What is the initial treatment for patients diagnosed with symptomatic multiple myeloma, a type of gammopathy?

Initial Treatment for Symptomatic Multiple Myeloma

The preferred initial treatment for patients diagnosed with symptomatic multiple myeloma is bortezomib/lenalidomide/dexamethasone (VRd), which should be offered to both transplant-eligible and transplant-ineligible patients. 1

Risk-Stratified Approach to Initial Therapy

Transplant-Eligible Patients

• For transplant-eligible patients, bortezomib/lenalidomide/dexamethasone (VRd) is a preferred primary therapy option 2
• The VRd regimen has demonstrated high response rates with 58% of patients achieving very good partial response (VGPR) or better after induction therapy 2
• After VRd induction, patients should proceed to high-dose melphalan (200 mg/m²) with autologous stem cell transplantation 1
• Following transplantation, maintenance therapy with lenalidomide should be continued until disease progression 1
• For high-risk patients (with del 17p, t(4;14), t(14;16), or t(14;20)), bortezomib-based maintenance therapy is preferred over lenalidomide alone 1

Transplant-Ineligible Patients

• For standard-risk patients ineligible for transplant, lenalidomide plus low-dose dexamethasone (Rd) continuously is recommended as initial therapy 2
• For intermediate-risk patients ineligible for transplant, cyclophosphamide-bortezomib-dexamethasone (CyBorD) is recommended 2
• For high-risk patients ineligible for transplant, bortezomib-lenalidomide-dexamethasone (VRd) is recommended until progression 2
• In very elderly or frail patients, melphalan-prednisone (MP) may be considered, reserving novel agents for later use 2

Evidence Supporting VRd as Initial Therapy

• The phase III SWOG S0777 trial demonstrated that VRd significantly improved progression-free survival (43 months vs 30 months) and overall survival (75 months vs 64 months) compared to Rd alone 3
• The VRd regimen showed a 100% overall response rate in phase II studies, with 74% of patients achieving VGPR or better and 52% achieving complete response (CR) or near CR 2
• The addition of daratumumab to VRd has shown promising results in recent studies, with 71% of patients achieving minimal residual disease negativity 4

Alternative Initial Therapy Options

• Bortezomib/thalidomide/dexamethasone (VTd) is a category 1 option for transplant-eligible patients, with a 94% response rate 2
• Bortezomib/cyclophosphamide/dexamethasone (VCd or CyBorD) has shown high response rates (88%) with 61% VGPR or better 2
• For transplant-ineligible patients, melphalan/prednisone/bortezomib (MPV) is recommended for high-risk patients 2
• Melphalan/prednisone/thalidomide (MPT) is an option for standard-risk transplant-ineligible patients 2

Administration Considerations

• Subcutaneous administration is the preferred route for bortezomib, as it significantly reduces peripheral neuropathy compared to intravenous administration 2
• Weekly bortezomib dosing (rather than twice weekly) reduces neuropathy while maintaining efficacy 2
• For daratumumab-containing regimens, either intravenous infusion or subcutaneous injection may be used, except in patients with significant thrombocytopenia 2
• Thromboprophylaxis is essential for patients on immunomodulatory drugs like lenalidomide 1

Monitoring and Response Assessment

• Response should be assessed with each treatment cycle using serum and urine electrophoresis 1
• Complete response requires <5% plasma cells in bone marrow and negative immunofixation 1
• Whole-body low-dose CT is preferred over conventional skeletal survey for bone assessment 1

Common Complications and Management

• Peripheral neuropathy is a common side effect of bortezomib and requires dose modification or switching to subcutaneous administration 5
• Thrombotic events are associated with immunomodulatory drugs (thalidomide, lenalidomide) and require thromboprophylaxis 2
• Carfilzomib can potentially cause cardiac, renal, and pulmonary toxicities requiring careful monitoring 2
• Infusion-related reactions are common with daratumumab and require appropriate pre-medication 6

By following this risk-adapted approach to initial therapy for symptomatic multiple myeloma, clinicians can optimize outcomes while minimizing treatment-related toxicities.