What is the prognosis and treatment for multiple myeloma?

Multiple Myeloma Prognosis and Treatment

The prognosis of multiple myeloma has dramatically improved over the past two decades, with 5-year survival increasing from 25% in 1975 to over 80% for stage I disease, driven by novel agents (proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies) combined with autologous stem cell transplantation in eligible patients. 1, 2

Prognostic Factors

Risk stratification is mandatory for all newly diagnosed patients to guide treatment intensity and predict outcomes 3:

• International Staging System (ISS) combines β2-microglobulin and serum albumin levels (Level of Evidence: 1A) 3

  • Stage I: β2M <3.5 mg/L and albumin >3.5 g/dL (5-year survival: 82%) 3, 1
  • Stage II: β2M <3.5 mg/L with albumin <3.5 g/dL OR β2M 3.5-5.5 mg/L 3
  • Stage III: β2M >5.5 mg/L 3

• Revised ISS (R-ISS) adds high-risk cytogenetics and LDH to ISS parameters 1, 2

• High-risk cytogenetics (Level of Evidence: 2B) include t(4;14), t(14;16), t(14;20), del(17p), gain 1q, or p53 mutation 3, 1

• Minimal residual disease (MRD) negativity strongly correlates with prolonged progression-free and overall survival 1, 4

Treatment Approach by Transplant Eligibility

Transplant-Eligible Patients (Age <65-70, Good Performance Status)

Triple-drug induction therapy followed by autologous stem cell transplantation remains the standard of care (Level of Evidence: 1A) 3:

Induction regimen options:

• Bortezomib + doxorubicin/thalidomide + dexamethasone (Level of Evidence: 1A) 3
• Bortezomib + cyclophosphamide + dexamethasone (Level of Evidence: 2B) 3
• Bortezomib + lenalidomide + dexamethasone (preferred based on recent data) 5, 2

Consolidation:

• High-dose melphalan 200 mg/m² IV is the preferred preparative regimen prior to autologous transplantation (Level of Evidence: II, B) 3, 4
• Peripheral blood progenitor cells should be used rather than bone marrow (Level of Evidence: III, B) 3, 4
• Median progression-free survival with this approach: 41 months 2

Maintenance therapy:

• Lenalidomide maintenance increases progression-free survival (Level of Evidence: 1A) and possibly overall survival (Level of Evidence: 2B) 3
• Thalidomide maintenance also increases progression-free survival (Level of Evidence: 1B) 3

Transplant-Ineligible Patients (Age >70-75, Poor Performance Status, Significant Comorbidities)

Novel agent-based triplet regimens are the standard of care (Level of Evidence: 1A) 3:

Preferred regimens:

• Daratumumab + lenalidomide + dexamethasone: median PFS 61.9 months vs 34.4 months with lenalidomide-dexamethasone alone (HR 0.56, p<0.0001) 6
• Bortezomib + melphalan + prednisone (Level of Evidence: 1A) 3
• Melphalan + prednisone + thalidomide (Level of Evidence: 1A) 3

Alternative option:

• Lenalidomide + low-dose dexamethasone showed statistically significant improvement in progression-free survival (Level of Evidence: 2B) 3

Treatment of Relapsed/Refractory Disease

Triplet therapy is superior to doublet therapy at first relapse and should contain two novel agents (proteasome inhibitor, immunomodulatory drug, or monoclonal antibody) plus steroids 3, 5:

For lenalidomide-refractory patients:

• Pomalidomide + bortezomib + dexamethasone: median PFS 11.2 vs 7.1 months (Level of Evidence: III) 3
• Daratumumab + carfilzomib + dexamethasone: median PFS not reached vs 15.8 months (Level of Evidence: III) 3
• Isatuximab + carfilzomib + dexamethasone: median PFS not reached vs 19.1 months (Level of Evidence: III) 3

Emerging therapies for heavily pretreated patients:

• CAR T-cell therapy and bispecific antibodies show major advancement but face challenges with cost, availability, and toxicity management 7, 8

Supportive Care (Mandatory for All Patients)

• Bisphosphonates (oral or IV) reduce skeletal-related events and should be given long-term for stage III or relapsed disease (Level of Evidence: II, A) 3, 5
• Surgical decompression for spinal cord compression from bone fragments 1
• Local radiotherapy for neurologic impairment 1

Monitoring Response

Response assessment frequency:

• Check M-protein (serum/urine electrophoresis) after 1-2 cycles initially to ensure no progression 3
• If responding, check every other cycle during active treatment 3
• Once in plateau phase, decrease frequency to every 3-6 months 4
• Resume frequent testing (every cycle) when M-protein shows upward trend 3

MRD assessment:

• Perform in patients achieving complete response using next-generation sequencing at 10⁻⁵ threshold 1, 6
• MRD negativity rate: 24.2% with daratumumab-lenalidomide-dexamethasone vs 7.3% with lenalidomide-dexamethasone alone 6

Common Pitfalls to Avoid

• Do not delay treatment in patients with symptomatic disease meeting CRAB criteria (hypercalcemia, renal insufficiency, anemia, bone lesions) 1, 5
• Do not use multiagent chemotherapy in elderly patients—it has proven inferior to melphalan-based regimens (Level of Evidence: I, A) 3
• Do not rely on random urine samples—24-hour urine collection is required for accurate light chain quantification 4
• Do not skip immunofixation even when electrophoresis shows no measurable protein 4
• Do not use bone marrow as stem cell source—peripheral blood progenitor cells are superior 3, 4

Special Considerations

High-risk disease:

• Consider allogeneic stem cell transplantation for young patients with high-risk cytogenetics, preferably in clinical trial context (Level of Evidence: 2B) 3
• Bortezomib-based consolidation is valuable for patients failing to achieve excellent response after autologous transplantation (Level of Evidence: 2A) 3

Smoldering (asymptomatic) myeloma:

• Observation without immediate treatment is recommended 5
• Monitor at 3-6 month intervals with laboratory tests 5