What is the diagnostic and treatment approach for multiple myeloma in a patient with an M spike, hypercalcemia, impaired renal function, anemia, and a history of chronic alcohol use?

Diagnostic Approach for M Spike and Multiple Myeloma

In a patient presenting with an M spike, hypercalcemia, impaired renal function, and anemia, you must immediately confirm the diagnosis of symptomatic multiple myeloma by demonstrating ≥10% clonal plasma cells on bone marrow biopsy plus documentation that the CRAB criteria are attributable to the plasma cell disorder—not to alcohol-related complications or other causes. 1, 2

Critical First Step: Establish True Myeloma-Related End-Organ Damage

The presence of CRAB features does NOT automatically confirm multiple myeloma—you must prove causality. 3

Common pitfall to avoid: In a patient with chronic alcohol use, renal impairment may be from alcohol-related nephropathy, anemia from nutritional deficiencies or chronic liver disease, and hypercalcemia from primary hyperparathyroidism. 3 These must be excluded before attributing symptoms to myeloma.

Verify Each CRAB Criterion:

• Hypercalcemia (>11.5 mg/dL): Rule out primary hyperparathyroidism with intact PTH level before attributing to myeloma 3, 1, 4
• Renal insufficiency (creatinine >2 mg/dL or CrCl <40 mL/min): Confirm this is myeloma-related (cast nephropathy, light chain deposition) rather than alcohol-related or prerenal azotemia 1, 2, 4
• Anemia (Hgb <10 g/dL or ≥2 g/dL below normal): Exclude iron deficiency, B12/folate deficiency, and alcohol-related bone marrow suppression before attributing to myeloma 3, 1, 4
• Bone lesions: Document lytic lesions on skeletal survey or MRI that are characteristic of myeloma 1, 2

Essential Diagnostic Workup

Mandatory Laboratory Tests:

• Serum protein electrophoresis with immunofixation to identify and characterize the monoclonal protein 2, 4
• 24-hour urine protein electrophoresis with immunofixation using a concentrated 24-hour collection—never use random urine samples 2, 4
• Nephelometric quantification of IgG, IgA, and IgM immunoglobulins 2, 4
• Serum free light chain (FLC) assay with kappa/lambda ratio measurement 2, 4
• Complete blood count, serum calcium, creatinine, and β2-microglobulin for staging 4, 5

Mandatory Bone Marrow Evaluation:

• Bone marrow aspiration and biopsy to quantify clonal plasma cell percentage (must be ≥10%) 2, 5, 6
• CD138 staining must be performed to accurately determine plasma cell percentage—failure to do this leads to underestimation 2, 4
• Cytogenetic/FISH studies are mandatory for risk stratification: specifically test for del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, and p53 mutation 2, 5, 6

Mandatory Imaging:

• Full skeletal X-ray survey (spine, pelvis, skull, humeri, femurs) to detect lytic bone lesions 2
• MRI of spine and pelvis if skeletal survey is negative but symptoms suggest bone involvement, or if spinal cord compression is suspected 2

Diagnostic Criteria Confirmation

Multiple myeloma requires BOTH:

1. ≥10% clonal bone marrow plasma cells (or biopsy-proven plasmacytoma) 2, 5, 6
2. At least ONE myeloma-defining event:
   • CRAB criteria attributable to plasma cell disorder 2, 5, 6
   • OR ≥60% bone marrow plasma cells 2, 5
   • OR involved/uninvolved serum FLC ratio ≥100 (with involved FLC ≥100 mg/L) 2, 5, 6
   • OR >1 focal lesion ≥5mm on MRI 2, 5

Risk Stratification (Mandatory Before Treatment)

High-risk cytogenetics fundamentally change treatment decisions—never overlook this step. 2, 5, 6

• High-risk features: del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, or p53 mutation 5, 6
• Double-hit myeloma: Any two high-risk factors 5, 6
• Triple-hit myeloma: Three or more high-risk factors 5, 6

International Staging System (ISS):

• Stage I: β2-microglobulin <3.5 mg/L AND albumin ≥3.5 g/dL 2
• Stage II: Neither Stage I nor III 2
• Stage III: β2-microglobulin ≥5.5 mg/L (worst prognosis) 2

Treatment Approach Once Diagnosis Confirmed

Treatment should be initiated immediately in all patients with symptomatic myeloma fulfilling CRAB criteria. 4, 7, 5

For Transplant-Eligible Patients:

• Induction therapy: Anti-CD38 monoclonal antibody (daratumumab) plus bortezomib, lenalidomide, dexamethasone (Dara-VRd) for 3-4 cycles, particularly for high-risk patients 5, 6
• Standard-risk patients: VRd (without daratumumab) is acceptable 5, 6
• Followed by: Autologous stem cell transplantation (ASCT) 5, 6
• Maintenance: Lenalidomide for standard-risk; bortezomib plus lenalidomide for high-risk myeloma 5, 6

For Transplant-Ineligible Patients:

• Preferred regimen: Daratumumab, lenalidomide, dexamethasone (DRd) until progression 8, 5, 6
• Alternative: VRd for 8-12 cycles followed by lenalidomide maintenance 5, 6
• For elderly patients: Melphalan/prednisone/thalidomide (MPT) or bortezomib/melphalan/prednisone (VMP) are standard options 3, 4

Critical Pitfalls to Avoid

• Never attribute CRAB criteria to myeloma without excluding other causes, especially in patients with alcohol use 3
• Never use random urine samples for protein electrophoresis—only 24-hour concentrated collections are acceptable 2, 4
• Never skip cytogenetic testing—high-risk features fundamentally alter treatment decisions 2, 5
• Never miss spinal cord compression—obtain urgent MRI when clinically indicated 2
• Always ensure CD138 staining to avoid underestimating plasma cell percentage 2, 4