Is there a benefit to switching from VCD (Vincristine, Cyclophosphamide, Dexamethasone) to VRD (Bortezomib, Lenalidomide, Dexamethasone) in a myeloma patient with proteinuria and a mild response to VCD?

Switching from VCD to VRD for Myeloma with Mild Response to VCD

For a myeloma patient with proteinuria showing a mild response to VCD (Bortezomib, Cyclophosphamide, Dexamethasone), switching to VRD (Bortezomib, Lenalidomide, Dexamethasone) is strongly recommended as it offers superior response rates and potentially improved outcomes.

Rationale for Switching to VRD

• VRD is likely to offer the best risk-benefit profile among triplet combinations for myeloma patients 1
• VRD produces higher very good partial response (VGPR), complete response (CR), and minimal residual disease (MRD) negativity rates compared to VCD 1
• In real-world analysis, VRD is associated with substantially higher overall response rates and CR/VGPR rates compared to VCD (p<0.001) 2
• The combination of bortezomib with lenalidomide (in VRD) shows synergistic activity compared to bortezomib with cyclophosphamide (in VCD) 1

Benefits for Patients with Proteinuria

• Bortezomib-based regimens are the preferred treatment option for myeloma patients with renal impairment 1
• VRD has shown higher rates of renal recovery (74%) compared to VCD (43%) in patients with renal impairment (p<0.001) 3
• Lenalidomide (in VRD) requires dose adjustment according to renal function but can still be effectively used with proper dosing 1
• Bortezomib-based therapy with lenalidomide has demonstrated promising results in monoclonal immunoglobulin deposition disease with an 86% decrease in median 24-hour proteinuria 4

Evidence for Improved Outcomes

• In matched real-world analysis, VRD showed improved progression-free survival (PFS) and overall survival (OS) in univariate analysis compared to VCD 2
• The benefit of VRD was especially notable among patients with standard-risk disease, those without severe renal dysfunction, and elderly patients 2
• Patients receiving VRD had better survival on univariate analysis, with a median PFS from transplantation of 44.6 months versus 34.1 months with VCD (p=0.004) 3
• Five-year OS was 79% with VRD versus 60% with VCD (p<0.001) in transplant-eligible patients 3

Response-Adapted Approach

• For patients with suboptimal response (minimal response/partial response) to initial therapy, switching treatment can improve outcomes 1
• In the Myeloma XI trial, 40% of patients upgraded their response when switching therapy after suboptimal initial response 1
• The impact of depth of response on outcome provides a strong rationale for choosing the most effective regimen when initial therapy shows inadequate response 1
• Post-treatment difference between involved and uninvolved serum-free light chains (dFLC) under 40 mg/l is a favorable prognostic factor for renal survival 4

Considerations for Implementation

• The standard VRD regimen may need dose adjustment based on the patient's renal function and overall condition 1
• For vulnerable patients, consider dose-attenuated regimens similar to "VCD-Lite" approach but with the VRD combination 5
• Monitor for potential side effects that differ between regimens - VRD may have less peripheral neuropathy than VCD with thalidomide but requires monitoring for other toxicities 1
• If transplant-eligible, VRD induction for 3-4 cycles followed by stem cell collection and autologous stem cell transplantation (ASCT) is recommended 1

Alternative Options

• If VRD is not feasible, consider adding daratumumab to VCD (DaraVCD) as monoclonal antibodies have shown significant improvements in outcomes 1, 6
• The CASTOR trial demonstrated that adding daratumumab to bortezomib-dexamethasone (DVd) improved PFS with HR=0.39 (95% CI: 0.28,0.53; p<0.0001) 6
• For patients with high-risk cytogenetics, carfilzomib-based regimens like KRD (Carfilzomib, Lenalidomide, Dexamethasone) could be considered 1
• In patients unable to tolerate lenalidomide, bortezomib-based therapy should still be continued but with optimized dosing to minimize toxicity 5

In conclusion, given the mild response to VCD and the presence of proteinuria, switching to VRD offers the best chance for improved disease control, better renal outcomes, and potentially longer survival. The evidence strongly supports this change in therapeutic approach.