autologous stem cell transplant following induction chemotherapy is standard of care for patients with symptomatic disease <65 years of age or those >65 years of age and able to undergo procedure. Although not curative, it improves complete response rates and prolongs median overall survival in MM by approximately 12 months with a mortality rate of 1–2% (1).

Medication

Chemotherapy options include bortezomib, cyclophosphamide, thalidomide, lenalidomide, and dexamethasone.

First Line

Bortezomib (1)[B]: Inhibits the ubiquitin-proteasome catalytic pathway in cells by binding to the 20S proteasome complexToxicity: Peripheral neuropathy, cytopenias, nauseaConsider herpes simplex virus (HSV) prophylaxis.Cyclophosphamide (1)[B]: Nitrogen mustard–derivative alkylating agentOften used in combination with prednisone or thalidomide in cases of relapsed diseaseToxicity: Cytopenias, anaphylaxis, interstitial pulmonary fibrosis, secondary malignancy, impaired fertilityThalidomide (1)[B]: Works by antiangiogenesis inhibition, immunomodulation, and inhibition of tumor necrosis factor aUsually combined with dexamethasoneToxicity: Birth defects, deep vein thrombosis (DVT), neuropathy, rash, nausea, bradycardiaDVT prophylaxisLenalidomide (1)[B]: Is an immunomodulatory drugOften combined with dexamethasoneToxicity: Deep vein thrombosis (DVT), cytopenias, birth defects risk, DVT prophylaxis: Aspirin is standard.Dexamethasone (1)[B]: Low doses (40 mg/wk) superior to higher dosesIncreases risk of DVTBisphosphonates (5)[A]: Do not have effect on mortality but decrease pain, decrease pathological vertebral fractures and fractures of other bonesNo bisphosphonate appears to be superior to others.Dose-adjust/monitor renal function.Monitor for osteonecrosis of jaw.

Second Line

Single agents or combinations as above

Additional Treatment

Local radiation therapy for bone pain (1): Should be limited for patients with disabling pain who have not responded to analgesics and/or chemotherapyAvoid extensive radiation therapy.Allogenic stem cell transplant (1): Advantages over autologous stem cell transplant include lack of graft contamination with tumor cells and lack of graft vs MM effectOnly 5–10% of patients are candidates due to age, lack of an HLA-matched sibling donor, and organ function.

General Measures

Maintain adequate hydration to prevent renal insufficiency.

Issues for Referral

Patients who have known or suspected multiple myeloma should be treated by a hematologist/oncologist.Patients with spinal or other bone pathology should be referred to orthopedics for support.

Additional Therapies

Effective pain management: Avoid NSAIDS due to nephrotoxicity.Kyphoplasty/vertebroplasty: Consider for symptomatic vertebral compressions (1).Plasmapheresis: For hyperviscosity syndrome (a rare complication) (1)Erythropoietin: For selected patients with anemia (1)Patients should receive vaccines for pneumococcus and influenza (1.)Do not administer zoster vaccine and other live-virus vaccines.

In-Patient Considerations

Initial Stabilization

Avoid IV radiographic contrast materials due to the high risk for contrast-induced nephropathy (1).Adequate hydrationAvoid nonsteroidal anti-inflammatory drugs (NSAIDs) to decrease chance of renal insufficiency.Manage hypercalcemia and control hyperuricemia.

Admission Criteria

Including but not limited to pain, infections, cytopenias, renal failure, bone complications, spinal cord compression

Nursing

Central to patient management and health care resource coordination

Ongoing Care

Patient Education

www.cancer.net; www.myeloma.org

Prognosis

Median survival overall is 3 years (1).Median survival by ISS stage (1): Stage I: 62 monthsStage II: 44 monthsStage III: 29 monthsMedian survival in patients with high-risk multiple myeloma (see “staging” for definition) is less than 2–3 years, even after autologous stem cell transplant; however, with more modern therapies, survivals of 10 years or more are being seen (1).

Complications

Many, including infection, pain, lytic bone lesions, hypercalcemia, hyperuricemia, spinal cord compression, anemia, hyperviscosity syndrome, renal insufficiency

References

1. Rajkumar SV, Kyle RA et al. Multiple myeloma: diagnosis and treatment. Mayo Clin. Proc. 2005;80:1371–82.

2. The NCCN Multiple Myeloma Clinical Practice Guidelines in Oncology (Version 2.2008). © 2008 National Comprehensive Cancer Network, Inc. Available at: http://www.nccn.org. Accessed April 29, 2010.

3. National Cancer Institute, SEER cancer statistics review, 1975–2007. http://seer.cancer.gov/csr/1975_2007/results_merged/sect_18_myeloma.pdf

4. Jagannath S et al. Pathophysiological underpinnings of multiple myeloma progression. J Manag Care Pharm. 2008;14:7–11.

5. Mhaskar, Redzepovic J, et al. Bisphosphonates in Multiple Myeloma. Cochrane Haematological Malignancies Group Cochrane Database of Systematic Reviews. 3, 2010.

Additional Reading

Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006;354:1362–9.

Codes

ICD9

203.00 Multiple myeloma, without mention of having achieved remission

Snomed

109989006 multiple myeloma (disorder)

Clinical Pearls

Multiple myeloma is a plasma cell malignancy that causes end organ damage.Suspect MM if high total protein:albumin ratioHigh index of suspicion for spinal cord compressionAvoid nephrotoxins (radiographic contrast material, NSAIDs, dehydration).Patients with MM are immunocompromised.