Infection: 

• Major cause of morbidity and mortality.
• Due to decreased normal Ig synthesis, T cell dysfunction, decreased opsonization, decreased leukocyte migration and function, renal impairment, treatment (chemotherapy induced immune dysfunction, steroids).
• Most common cause of death within first month of receiving treatment is infection (45%); pneumonia most common bacterial infection (66%).
• Highest risk of infection within the first year of therapy initiation (particularly in the first three months), and in patients with relapsed or refractory disease. Second peaks around 6 months and then third peak several years after diagnosis.
  • Patients with MM have a 7-fold higher risk of infection compared to the general population; 11-fold within the first year of diagnosis.
  • Risk of viral infection 10-fold higher overall compared to the general population; 18-fold risk increase in the first year.
    • Most common bacterial infections: sepsis, pneumonia, cellulitis, UTI/pyelonephritis, meningitis, osteomyelitis.
    • Gram-positive bacteria account for over half of infections; most common bacteria pneumoniae and Staphylococcus aureus. E. coli most common gram-negative.
    • Pneumocystis jirovecii is a risk for those receiving dexamethasone for relapsed/refractory MM.
    • Most common viral infections: HZV (69.3%), HSV (23.3%), cytomegalovirus (CMV) (8.3%). Influenza associated with increased need for hospitalization.
•  If febrile, assume infection. Look for source and obtain CBC, electrolytes, renal/liver function, UA, blood cultures, chest imaging (chest x-ray, chest CT in select cases). Respiratory symptoms – obtain swabs. Stool samples (C. diff) for diarrhea, abdominal imaging for abdominal symptoms
•  Treatment: source directed; broad spectrum antibiotics should be administered in those with sepsis/septic shock.
  • Concern for viral infection with HSV or HZV on history and exam may necessitate antivirals.
  • If no source on initial evaluation, think about LUCCAASS – lung, urine, cardiac, CNS, arthritis, abdomen, skin, spine. Consider CMV reactivation and invasive fungal disease.

Musculoskeletal/Orthopedic:

• Osteolytic bone disease present in 70%; another 20% have osteopenia but no lytic lesions.
• Due to the imbalance of decreased bone formation and increased resorption, leads to pain, osteoporosis, and pathologic fractures; can occur at any time during the disease.
  • One study found that osteoporosis, pathologic fractures (fracture through an area of bone pathology), compression fractures present in 20-25% at initial diagnosis.
  • MM increases the risk of fracture 9-fold, primarily pathologic fractures.
• 60% have bony pain.
  • Usually involves central skeleton (neck, back, shoulders, pelvis, hip), caused by movement, less common at night, usually mild to moderate in intensity but can be severe in 10% of cases.
  • Consider obtaining axial skeleton survey if new diagnosis of MM suspected.
  • Up to 80% of patients have a fracture at the time of presentation. Patients suspected to have an impending fracture (determined by pain and/or radiographs) should undergo CT to determine if they should undergo prophylactic fixation versus radiotherapy.
• If known MM with new fracture, even if traumatic, evaluate for pathologic fractures.
  • Pathologic fracture can occur with minimal trauma (much less than typically required for a fracture through normal bone) due to bony disease.
    • Most common sites of pathologic fractures: femur, tibia, humerus, thoracic/lumbar spine.
  • Insufficiency fractures are different, also common in MM, which occur in areas of metabolically weakened bone.
    • Most common sites include spine, sacrum, femoral neck, proximal femur, sternum, pubic rami, fibula, tibia.
  • If concerned for pathologic or insufficiency fracture, obtain complete radiographs of the affected long bone. May need CT for further evaluation and surgical planning, or if initial x-ray unremarkable (common in insufficiency fractures). MRI is test of choice if available and concerned for insufficiency fracture.
  • Management goals are to minimize pain with analgesia and maximize function and skeletal integrity. Reduce and splint; ortho consult.

Neurologic:

• Spinal cord compression:
  • Most serious neurologic complication; associated with a vertebral body plasmacytoma or vertebral body fracture (5-20% of patients).
  • Most common site thoracic spine, followed by lumbar and sacral spine. May lead to cord compression or cauda equina syndrome.
    • If a patient with MM has worsening back pain, obtain imaging. MRI recommended for evaluation of cord/cauda equina compression. Consult spine specialist.
    • Treatment: dexamethasone 10 mg IV bolus (then q6 hours) and radiation.
    • If associated with spinal instability or vertebral body collapse, urgent surgical decompression may be necessary.
•  Nerve root compression is most common neurologic complication overall.
  • Occurs most commonly in the thoracic and lumbosacral areas due to a paravertebral plasmacytoma or bony collapse.
  • Present with back pain with radicular radiation and sensory changes but no other evidence of cord compression.
  • MRI for evaluation if acute worsening; treatment is dexamethasone, radiation, and possibly a change in systemic chemotherapy.
• Peripheral neuropathy is uncommon at time of initial diagnosis but is more common with disease progression due to demyelination or axonal injury associated with MM therapies.
  • Bortezomib causes neuropathy in 35% but is reversible in 70% of patients with reduced doses or discontinuation.
  • Present with sensory changes; may develop motor symptoms, hand tremor, ataxia. Most patients have a relatively mild course.
  • Treatment generally supportive: nerve-directed analgesia with pregabalin or gabapentin in patients with pain or more severe disease. For more severe or rapidly progressive disease, plasma exchange and rituximab.
  • Autonomic nervous system involvement rare but is more common in those with concomitant amyloidosis. Presents with labile BPs and orthostatic hypotension.
• CNS involvement may include intracranial myeloma.
  • Intracranial myeloma or plasmacytoma can extend into the skull base and the orbit; ocular pain, exophthalmos, diplopia, intracranial bleeding and mass effect with headaches, vision or speech changes, focal extremity weakness or sensory chances, altered mental status.
  • Obtain head CT; if ocular signs or symptoms present, obtain CT orbits.
  • Treatment includes neurosurgery and/or ophthalmology consultation (if ocular pathology present). If elevated ICP present, elevate head of bed, provide analgesics/antiemetics, hyperosmotic agents.
•  Leptomeningeal myelomatosis: involvement of the meninges and CSF (≤1%).
  • May occur in more advanced stages.
  • Presents with paraparesis, elevated ICP, change in mental status, CN palsies (most commonly CN V and VI).
  • LP for CSF, MRI. CSF reveals elevated protein, plasma cells, and M-protein. MRI typically demonstrates leptomeningeal enhancement.
  • Treatment includes intrathecal therapy (hydrocortisone, methotrexate, cytarabine), systemic treatment, radiation. Median survival following diagnosis 3 months.
• Encephalopathy may occur due to elevated serum ammonia in the absence of liver disease.
  • Due to myeloma cell lines producing elevated ammonia. Diagnosis of exclusion.
  • Treatment includes chemotherapy; decreases serum ammonia resolves the confusion.

Cardiac:

• Increased risk of cardiac complications; Carfilzomb may cause toxicity in up to 18.1% of patients, severe toxicity in 2.2%.
• Toxicity includes hypertension, arrhythmias, chest pain, ACS, pulmonary hypertension, heart failure (systolic or diastolic)
  • Up to 90% of cases present within 3 months of treatment; majority are transient. May be due to endothelial toxicity, cardiac myocyte proteasome system inhibition, and cardiorenal syndrome
• Obtain ECG, troponin, BNP, imaging in those with chest pain, fatigue, shortness of breath, or edema
• Usual treatments for ACS/CHF.

Thrombotic:

• Increased risk of VTE (relative risk 9.2, 95% CI 7.9-10.8), particularly immunomodulators lenalidomide, pomalidomide and thalidomide.
• Other risk factors: VTE, central venous catheter, prior surgery, immobilization, and medications (high-dose dexamethasone, multiagent chemotherapy, carfilzomib).
• VTE incidence highest in the first 6 months of therapy, also in those with refractory or relapsed MM.
• Patients are typically started on aspirin while on immunomodulator-based chemotherapy, though those at higher risk may be started on LMWH, DOACs, or warfarin.
• If DVT or PE diagnosed, treat with therapeutic dose LMWH or DOAC.

Endocrine:

• Risk of adrenal insufficiency and thyroid dysfunction.
  • Prolonged administration of corticosteroids can lead to adrenal insufficiency.
  • Thyroid dysfunction may occur, most commonly with lenalidomide. Occurs in up to 10% of patients, median time of 4 months.
  • Hypothyroidism is the most common form of thyroid dysfunction in MM; decompensated hypothyroidism rare.
• Obtain thyroid function testing, electrolytes, renal function, liver function, lactate, and venous blood gas in those with fatigue, fever, hypotension, vomiting/diarrhea, edema.
  • Treatment of adrenal insufficiency: resuscitation with IV fluids, broad-spectrum antibiotics, glucose, corticosteroids.
  • Treatment of mild hypothyroidism: consult patient’s oncologist and endocrinology. Severe decompensated hypothyroidism management: resuscitation, corticosteroids, broad-spectrum antibiotics, thyroid hormone supplementation.

Summary:

• MM is a common hematologic cancer due to monoclonal plasma cell proliferation.
• Presentation of MM varies; patients may present with end organ injury. Most common presenting findings include anemia, bone pain, renal injury, fatigue, hypercalcemia, and weight loss.
• Hematologic emergencies include anemia, hyperviscosity syndrome, bleeding, and coagulopathy.
• Renal injury is a common complication, and hypercalcemia may occur.
• Patients are at significant risk of infection and sepsis.
• Osteolytic bone disease is common, which is associated with increased risk of fracture.
• Spinal cord compression is the most severe neurologic complication.
• Other complications include cardiac issues, VTE, and endocrine disorders.

References/Further Reading:

1. Long B, McCurdy A, Koyfman A, Rosenberg H. An emergency medicine review: Multiple myeloma and its complications. Am J Emerg Med. 2025 Feb;88:172-179. doi: 10.1016/j.ajem.2024.11.073.
2. International Myeloma Foundation. International Myeloma Working Group (IMWG) criteria for the diagnosis of multiple myeloma. 2024. Available at https://www.myeloma.org/international-myeloma-working-group-imwg-criteria-diagnosis-multiple-myeloma. Accessed May 27, 2024.
3. SEER Stat Fact Sheets: Myeloma https://seer.cancer.gov/statfacts/html/mulmy.html Accessed September 26, 2024.
4. van de Donk NWCJ, Pawlyn C, Yong KL. Multiple myeloma. Lancet. 2021 Jan 30;397(10272):410-427.
5. Rajkumar SV. Multiple myeloma: 2022 update on diagnosis, risk stratification, and management. Am J Hematol. 2022 Aug;97(8):1086-1107.
6. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group Updated Criteria for the Diagnosis of Multiple Myeloma. Lancet Oncol. 2014;15:e538–48.
7. Hussain M, Yellapragada S, Al Hadidi S. Differential Diagnosis and Therapeutic Advances in Multiple Myeloma: A Review Article. Blood Lymphat Cancer. 2023 Sep 15;13:33-57.
8. Holstein SA, Liu H, McCarthy PL. Multiple myeloma. Hematol Oncol Clin North Am. 2014 Dec;28(6):1113-29.
9. Cowan AJ, Green DJ, Kwok M, et al. Diagnosis and Management of Multiple Myeloma: A Review. JAMA. 2022 Feb 1;327(5):464-477.
10. Chakraborty R, Majhail NS. Treatment and disease-related complications in multiple myeloma: Implications for survivorship. Am J Hematol. 2020 Jun;95(6):672-690.
11. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003 Jan;78(1):21-33.
12. Bladé J, Rosiñol L. Complications of multiple myeloma. Hematol Oncol Clin North Am. 2007 Dec;21(6):1231-46, xi.
13. Melton LJ 3rd, Kyle RA, Achenbach SJ, Oberg AL, Rajkumar SV. Fracture risk with multiple myeloma: a population-based study. J Bone Miner Res. 2005 Mar;20(3):487-93.
14. Nucci M, Anaissie E. Infections in patients with multiple myeloma in the era of high-dose therapy and novel agents. Clin Infect Dis. 2009;49:1211.
15. Blimark C, Holmberg E, Mellqvist UH, et al. Multiple myeloma and infections: a population-based study on 9253 multiple myeloma patients. Haematologica. 2015;100:107.