Multiple myeloma natural history

Multiple myeloma Microchapters
Home
Patient Information
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Differentiating Multiple Myeloma from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
Diagnostic Criteria
Staging
History and Symptoms
Physical Examination
Laboratory Findings
Electrocardiogram
X Ray
Echocardiograph and Ultrasound
CT
MRI
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
Future or Investigational Therapies
Case Studies
Case #1
Multiple myeloma natural history On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Multiple myeloma natural history All Images X-rays Echo and Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Multiple myeloma natural history
CDC on Multiple myeloma natural history
Multiple myeloma natural history in the news
Blogs on Multiple myeloma natural history
Directions to Hospitals Treating Multiple myeloma
Risk calculators and risk factors for Multiple myeloma natural history

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2] Shyam Patel [3]

Overview

The natural history of multiple myeloma begins with an asymptomatic phase, then progresses to symptomatic involvement and organ involvement. Outcomes are generally good if treatment is begun at an appropriate time. Complications of multiple myeloma include hematologic complications, such as cytopenias, and skeletal complications, such as pathologic fractures. The prognosis of multiple myeloma is based on chromosome changes, stage of disease, kidney function, labelling index, age, performance status, and various laboratory values.

Natural History

• Multiple myeloma: The natural history of multiple myeloma usually begins with an asymptomatic phase. Monoclonal paraprotein or free light chains can be elevated in the absence of symptoms and are frequently detected on laboratory testing. If left untreated, most of the patients with multiple myeloma will gradually develop fatigue, bone pain, and pallor. In as many as 30-40% cases the diagnosis may be incidental and is often diagnosed on routine blood screening. Additional laboratory workup can reveal signs of end-organ damage, such as anemia, renal dysfunction, or elevated calcium. Bony pain can ensue if left untreated. Upon recognition of a possible diagnosis of multiple myeloma, a bone marrow biopsy is usually performed for definitive diagnosis. Once treatment with induction therapy is underway, patient typically experience improvement in laboratory measures, such as reduction in monoclonal paraprotein, reduction in free light chain levels, reduction in calcium, increase in hemoglobin, and improvement in glomerular filtration rate (GFR). The improvement in laboratory parameters is typically seen within 1-3 months after starting induction chemotherapy. After 6-8 cycles of induction chemotherapy, patients will typically proceed to autologous stem cell transplant. If transplant is not performed, the natural history of the disease is characterized by relapse, in which the malignant plasma cell clone is resistant to the initial induction chemotherapy regimen.
• Plasmacytoma: The natural history of plasmacytoma begins with a symptomatic phase, which typically presents as a solid mass. The first diagnostic step is typically a tissue biopsy, which reveals the presence of clonal plasma cells. Once the diagnosis is made, further workup includes assessment for systemic involvement. In most cases, a diagnosis of plasmacytoma is not concurrent with a diagnosis of multiple myeloma. However, the natural history of plasmacytoma is such that there is a risk of progression to active multiple myeloma after many years. After a median follow-up of 58 months, 67% of patients will develop progression to multiple myeloma. Approximately 20% of patients will die from progression of disease.

Complications

Complications that can develop as a result of multiple myeloma are divided into hematologic complications and systemic complications:

Hematologic complications

Hematologic complications of multiple myeloma are due to the accumulation of excess numbers of abnormal plasma cells, which impairs normal hematopoiesis. This is referred to as myelophthisis, or the replacement of normal bone marrow by infiltrating tumor cells. This can result in complications such as anemia, thrombocytopenia, and leukopenia.

• Anemia: Impaired erythroid progenitor formation leads to decreased red blood cell production, which results in anemia. The anemia is usually normocytic (mean corpuscular volume of 80-100 femtoliters). Patients can experience signs and symptoms including fatigue, mucosal and conjunctival pallor, shortness of breath, and decreased exercise tolerance. Severe anemia can occur in patients who have concurrent renal dysfunction from multiple myeloma, as erythropoietin production is impaired in patients with renal complications. Patients may require red blood cell transfusion if the hemoglobin level is less than 7 g/dl or if severe symptomatic anemia develops. Complications from transfusion include HIV infection, hepatitis B infection, hepatitis C infection, pulmonary edema from volume overload, alloimmunization to red blood cell products, and hemosiderosis (iron overload state).
• Thrombocytopenia: Impaired megakaryocyte formation leads to decreased platelet production, which results in thrombocytopenia. Patients can experience signs and symptoms including mucosal bleeding, upper and lower gastrointestinal bleeding, bruising, petechiae, and ecchymoses. In rare cases, fatal hemorrhage can occur. Patients may require platelet transfusion if the platelet count is less than 10,000 cells per microliter, or less than 50,000 cells per microliter in the setting of bleeding diathesis.
• Leukopenia: Impaired granulocyte and lymphocyte progenitor formation leads to decreased mature white blood cell production, which results in leukopenia. Patients can experience signs and symptoms including localized infections (pneumonia, urinary tract infections, cellulitis, dental infections), fevers, chills, and sepsis. In rare cases, infection can be very severe and lead to severe sepsis. Patients may require treatment with antibiotics. Of note, although the plasma cell burden is increased in multiple myeloma, these plasma cells do not function in a normal manner, and the abnormal paraprotein production in multiple myeloma does not confer adequate humoral immunity. Thus, patient can have normal plasma cell counts but can be functionally immunosuppressed.

Systemic complications

Systemic complications of multiple myeloma are due to the effects of plasma cells on various non-hematologic organs, such as the kidneys, bones, and nervous system.

• Skeletal complications: Skeletal-related events are diverse and include asymptomatic lytic lesions, symptomatic lytic lesions, and pathologic fractures. Pathologic fractures in the appendicular skeleton (long bones) can result in functional impairment and impaired mobility. Pathologic fractures in the axial skeleton (vertebral column) can result in more serious complications. Spinal cord compression occurs if pathologic fractures occur in the vertebral column with impingement of bony fragments on the spinal cord. Symptoms include back pain, numbness, dysthesias, decreased deep tendon reflexes, and loss of bowel or bladder control. Spinal cord compression is an oncologic emergency and requires urgent neurosurgical decompression, radiation therapy, and administration of dexamethasone 10mg IV followed by 4 mg PO every 6 hours to prevent further cord compromise.
• Hypercalcemia: In patients with multiple myeloma, calcium is frequently greater than 11 mg/dl. Hypercalcemia can result in signs and symptoms include nephrolithiasis (kidney stones), psychiatric disturbance, bony pain, and constipation. Treatment of hypercalcemia includes calcitonin, bisphosphonates, denosumab, furosemide, and corticosteroids.
• Renal failure: Multiple myeloma is associated with both acute renal failure and chronic renal failure. The mechanism of renal failure is usually due to abnormal deposition of immunoglobulin light chains in renal tubules, a process known as cast nephropathy. Signs and symptoms of renal failure include decreased urine output, volume overload, nausea, pruritic, metallic taste, and normocytic anemia due to erythropoietin deficiency.
• Neurologic complications: The effects of abnormal plasma cells on the nervous system can result in neurologic impairment. Multiple myeloma can cause neurologic complications via various mechanisms, including plasma cell infiltration of tissues of the central nervous system, plasma cell infiltration of tissues of the peripheral nerves (resulting in carpel tunnel syndrome), osseous destruction in areas abutting nerve roots (resulting in radiculopathy), or osseous destruction in areas abutting the spinal cord (result in spinal cord compression).

Prognosis

The prognosis of multiple myeloma depends of a variety of factors. The most important factor that determines disease biology and prognosis is cytogenetics. Overall, prognosis is generally good with appropriate treatment. Without treatment, multiple myeloma will result in death with a median survival of 7 months. The median overall survival for newly diagnosed multiple myeloma ranges from 2 to 10 years. The 5-year overall survival rate of multiple myeloma is approximately 46%. However, the prognosis is far better in the current era since multiple new therapeutic interventions have been introduced. The table below lists common prognostic factors for multiple myeloma.

Prognostic Factor	Description
Chromosome changes	Cytogenetic analysis of multiple myeloma cells has prognostic value, with deletion of chromosome 13, non-hyperdiploidy, and the balanced translocations t(4;14), t(14;16), and t(14;20) conferring a poorer prognosis. Gain of chromosome 1q21 is associated with a somewhat poor prognosis. The 11q13 and 6p21 cytogenetic abnormalities are associated with a better prognosis.
Stage	Advanced stage of multiple myeloma, such as Durie-Salmon or International Staging System (ISS) stage III, are associated with poor prognosis.
Kidney function	An elevated level of creatinine is associated with poor prognosis.
Labelling index	The labeling index indicates how fast the cancer cells are growing. A high plasma cell labeling index (PCLI) or proliferation (reproduction) rate (Ki-67) is associated with poor prognosis.
Age	Older patients have worse prognosis than younger patients.
Associated plasma cell disorder	The presence of plasma cell leukemia or soft tissue plasmacytoma is associated with a particularly poor prognosis among patients with multiple myeloma.
Performance status	Performance status is ranked on a 0–5 scale per the Eastern Cooperative Oncology Group (ECOG) classification. The lower the number, the healthier and more active the person is, and the better the prognosis. Performance status is important in multiple myeloma because people who are healthier can withstand more intensive treatment.
Beta-2-microglobulin	A higher level of beta-2-microglobulin is associated with poor prognosis. This laboratory value is incorporated into the International Staging System (ISS).
Albumin level	A lower albumin level is associated with poor prognosis. This laboratory value is incorporated into the International Staging System (ISS).
Lactate dehydrogenase level	A higher level of lactate dehydrogenase (LDH) is associated with poor prognosis. This laboratory value is incorporated into the Revised International Staging System (R-ISS).
Response to treatment	Patients whose cancer responds to treatment and enters complete remission have a better prognosis than people whose cancer does not respond to the initial treatment.

The prognosis for solitary plasmacytoma is generally very good. The median survival is 10 years. The 5-year survival rate is 72% and the 20-year survival rate is 37%.