Symptoms of Multiple Myeloma
Multiple myeloma presents with a constellation of symptoms captured by the CRAB criteria: hypercalcemia (causing fatigue, confusion, constipation, and thirst), renal insufficiency (kidney dysfunction), anemia (causing weakness and fatigue), and bone lesions (causing bone pain and pathologic fractures). 1
Cardinal Symptoms (CRAB Criteria)
The International Myeloma Society uses CRAB criteria as the diagnostic framework for symptomatic multiple myeloma 1:
Hypercalcemia
- Serum calcium >11.5 mg/dL (2.9 mmol/L) 1, 2
- Symptoms include fatigue, confusion, constipation, and excessive thirst 1
- This is a defining diagnostic criterion requiring immediate treatment 2
Renal Insufficiency
- Serum creatinine >2.0 mg/dL or creatinine clearance <40 mL/min 1
- Leads to progressive kidney dysfunction 1
- Approximately 19% of patients present with acute kidney injury 3
Anemia
- Hemoglobin <10 g/dL or ≥2 g/dL below normal 1
- Normochromic, normocytic pattern 1
- Results in weakness and fatigue 1
- Present in approximately 73% of patients at diagnosis 3
Bone Lesions
- Lytic lesions, severe osteopenia, or pathologic fractures 1
- Causes bone pain—the most common presenting symptom 4, 3
- Approximately 79% of patients have osteolytic bone disease at presentation 3
Additional Clinical Presentations
Common Symptoms
- Generalized weakness and weight loss are frequently reported 4
- Recurrent infections due to immunoglobulin dysfunction 5
- Neuropathy, including numb chin syndrome, can be an initial manifestation 6
Diagnostic Challenge
The non-specific nature of these symptoms often leads to delayed diagnosis, as they can mimic chronic or benign conditions 7. Patients are frequently seen by multiple physicians before hematology referral 7. A combination of unexplained symptoms—particularly bone pain with anemia or renal impairment—should immediately prompt diagnostic evaluation for myeloma 4.
Treatment Overview
For Transplant-Eligible Patients (<65 years or fit)
Induction therapy with bortezomib-based triple combinations (such as VTD: bortezomib, thalidomide, dexamethasone) followed by high-dose therapy with autologous stem cell transplantation (ASCT) is the standard of care 1. This approach combined with maintenance lenalidomide achieves median progression-free survival of 41 months 3.
For Transplant-Ineligible Patients (≥65 years or unfit)
Standard regimens include bortezomib, melphalan, prednisone (VMP) for 8-12 cycles 1. Alternatively, daratumumab combined with lenalidomide and dexamethasone (DRd) demonstrates superior outcomes, with median PFS of 61.9 months versus 34.4 months for lenalidomide-dexamethasone alone 8.
Supportive Care Essentials
- Long-term bisphosphonates (zoledronic acid or pamidronate) reduce skeletal-related events 1
- Aggressive hydration with normal saline for hypercalcemia management 1
- Bortezomib-based regimens can be administered without dose adjustment in renal impairment 1
Treatment Timing
Initiate treatment promptly in patients meeting CRAB criteria to reduce morbidity and mortality 1. However, immediate treatment is not recommended for indolent/smoldering myeloma 1.
Critical Pitfall
The heterogeneous presentation and non-specific symptoms create diagnostic delays that allow disease progression to advanced stages with life-threatening complications 7. Any combination of unexplained bone pain, anemia, renal dysfunction, or hypercalcemia warrants immediate serum and urine protein electrophoresis, serum free light chain assay, and skeletal imaging 1, 4.