Diagnosis and Treatment of Multiple Myeloma
The diagnosis of multiple myeloma requires ≥10% clonal bone marrow plasma cells or a biopsy-proven plasmacytoma plus evidence of end-organ damage (CRAB criteria) or specific biomarkers indicating disease severity. 1, 2
Diagnostic Criteria
Required Elements for Diagnosis
- ≥10% clonal bone marrow plasma cells or biopsy-proven plasmacytoma
- PLUS one or more of the following multiple myeloma defining events (MDE):
- CRAB features attributable to the plasma cell disorder:
- C: Hypercalcemia (serum calcium >11 mg/dL)
- R: Renal insufficiency (creatinine >2 mg/dL or creatinine clearance <40 mL/min)
- A: Anemia (hemoglobin <10 g/dL or >2 g/dL below normal)
- B: Bone lesions (one or more osteolytic lesions on skeletal radiography, CT, or PET-CT)
- OR one of the following biomarkers of malignancy:
- Bone marrow clonal plasma cells ≥60%
- Serum involved/uninvolved free light chain (FLC) ratio ≥100 (provided involved FLC is ≥100 mg/L)
1 focal lesion on MRI (≥5 mm in size)
- CRAB features attributable to the plasma cell disorder:
Essential Diagnostic Workup
Laboratory Studies:
- Complete blood count with differential
- Serum chemistries including calcium, creatinine
- Serum protein electrophoresis (SPEP) and immunofixation
- Serum free light chain assay
- 24-hour urine protein electrophoresis and immunofixation
- Beta-2 microglobulin, albumin, and LDH (for staging)
Bone Marrow Examination:
- Bone marrow biopsy and aspiration (performed simultaneously)
- Assessment of plasma cell percentage and morphology
- Immunophenotyping by flow cytometry
- FISH analysis for high-risk cytogenetic abnormalities
Imaging:
- Skeletal survey or low-dose whole-body CT
- Consider MRI for suspected spinal cord compression or to detect focal lesions
- PET-CT may be useful for disease assessment
Risk Stratification
International Staging System (ISS)
- Stage I: Beta-2 microglobulin <3.5 mg/L and albumin ≥3.5 g/dL
- Stage II: Not meeting criteria for Stage I or III
- Stage III: Beta-2 microglobulin ≥5.5 mg/L
Cytogenetic Risk Classification
- High-risk features: del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, or p53 mutation
- Double-hit myeloma: Presence of any two high-risk factors
- Triple-hit myeloma: Three or more high-risk factors
Treatment Approach
Transplant-Eligible Patients
Induction Therapy:
- Standard risk: Bortezomib, lenalidomide, dexamethasone (VRd)
- High risk: Consider daratumumab-VRd (Dara-VRd)
- Typically 3-4 cycles before proceeding to transplant
Autologous Stem Cell Transplantation (ASCT)
- Standard of care for eligible patients
- Selected standard-risk patients may delay transplant until first relapse
Maintenance Therapy:
- Standard risk: Lenalidomide maintenance
- High risk: Bortezomib plus lenalidomide maintenance
Transplant-Ineligible Patients
Primary Therapy:
Maintenance Therapy:
- Similar approach to transplant-eligible patients based on risk
Relapsed/Refractory Disease
- Triplet regimens typically needed at relapse
- Options include:
Supportive Care
- Thromboprophylaxis for patients on immunomodulatory drugs
- Bisphosphonates for bone disease
- Antimicrobial prophylaxis to prevent infections
- Regular monitoring of M-protein levels to assess response
- Assessment for treatment-related toxicities
Common Pitfalls and Caveats
- Diagnostic confusion: Distinguish multiple myeloma from MGUS and smoldering multiple myeloma
- Inadequate risk assessment: Failure to perform FISH analysis for high-risk cytogenetics
- Delayed recognition: Nonspecific symptoms may lead to delayed diagnosis
- Renal function monitoring: Critical to preserve renal function and adjust medication dosing
- Hydration management: Adequate hydration is essential, especially during initial therapy, to prevent tumor lysis syndrome and renal toxicity 4
Multiple myeloma treatment should be initiated promptly after diagnosis, with referral to a hematologist/oncologist for specialized care and consideration of clinical trials when appropriate.