What is the initial treatment approach for a newly diagnosed multiple myeloma patient with good performance status?

Initial Treatment of Newly Diagnosed Multiple Myeloma in Good Performance Status Patients

For newly diagnosed multiple myeloma patients with good performance status who are transplant-eligible, VRd (bortezomib, lenalidomide, dexamethasone) for 3-4 cycles followed by autologous stem cell transplantation and lenalidomide maintenance is the standard of care. 1, 2

Risk Stratification First

Before initiating treatment, perform cytogenetic risk assessment using FISH on bone marrow samples to determine treatment intensity 1, 2:

• Standard-risk features: hyperdiploidy, t(11;14), t(6;14) 2
• High-risk features: t(4;14), t(14;16), t(14;20), del(17p), 1q amplification/del(1p), ISS stage III, high LDH, plasma cell labeling index >3%, extramedullary disease 1, 2

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

Standard-Risk Disease

Induction therapy: VRd (bortezomib, lenalidomide, dexamethasone) for 3-4 cycles achieves 58% VGPR or better and 52% complete response rates 1, 2. This regimen demonstrated superior PFS and OS compared to lenalidomide plus dexamethasone alone in the SWOG randomized trial 1.

Treatment sequence 1:

1. VRd induction × 3-4 cycles
2. Stem cell harvest
3. High-dose melphalan (200 mg/m²) with autologous stem cell transplantation
4. Lenalidomide maintenance until progression

The IFM/DFCI 2009 phase III trial confirms improved response and PFS when transplant is used as part of initial therapy, with median PFS of 50 months versus 36 months without transplant (HR 0.65, p<0.001) 1, 2.

High-Risk Disease

For high-risk cytogenetics, especially double-hit or triple-hit myeloma, add daratumumab to VRd (Dara-VRd) 1. The randomized phase II trial showed Dara-VRd produces better and deeper responses compared to VRd alone 1.

Treatment sequence for high-risk 1, 2:

1. Dara-VRd induction × 4 cycles
2. Stem cell harvest
3. Autologous stem cell transplantation (consider tandem ASCT based on EMN02 trial data)
4. Bortezomib-based maintenance (not lenalidomide alone) until progression

The HOVON-65 trial demonstrated that bortezomib-based maintenance provides better outcomes for high-risk patients, as lenalidomide maintenance showed limited benefit in this subgroup 1.

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

Standard-Risk Disease

DRd (daratumumab, lenalidomide, dexamethasone) until progression is preferred for transplant-ineligible standard-risk patients 1. The MAIA trial (NCT02252172) demonstrated median PFS of 61.9 months with DRd versus 34.4 months with Rd alone (HR 0.56, p<0.0001), representing a 44% reduction in risk of disease progression or death 3. Overall survival showed 32% reduction in risk of death (HR 0.68, p=0.0013) 3.

Alternative regimen: VRd × 8-12 cycles followed by lenalidomide maintenance 1, 2.

High-Risk Disease

VRd × 8-12 cycles followed by bortezomib-based maintenance until progression 1, 2. High-risk transplant-ineligible patients require indefinite combination therapy due to shortened PFS when therapy is discontinued 1.

Special Clinical Situations

Renal Failure

Start bortezomib-based regimens immediately without dose adjustment 2, 4. VCd (bortezomib, cyclophosphamide, dexamethasone) is the preferred regimen for acute renal failure due to light-chain cast nephropathy 1, 4. Bortezomib can be administered safely in severe renal impairment and dialysis 2, 4.

Avoid or adjust: Lenalidomide and pomalidomide require dose modifications based on creatinine clearance using Cockroft-Gault formula 1.

Pre-existing Neuropathy

Use DRd instead of VRd to avoid bortezomib-related neuropathy 1. If bortezomib is necessary, administer subcutaneously and weekly (rather than twice weekly) to reduce neuropathy risk while maintaining efficacy 1.

Essential Supportive Care

Thromboprophylaxis is mandatory for all patients on immunomodulatory drugs 2, 4:

• Standard-risk patients: aspirin
• High-risk patients (prior thrombosis, immobility, concurrent erythropoietin): low-molecular weight heparin, warfarin, or direct thrombin inhibitors

Antimicrobial prophylaxis 2, 4:

• Herpes zoster prophylaxis for all patients on proteasome inhibitors
• Pneumocystis jiroveci prophylaxis for patients on high-dose dexamethasone
• Levofloxacin during first two cycles for all newly diagnosed patients

Bone protection: Initiate bisphosphonates immediately for painful bone lesions and hypercalcemia 2.

Critical Pitfalls to Avoid

Do not use carfilzomib-lenalidomide-dexamethasone (KRd) as initial therapy 1. The ECOG randomized trial showed no significant benefit over VRd in standard-risk patients, and KRd carries higher risk of serious cardiac, renal, and pulmonary toxicity 1.

Avoid prolonged induction (>4-6 cycles) in transplant-eligible patients as this may impair stem cell collection 4. After prolonged lenalidomide therapy, plerixafor may be needed for adequate stem cell mobilization 1.

Do not modify therapy based on MRD results outside of clinical trials except in young patients with high-risk MM, especially double or triple-hit disease 1. While MRD negativity correlates with improved PFS and OS, randomized trials have not shown that changing therapy to achieve MRD negativity improves outcomes 1.