What is multiple myeloma?

• Hematologic malignancy with proliferation of monoclonal plasma cells that accumulate in the bone marrow.
• Causes excess monoclonal immunoglobulin production, osteoclast activation, and osteoblast dysfunction.
  • Leads to cytopenias, renal tubular dysfunction and damage, hyperviscosity, and destructive bone disease.

What are the numbers?

• Multiple myeloma (MM) is the second most common hematologic malignancy (1-2% of all cancers); estimated incidence of 4.5-7 per 100,000 per year.
  • Estimated 2024 incidence in the U.S. was 35,780 adults; > 12,500 deaths related to MM.
• Most patients 65-70 years at time of diagnosis; < 10% under 50 years.
• Median survival of 10 years following diagnosis.
• > 95% experience a complication from the disease itself or due to treatment.

Initial presentation of MM: 

• Variety of symptoms and severities; range from no/subacute to severe end organ injury.
• Classic association with complications is CRAB: hyperCa, renal, anemia, bone.
  • At initial presentation: anemia (73%), bony pain (58%), renal injury (48%), fatigue (32%), hypercalcemia (28%), and weight loss (24%).
• More rare complications at initial presentation: paresthesias (5%); hepatomegaly (4%); and splenomegaly, lymphadenopathy, or fever (all ~1%).
• Over 3% have extramedullary disease (myeloma outside of the bone marrow), involvement of the central nervous system (CNS), plasma cell leukemia.
• We may not view this as an ED diagnosis, but literature suggests the most common route to diagnosis is through the ED…consider in patients with unexplained anemia; elevated serum creatinine, calcium, total protein; AKI with proteinuria; decreased albumin; bony pain with lytic lesions, especially if they present with unexplained bone pain, fatigue, or weight loss that is not explained by other etiologies.
• Major complications: divided into hematologic, renal, hyperCa, infection, MSK/orthopedic, cardiac, thrombotic, endocrine.

Hematologic issues:

• Most common complication is anemia: fatigue/weakness, chest pain, shortness of breath, near syncope/syncope, pallor.
  • Normocytic, normochromic anemia with hemoglobin < 12 g/dL present in 73% at the time of diagnosis; up to 97% having anemia at some point.
  • Etiologies: bone marrow replacement by plasma cells (most common cause), relative erythropoietin (EPO) deficiency, dilution with large M protein, bleeding, RBC consumption, renal failure, nutritional deficiencies (e.g., B12, folate), treatment effects (chemotherapy or radiation therapy).
  • Transfusion necessary if symptomatic; some may receiving recombinant human EPO.
• Hyperviscosity syndrome is rare.
  • Due to decreased capillary flow and organ congestion.
  • Fever and fatigue; signs/symptoms of end organ injury including CNS (headache, blurry vision, focal weakness, confusion), cardiac (pulmonary edema, chest pain), pulmonary (dyspnea, hypoxia), hematologic (bleeding).
  • Labs: platelets > 600,000/microL, leukocytosis > 100,000, red cell mass > 25% of normal, renal injury, and elevated serum viscosity (> 4-5 cp, globulin gap > 4).
  • Management: hematology/oncology consult, IV fluids, antibiotics, plasmapheresis.
• Increased bleeding/coagulopathy.
  • Due to bone marrow failure and dysfibrinogenemia.

Renal complications: 

• 50% of patients have serum creatinine > 2 mg/dL at the time of initial diagnosis; up to 12% can be in renal failure.
• Renal injury multifactorial: light chain excretion (“myeloma kidney”), Ig tissue deposition (systemic amyloidosis, Ig deposition disease), tubular dysfunction (Fanconi syndrome), hypercalcemia.
• Renal injury in patients with MM is reversible in 20-60% of patients.
  • Higher rates of recovery if serum creatinine < 4 mg/dL, 24-hour urine protein excretion < 1 g/24 hours.
• Consider renal issues in those with change in urine output, altered mental status, or volume abnormalities (hypervolemia with edema or hypovolemia with dehydration).
• Obtain renal function, electrolytes, ECG; if altered, head CT.
• Management: Goal urine output is 3 L per day; if no contraindications to fluid (pulmonary edema, severe heart failure), start IV fluids.
  • Sodium bicarbonate infusion for AKI with metabolic acidemia.
  • Consult nephrology; HD may be necessary.
  • Treat HyperK if present.
  • Hold nephrotoxic agents, diuretics, ACEis.

Hypercalcemia:

• Due to bone demineralization.
• 15-28% of patients at diagnosis and can occur at any point in the disease.
• Consider in patients with polyuria, polydipsia, dehydration, constipation, and neurologic changes (AMS).
• If hyperCa present on labs but no symptoms, get an ionized level; elevated serum calcium can be due to binding of the M protein and calcium.
• Treatment depends on symptoms and level:
  • Mild: Ca < 12 mg/dL, no or mild symptoms (fatigue, constipation, depression); no emergent treatment necessary, encourage oral hydration. Avoid high calcium diets, dehydration, thiazide diuretics, lithium carbonate, prolonged bed rest, vitamin D supplements > 800 IU/day.
  • Moderate: Ca 12-14 mg/dL; mild polyuria, polydipsia, dehydration, fatigue, weakness, nausea, anorexia; encourage oral hydration. If symptoms severe, treat as severe.
  • Severe: > 14 mg/dL; symptoms from the moderate category that are more severe or neurologic changes such as lethargy, confusion, coma; ECG changes (QTc shortening).
    • Fluid resuscitation with NS at 200-300 mL/hour; target urine output 100-150 mL/hr.
    • Administer 4 units/kg Calcitonin SubQ or IV.
    • Bisphosphonates: pamidronate 90 mg or zoledronic acid 4 mg, both dose-adjusted for renal function. No research or expert consensus on the management of patients with hypercalcemia who have experienced osteonecrosis of the jaw secondary to bisphosphonate therapy. Consultation with oral maxillofacial surgery and endocrinology may be required in these rare cases.
    • Denosumab: human monoclonal antibody used for the treatment of osteoporosis may be useful in the treatment of hypercalcemia in MM; not cleared by the kidney. Specific level of kidney dysfunction where preferable over bisphosphonates unclear. Denosumab may also be necessary in those with hypercalcemia refractory to zoledronic acid or if there are contraindications to bisphosphonates (e.g., serum creatinine > 4.5 mg/dL, allergy).
    • Electrolyte repletion – hypokalemia or hypomagnesemia.
    • Diuresis not routinely recommended for hypercalcemia (furosemide for insufficiency/heart failure with volume overload).
    • HD necessary in those refractory to other therapies, anuric with renal failure, calcium > 18 mg/dL, neurologic symptoms, or those in whom IV fluid resuscitation is not possible (pre-existing volume overload from heart failure).

Stay tuned for part 2, where we cover infectious, musculoskeletal, neurologic, cardiac, thrombotic, and endocrine issues.

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.