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

Multiple Myeloma Treatment

Initial Treatment for Transplant-Eligible Patients

Bortezomib, lenalidomide, and dexamethasone (VRd) followed by autologous stem cell transplantation (ASCT) and continuous lenalidomide maintenance until progression is the standard of care for transplant-eligible patients with newly diagnosed multiple myeloma. 1, 2, 3

Induction Therapy

• Administer VRd for 4-6 cycles consisting of bortezomib 1.3 mg/m² subcutaneously on days 1,4,8,11; lenalidomide 25 mg orally days 1-21; and dexamethasone 40 mg weekly in 28-day cycles 1, 3

• Use subcutaneous bortezomib preferentially over intravenous administration to reduce peripheral neuropathy risk 1, 2

• Limit exposure to alkylating agents (melphalan, cyclophosphamide) and nitrosoureas before stem cell harvest to preserve stem cell reserve 1

• Consider adding daratumumab to VRd (creating DVRd regimen) for higher-risk patients, though this increases toxicity and is not yet universally standard 4

Stem Cell Transplantation

• Perform ASCT with high-dose melphalan 200 mg/m² using peripheral blood progenitor cells as the preferred stem cell source 1, 2, 3

• ASCT provides median progression-free survival of 50 months versus 36 months with delayed transplant 3

Maintenance Therapy

• Continue lenalidomide maintenance continuously until progression (category 1 recommendation), which provides median progression-free survival of 41 months 1, 2

• For high-risk cytogenetics [t(4;14), t(14;16), del(17p), gain 1q], consider bortezomib-based maintenance over lenalidomide alone, as bortezomib partially overcomes adverse effects of these abnormalities 1, 2, 3

• Discuss secondary malignancy risk with patients, particularly increased risk with lenalidomide maintenance post-transplant 1

Initial Treatment for Transplant-Ineligible Patients

Triplet therapy with daratumumab-lenalidomide-dexamethasone (DRd) or bortezomib-lenalidomide-dexamethasone (VRd) should be administered continuously until progression for transplant-ineligible patients. 1, 2, 3

Preferred Regimens

• Daratumumab-lenalidomide-dexamethasone (DRd) provides median progression-free survival of 61.9 months and 32% reduction in death risk versus lenalidomide-dexamethasone alone 5

• Bortezomib-lenalidomide-dexamethasone (VRd) remains standard when daratumumab is unavailable or contraindicated 1, 2

• Daratumumab-bortezomib-melphalan-prednisone may be considered as alternative triplet regimen 1

Dose Modifications for Elderly/Frail Patients

• Reduce dexamethasone to 20 mg weekly for patients >75 years or body mass index <18.5 5

• Further reduce dexamethasone to 8-20 mg weekly for frail patients >75 years 2

• Consider doublet regimens (lenalidomide-dexamethasone or bortezomib-dexamethasone) only for patients unable to tolerate triplet therapy 1

Continuous Therapy

• Continue treatment until disease progression rather than fixed-duration therapy, as continuous therapy improves both progression-free survival and overall survival 1, 2

Treatment of First Relapse

Triplet therapy with daratumumab-lenalidomide-dexamethasone (DRd) is the preferred regimen for first relapse in lenalidomide-sensitive patients, providing median progression-free survival of 45.0 months. 1, 2, 3, 5

Lenalidomide-Sensitive Relapse (>6 months off lenalidomide)

• Daratumumab-lenalidomide-dexamethasone (DRd) provides 91.3% overall response rate and 63% reduction in progression risk versus lenalidomide-dexamethasone alone 1, 5

• Carfilzomib-lenalidomide-dexamethasone (KRd) is an alternative option 1, 3

• Elotuzumab-lenalidomide-dexamethasone (ERd) may be considered 1

Lenalidomide-Refractory Relapse

• Daratumumab-bortezomib-dexamethasone (DVd) is preferred for lenalidomide-refractory patients 1, 2, 3

• Daratumumab-pomalidomide-dexamethasone (DPd) for dual-refractory (lenalidomide and proteasome inhibitor) disease 1

• Carfilzomib-pomalidomide-dexamethasone (KPd) as alternative 1

Transplant Consideration at Relapse

• Offer ASCT to transplant-eligible patients who did not receive it after primary induction 1

• Consider repeat ASCT if progression-free survival after first transplant was ≥18 months 1

Treatment of Second or Subsequent Relapse

Treatment selection depends on prior therapies and refractoriness pattern, with preference for monoclonal antibody-based triplet regimens. 1

Single Refractory (IMiD or PI, not both)

• If lenalidomide-refractory only: Use daratumumab-bortezomib-dexamethasone (DVd) or daratumumab-lenalidomide-dexamethasone (DRd) 1

• If proteasome inhibitor-refractory only: Use daratumumab-lenalidomide-dexamethasone (DRd) or carfilzomib-based regimens 1

Dual Refractory (Lenalidomide and Bortezomib/Ixazomib)

• Pomalidomide-based regimens: Daratumumab-pomalidomide-dexamethasone (DPd) or carfilzomib-pomalidomide-dexamethasone (KPd) 1

Triple Refractory

• If bortezomib/ixazomib refractory: Daratumumab-pomalidomide-cyclophosphamide-dexamethasone (DPCd) or carfilzomib-lenalidomide-dexamethasone (KRd) 1

• If lenalidomide refractory: Alkylator-based regimens or proteasome inhibitor with panobinostat 1

• If daratumumab-refractory: Consider elotuzumab-based regimens 1

High-Risk Cytogenetics Management

Bortezomib-based regimens partially overcome poor prognosis associated with t(4;14), t(14;16), and del(17p), though these abnormalities retain some adverse influence. 1, 2, 3

• Perform fluorescence in situ hybridization (FISH) at diagnosis and at relapse for del(17p) and 1q abnormalities 1

• Use bortezomib-containing induction and maintenance for patients with t(4;14), t(14;16), or del(17p) 1, 2, 3

• High-risk patients with early relapse post-transplant should be treated immediately even with biochemical relapse only 1

• VRd followed by double ASCT may overcome t(4;14) adverse effects more effectively than single ASCT 1

Plasma Cell Leukemia or Extensive Extramedullary Disease

VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide) for 2 cycles followed by ASCT in eligible patients is the recommended approach for secondary plasma cell leukemia or extensive extramedullary disease. 1

• For ASCT-ineligible patients: Use daratumumab-based regimens, bendamustine-based therapy, alkylator-based regimens, or anthracycline-containing regimens 1

• These aggressive variants require immediate intensive therapy as they present difficult therapeutic challenges 1

Essential Supportive Care Measures

Thromboprophylaxis

• Administer full-dose aspirin for all patients receiving immunomodulatory drugs (lenalidomide, pomalidomide, thalidomide) 1, 2, 3

• Use therapeutic anticoagulation for patients at high risk for thrombosis 1

Infection Prophylaxis

• Herpes zoster prophylaxis with acyclovir or valacyclovir for all patients on proteasome inhibitors 1, 2, 3

• Pneumocystis jiroveci prophylaxis for patients receiving high-dose glucocorticosteroids 3

Bone Disease Management

• Administer bisphosphonates (oral or intravenous) to reduce skeletal-related events for patients with stage III or relapsed disease 1, 2, 6

Renal Impairment

• Bortezomib-based regimens are preferred for patients with renal failure, as neither thalidomide nor bortezomib requires dose adjustment 1

• Adjust lenalidomide dose based on creatinine clearance for patients with renal impairment 2

Response Monitoring

• Assess response with each treatment cycle using serum and urine protein electrophoresis and serum free light chains 2, 3

• Once best response achieved or on maintenance, assess at minimum every 3 months 3

• Complete response requires <5% plasma cells in bone marrow and negative immunofixation 3, 6

• Minimal residual disease (MRD) negativity at threshold of 10⁻⁵ correlates with prolonged progression-free and overall survival 6, 5

Critical Pitfalls to Avoid

• Do not use lenalidomide-based regimens in patients progressing on lenalidomide maintenance—switch to proteasome inhibitor with monoclonal antibody 3

• Do not delay restaging at relapse—evaluation for disease evolution to plasma cell leukemia or extramedullary disease is critical as treatment approach differs dramatically 1, 3

• Do not use single or doublet therapy when triplet combinations are tolerated—triplet regimens consistently demonstrate superior outcomes 1, 3

• Do not overlook high-risk cytogenetics—these patients require intensified therapy with bortezomib-based maintenance rather than lenalidomide alone 2, 3

• Do not use intravenous bortezomib when subcutaneous administration is available—subcutaneous route significantly reduces peripheral neuropathy risk 1, 2