Multiple Myeloma Emergencies
- Aug 29th, 2017
- Jane Xiao
Authors: Jane Xiao, MD (@DrJaneX, EM Chief Resident at Beaumont Health) and Brett R Todd, MD, FACEP (@Brett_R_Todd, Assistant EM Residency Director at Beaumont Health) // Edited by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit)
A 70-year-old African American male with a history of diabetes mellitus presents with low back pain. Although he has a chronic history of low back pain, it is significantly worse this month and prevents him from sleeping at night. He denies trauma. Warm compresses, acetaminophen, ibuprofen, and even a few days of Norco haven’t helped. His wife notes the patient seems to be stumbling more frequently, and three months ago he broke a rib after tripping and running into a wall. She complains that she can’t get any sleep because of his tossing and turning at night. His health this year hasn’t been great. He has had several respiratory infections this past winter. He has no personal history of cancer, no unintentional weight loss, and no smoking history. He is now retired but used to work as a welder in a shipyard. The patient is stable, but he has lumbar spine tenderness so you send off some basic labs and a lumbar spine film. Lumbar spine films show osteopenia and a “punched out” lytic bone lesion in L3 vertebral body. You suspect a diagnosis of multiple myeloma.
Multiple myeloma is the most common primary bone tumor in people over 40 years old, and peak incidence occurs in the seventh decade of life. It represents 10-15% of hematologic neoplasms and 1% of all cancer deaths (1). Risk factors include radiation exposure, chemical exposure, male gender, and African American race. Lower socioeconomic status has also been linked to increased incidence of multiple myeloma due to exposure to wood dust, agricultural pesticides, sheet metal manufacturing, and the nuclear industry (2-4).
The exact etiology of multiple myeloma is not clear, but is associated with mutations of the RAS oncogene. This results in a plasma cell cancer (Image 1) which produces large quantities of immunoglobulins or their fragments (usually IgG or IgA, or light chains) (1-4).
There is no cure for multiple myeloma. The mainstay of treatment is melphalan (6 – 9 mg/m2 daily), an oral alkylating agent, with prednisone (40 – 60 mg/d) (1). Thalidomide, lenalidomide, or bortezomib are often used as well but can be associated with increased risk for venous thromboembolism and sensory neuropathy (8-10). Patients under 65 years of age who present with advanced disease may be considered for autologous stem cell rescue but often have recurrent disease. Mortality with stem cell rescue approximates 20%, primarily due to graft versus host disease (1,5).
Multiple myeloma is a difficult diagnosis to make; 30% of cases are diagnosed incidentally, and another 30% are diagnosed after pathologic fractures. Emergency physicians should suspect multiple myeloma based on pathologic fractures, back or bone pain at rest, normocytic anemia, and renal failure in an older patient. On exam, signs of amyloid deposition such as macroglossia, retinal hemorrhage, cotton wool spots, macular detachment, carpal tunnel compression, and cardiomegaly suggest the diagnosis, however these are usually late findings (1-4).
The formal diagnosis of multiple myeloma requires one major and one minor criteria, or three minor criteria (Table 1), which are not feasible in the emergency department setting.
Case #1 Follow up
The patient’s back pain improves after administering hydromorphone. An emergent spinal MRI is ordered to rule out cord compression He is admitted to the oncology service for the evaluation and treatment of a suspected new diagnosis of multiple myeloma.
In cases of known or suspected multiple myeloma, what should the emergency physician be vigilant for?
A 58-year-old African American male with a history of multiple myeloma presents with several days of fatigue, cough, and nausea. He notes a dry mouth despite hydrating well at home and increased urination. He has stayed in bed for the last week due to worsening back pain. On exam, he appears lethargic and pale. A fingerstick glucose is 50, and he slowly responds to an amp of dextrose. He is placed on a cardiac monitor and found to have the following vital signs: temp 100.6F, heart rate 115, respiratory rate 18, blood pressure 105/60, SpO2 93% on room air. IV fluids are started, and his hypoxia improves with 2L nasal cannula. His workup is significant for hemoglobin 7.9, white blood cell count 2.4, platelet count 80,000, creatinine 2.3, 3+ proteinuria, and glucosuria.
The two most common causes of death in multiple myeloma patients are frequent respiratory infections and renal failure. The average prognosis in clinically active patients from time of diagnosis is three years (1). The most important emergent diagnosis to consider are spinal cord compression, renal failure, hypercalcemia, and infection.
Spinal Cord Compression
Multiple myeloma patients are at increased risk for developing spinal cord compression due to lytic lesions and compression fractures of the lumbar spine. Multiple myeloma promotes osteoclastic activity, which causes not only the classic “punched out” lytic bone lesion (Image 2) but also vertebral compression fractures from general osteopenia. Lytic lesions (Image 3) are typically found in the axial skeleton (1).
These lytic lesions and compressions fractures are often the cause of back pain in multiple myeloma patients. Cord compression can present without any significant neurologic deficit, and the progression to irreversible paraplegia can be abrupt. Emergency physicians must maintain a low threshold for obtaining a spinal MRI and emergent surgical consultation in the multiple myeloma patient with suspected epidural involvement. Initial management of cord compression includes initiation of steroids (dexamethasone 16 mg IV or PO daily) and emergent neurosurgical consultation for laminectomy or decompression (1).
The development of renal failure in multiple myeloma patients is a poor prognostic indicator. The pathophysiology is multifactorial (1-4,6,7). Kidney injury occurs from damage to the glomeruli, tubules, and interstitium from deposition and direct nephrotoxic effects of the excess plasma cells and overproduced proteins. Nonsteroidal anti-inflammatory drugs (NSAIDs) are contraindicated in multiple myeloma patients. Multiple myeloma patients with renal failure are more likely to become dialysis dependent, and once this occurs, average life expectancy decreases dramatically from 3-5 years to 3.5 months (6). The development of renal failure also limits chemotherapeutic options to control the underlying disease.
Hypercalcemia in multiple myeloma is primarily caused by plasma cells secreting osteoclast-activating factors (1-4). Patients will present with typical symptoms of hypercalcemia such as polyuria, constipation, confusion, nausea, vomiting, and lethargy. Hypercalcemia can cause both dehydration and nephrocalcinosis, and both contribute to kidney injury. Therefore multiple myeloma patients are often on bisphosphonates to prevent the development of hypercalcemic episodes. Initial emergency department management is the same: aggressive fluid hydration (3+ liters normal saline over 12-24 hours), cardiac stabilization, and consideration for loop diuretics (furosemide 20 – 40 mg intravenous q12h). Calcitonin (4 IU/kg subcutaneously q12h) can also be used in the immediate setting until a bisphosphonate can take effect (1). However tachyphylaxis is likely with administration of calcitonin. For further details on management of hypercalcemia, check out these emDocs blog posts:
Multiple myeloma patients are immunocompromised. As mentioned above, renal failure and infections are the most common causes of death in this patient population. They develop leukopenia (and anemia and thrombocytopenia) as the bone marrow becomes crowded with plasma cells. Overproduced proteins can interfere with phagocytic cell function. They frequently have S. pneumoniae, S. aureus, H. influenza, and Klebsiella respiratory infections and gram negative UTIs. These patients are often treated with chemotherapy drugs, which also increases their risk for infection. Any signs of infection should be evaluated thoroughly, and broad spectrum antibiotics should be initiated early (1-5).
Hematologic Complications (1-3)
- Hyperviscosity syndrome: Similar to how sickle cell patients develop pain crises when sickled cells clump together, the overproduced proteins in multiple myeloma can clump together and occlude blood vessels and cause organ damage. These patients can present just like sickle cell patients, with headache, mental status changes, retinal hemorrhage, etc. Hyperviscosity may be another cause of back pain in multiple myeloma patients. This may be treated with either plasmapheresis or treating the underlying disease to reduce serum immunoglobulin levels.
- Anemia: Most patients develop symptomatic anemia secondary to both kidney failure and bone marrow suppression. In multiple myeloma patients who present with septic shock, anemia may cause simultaneous high-output cardiac failure. Patients are often placed on erythropoietin (40,000U subcutaneous weekly).
- Bleeding: Overproduced proteins can interfere with platelet function and coagulation factors. Patient can present with ecchymosis, purpura, mucocutaneous bleeding, and retinal hemorrhages.
- Amyloidosis: Large amounts of insoluble proteins can form beta-pleated sheets that deposit all over the body. On history patients may complaints of peripheral neuropathy or carpal tunnel syndrome. On physical exam, this may be observed with macroglossia and hepatosplenomegaly. In patients who develop infiltrative cardiomyopathy with orthostatic hypotension, the median survival is about 6 months.
- Fanconi syndrome, which causes increased excretion of glucose, bicarbonate, phosphates, uric acid, and potassium. Electrolyte abnormalities are best corrected by treating the underlying active disease and removing the excess protein load either by plasmapheresis or treating the underlying disease with chemotherapy.
Case #2 Follow up
This patient shows signs of a respiratory infection and sepsis. He is treated in the emergency department with the sepsis bundle including broad spectrum antibiotics and cultures. He generously fluid resuscitated for both his sepsis and suspected hypercalcemia. Because the patient showed some PR prolongation, you also order furosemide. His vital signs improve, and he is admitted to the oncology service. This case emphasizes that complications of multiple myeloma can often occur simultaneously. For example, a multiple myeloma patient with back pain admitted to the hospital will likely lay in bed for most of the day. Prolonged inactivity and decreased oral intake will increase the risk for hypercalcemia and renal failure. This patient may then develop a hospital acquired infection. Fever will further dehydrate him, worsen his kidney injury, and limit his chemotherapeutic options.
- Multiple myeloma is difficult to diagnose. Elderly patients with unremitting back pain or pathologic fractures of the axial skeleton should be considered for multiple myeloma evaluation. Emergency department X-rays may clinch the diagnosis with punched out lytic bone lesions.
- Cord compression is the most important emergency diagnosis. The absence of neurologic symptoms does not preclude cord compression.
- The two most common causes of death in multiple myeloma patients are frequent infections, usually respiratory, and renal failure. Their disease process and medications make them immunocompromised.
- Renal failure in multiple myeloma patients is multifactorial and has a poor prognosis. Treat acute kidney injury aggressively and contact oncology early.
- Electrolyte abnormalities should be treated by managing the underlying disease process. Multiple myeloma patients are especially prone to hypercalcemia due to osteoclastic bone activity. Treat with generous fluid hydration, and consider loop diuretics (controversial), calcitonin, bisphosphonates in conjunction with their oncologist.
- Multiple myeloma medications may cause venous thromboembolism and neuropathy.
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References / Further Reading:
- Hillman RS, Ault KA. Hematology in clinical practice. 5th ed. New York: McGraw-Hill Medical; 2011.
- Andreoli TE, Benjamin IJ, Griggs RC, Wing EJ. Andreoli and Carpenter’s Cecil essentials of medicine. Philadelphia: Saunders Elsevier; 2010.
- George ED, Sadovsky R. Multiple Myeloma: Recognition and Management. American Family Physician. http://www.aafp.org/afp/1999/0401/p1885.html. Published April 1, 1999. Accessed July 29, 2017.
- Moses MDS. Multiple Myeloma. Family Practice Notebook. http://www.fpnotebook.com/HemeOnc/Marrow/MltplMylm.htm. Published July 6, 2017. Accessed July 29, 2017.
- Bird JM, Owen RG, et al. Guidelines for the diagnosis and management of multiple myeloma 2011. Brit J of Haematology. 2011;154:32-75.
- Wirk B. Renal failure in multiple myeloma: a medical emergency. Bone Marrow Transplant. 2011;46(6):771-83.
- Mussap M, Merlini G. Pathogenesis of renal failure in multiple myeloma: any role of contrast media? Biomed Res Int. 2014;2014:167125.
- Carrier M, Le GG, Tay J, Wu C, Lee AY. Rates of venous thromboembolism in multiple myeloma patients undergoing immunomodulatory therapy with thalidomide or lenalidomide: a systematic review and meta-analysis. J Thromb Haemost 9: 653, 2011.
- Rajkumar SV. Thalidomide therapy and deep venous thrombosis in multiple myeloma. Mayo Clin Proc. 2005;80(12):1549-51.
- Khorana AA, McCrae KR. Risk stratification strategies for cancer-associated thrombosis: an update. Thromb Res 133(Suppl 2): S35, 2014.
- Image 1, Myeloma cells: http://www.mayoclinic.org/diseases-conditions/multiple-myeloma/multimedia/multiple-myeloma/img-20008071
- Image 2, Skull lytic lesions: http://www.myelomapennstate.net/Contents/08a-BoneDis-Eval.htm
- Image 3, Spine lytic lesions: http://www.stritch.luc.edu/lumen/MedEd/Radio/curriculum/Neurology/Spine_plain_xray_2013.htm