What is the recommended treatment approach for a patient diagnosed with multiple myeloma?

Multiple Myeloma: Diagnostic Approach and Treatment

Diagnostic Criteria and Initial Workup

Multiple myeloma is diagnosed by demonstrating clonal bone marrow plasma cells ≥10% or biopsy-proven plasmacytoma, plus either CRAB criteria (hypercalcemia, renal insufficiency, anemia, bone lesions) or specific biomarkers including ≥60% clonal plasma cells, involved/uninvolved free light chain ratio ≥100, or MRI with more than one focal lesion 1, 2.

Essential Laboratory Studies

• Obtain serum protein electrophoresis (SPEP) with immunofixation to detect monoclonal protein 2
• Measure serum free light chains and calculate the involved/uninvolved ratio 1, 3
• Check complete blood count (73% present with anemia), serum creatinine (19% have acute kidney injury), serum calcium (hypercalcemia is a CRAB criterion), β2-microglobulin, albumin, and LDH 2, 3
• Perform 24-hour urine protein electrophoresis with immunofixation 2
• Quantify IgG, IgA, and IgM immunoglobulin levels 2

Required Tissue and Imaging Studies

• Bone marrow aspiration and biopsy to quantify plasma cell infiltration (≥10% required for diagnosis) 2
• Cytogenetic analysis by FISH to detect high-risk features: t(4;14), t(14;16), t(14;20), del(17p), gain 1q, or p53 mutation 1, 2
• Whole-body imaging with CT, PET-CT, or MRI to assess bone disease (79% have osteolytic lesions at presentation) and extramedullary involvement 2, 3

Risk Stratification

All patients must undergo risk stratification using the Revised International Staging System (R-ISS), which combines β2-microglobulin, albumin, LDH levels, and high-risk cytogenetics 4, 1.

Revised ISS Classification

• Stage I: β2-microglobulin <3.5 mg/L, albumin ≥3.5 g/dL, normal LDH, no high-risk cytogenetics (median 5-year survival 82%) 1, 3
• Stage II: Not Stage I or III 1
• Stage III: β2-microglobulin >5.5 mg/L or high-risk cytogenetics or elevated LDH 1, 3

High-Risk Disease Definition

• Presence of t(4;14), t(14;16), t(14;20), del(17p), gain 1q, or p53 mutation defines high-risk disease (approximately 25% of patients) 1, 5

Treatment Algorithm

Step 1: Determine Transplant Eligibility

Assess transplant eligibility based on age (typically <65-70 years), ECOG performance status (0-2), and absence of severe comorbidities 4, 1, 2.

Step 2A: Transplant-Eligible Patients

Induction therapy with a triple-drug regimen containing a proteasome inhibitor (bortezomib), immunomodulatory agent (lenalidomide), and dexamethasone is the standard of care 4, 1, 3.

Recommended Induction Regimens

• Bortezomib-lenalidomide-dexamethasone (VRd): This combination achieves median progression-free survival of 41 months compared to historical 8.5 months without therapy 3
• Alternative: Bortezomib-thalidomide-dexamethasone (VTD) or bortezomib-cyclophosphamide-dexamethasone (VCd) 4
• Administer 3-4 cycles of induction therapy before stem cell collection 5

Autologous Stem Cell Transplantation

• High-dose melphalan 200 mg/m² followed by autologous stem cell transplantation remains standard of care for eligible patients 4, 2
• Use peripheral blood progenitor cells rather than bone marrow as the stem cell source 4
• Melphalan 200 mg/m² is superior to melphalan 140 mg/m² plus total body irradiation 4

Post-Transplant Management

• Lenalidomide maintenance therapy increases progression-free survival (Level 1A evidence) and possibly overall survival (Level 2B evidence) 4, 1
• For patients achieving less than very good partial response (VGPR) after first transplant, consider a second autologous transplant 5
• For high-risk patients, bortezomib-based consolidation is valuable, especially for those who failed to achieve excellent response 4

Step 2B: Transplant-Ineligible Patients

For patients ineligible for transplant, daratumumab-lenalidomide-dexamethasone (DRd) or bortezomib-melphalan-prednisone (VMP) are the standards of care 1, 2.

Preferred Regimen: Daratumumab-Lenalidomide-Dexamethasone

• Daratumumab 16 mg/kg IV plus lenalidomide 25 mg orally days 1-21 plus dexamethasone 40 mg weekly (20 mg for patients >75 years or BMI <18.5) in 28-day cycles 6
• This regimen achieved median PFS of 61.9 months versus 34.4 months with lenalidomide-dexamethasone alone (44% reduction in disease progression risk) 6
• Overall response rate: 92.9% with DRd versus 81.3% with Rd alone 6
• Demonstrated 32% reduction in risk of death (HR 0.68) after 56 months follow-up 6

Alternative Regimens

• Bortezomib-melphalan-prednisone (VMP): Bortezomib 1.3 mg/m² subcutaneously days 1,8,15,22; melphalan 9 mg/m² orally days 1-4; prednisone 60 mg/m² orally days 1-4; repeated every 35 days 4, 2
• Lenalidomide-low-dose dexamethasone (Rd): Lenalidomide 25 mg orally days 1-21; dexamethasone 40 mg orally days 1,8,15,22; repeated every 28 days 4, 2
• Melphalan-prednisone-thalidomide is also a standard option 4

Supportive Care (Critical for Quality of Life)

Long-term bisphosphonate therapy is the only guideline-recommended adjunctive treatment to reduce skeletal-related events and must be initiated for all patients with stage III or relapsed disease 4, 1, 7.

Bone Disease Management

• Administer bisphosphonates (oral or intravenous) to reduce pathologic fractures and bone pain (Level II, A evidence) 4, 7
• Surgical decompression is required for spinal cord compression due to bone fragments 1
• Local radiotherapy for patients with neurologic impairment from bone lesions 1

Renal Protection and Tumor Lysis Prophylaxis

• For patients with high tumor burden, renal insufficiency, or elevated LDH, initiate aggressive IV hydration with normal saline at 150-200 mL/hour to achieve urine output >100 mL/hour 2
• Administer rasburicase 0.2 mg/kg IV as a single dose (or 3-6 mg fixed dose) in high-risk patients before starting chemotherapy 2
• Do not delay effective bortezomib-based chemotherapy while attempting conservative measures alone, as this worsens outcomes 2

Infection Prevention

• Implement antiviral prophylaxis during proteasome inhibitor therapy 8
• Monitor for and aggressively treat infections, as immunoglobulin suppression increases infection risk 5

Response Monitoring

Check M-protein (serum/urine electrophoresis) after 1-2 cycles initially to ensure no progression, then every other cycle during active treatment 1.

Response Criteria

• Stringent complete response (sCR): Normal serum/urine immunofixation, <5% plasma cells in bone marrow, no soft tissue plasmacytomas 4
• Complete response (CR): Negative immunofixation, <5% plasma cells in bone marrow 4
• Very good partial response (VGPR): ≥90% reduction in M-protein 4
• Partial response (PR): ≥50% reduction in serum M-protein and ≥90% reduction in 24-hour urine M-protein 4

Minimal Residual Disease (MRD) Assessment

• Perform MRD testing in patients achieving complete response using next-generation sequencing at 10⁻⁵ threshold 1, 6
• MRD negativity correlates with prolonged progression-free and overall survival 1
• In the MAIA trial, 50.9% of patients achieving CR or better in the DRd arm were MRD-negative versus 29.3% in the Rd arm 6

Treatment of Relapsed/Refractory Disease

Triplet therapy containing two novel agents (proteasome inhibitor, immunomodulatory drug, or monoclonal antibody) plus steroids is recommended for relapsed/refractory patients 1, 2.

First Relapse Regimens

• Carfilzomib-lenalidomide-dexamethasone (KRd): Carfilzomib 20 mg/m² (cycle 1) and 27 mg/m² (subsequent cycles) IV days 1,2,8,9,15,16; lenalidomide 25 mg orally days 1-21; dexamethasone 40 mg days 1,8,15,22; 28-day cycles 2
• Pomalidomide-bortezomib-dexamethasone for lenalidomide-refractory patients (median PFS 11.2 months) 1

Triple-Class Refractory Disease

• Selinexor-dexamethasone or belantamab mafodotin monotherapy 2
• For patients with t(11;14) who are lenalidomide-refractory and proteasome inhibitor-sensitive: venetoclax-bortezomib-dexamethasone (VenVd) 2

Critical Pitfalls to Avoid

• Never delay treatment in symptomatic patients (those meeting CRAB criteria) while attempting observation—immediate intervention is required 7
• Do not use multiagent chemotherapy in elderly transplant-ineligible patients—it is inferior to novel agent-based regimens 4
• Avoid extended delays in chemotherapy initiation for renal patients while attempting conservative measures alone, as this worsens outcomes 2
• Do not omit bisphosphonates—they are the only proven adjunctive therapy to prevent skeletal events and improve quality of life 7
• Never treat smoldering (asymptomatic) myeloma without CRAB criteria or biomarkers of malignancy—observation with monitoring at 3-6 month intervals is appropriate 2