What is the initial treatment for patients diagnosed with plasma cell dyscrasia, specifically multiple myeloma?

Initial Treatment for Plasma Cell Dyscrasia (Multiple Myeloma)

Transplant-Eligible Patients

For transplant-eligible patients with newly diagnosed multiple myeloma, bortezomib/lenalidomide/dexamethasone (VRd) is the preferred initial treatment regimen, administered for 4 cycles followed by autologous stem cell transplantation with high-dose melphalan (200 mg/m²). 1, 2

Induction Therapy Details

• VRd regimen achieves 79.3% VGPR or better response rates and 47.6% complete response rates 1
• The phase III SWOG S0777 trial demonstrated median PFS of 43 months with VRd versus 31 months with lenalidomide/dexamethasone alone, with median OS not reached versus 63 months respectively 1
• Bortezomib should be administered subcutaneously rather than intravenously to significantly reduce peripheral neuropathy risk 2
• Weekly bortezomib dosing (rather than twice-weekly) reduces neuropathy while maintaining efficacy 1, 2

Alternative Regimens for Transplant-Eligible Patients

• Cyclophosphamide/bortezomib/dexamethasone (CyBorD) is the preferred alternative, particularly for patients with acute renal insufficiency, with 88% ORR and 61% VGPR or better 1
• CyBorD can be switched to VRd after renal function improves 1
• Carfilzomib/lenalidomide/dexamethasone (KRd) showed similar PFS to VRd (34.6 vs 34.4 months) but with increased cardiac, pulmonary, and renal toxicities in the ENDURANCE trial 1, 3

Transplant-Ineligible Patients

For transplant-ineligible patients, daratumumab/lenalidomide/dexamethasone (DRd) is now the preferred first-line regimen based on the MAIA trial results. 4

DRd Regimen Evidence

• The MAIA trial demonstrated median PFS of 61.9 months with DRd versus 34.4 months with lenalidomide/dexamethasone alone (HR 0.56) 4
• Overall survival showed 32% reduction in risk of death (HR 0.68) 4
• Overall response rate was 92.9% with DRd versus 81.3% with Rd, with 47.6% achieving complete response or better 4
• Daratumumab is administered at 16 mg/kg intravenously 4

Alternative for Transplant-Ineligible Patients

• Bortezomib/melphalan/prednisone (VMP) remains an option, with median PFS of 18.3 months versus 14 months for melphalan/prednisone alone 5
• VRd can be used in transplant-ineligible patients, continued for 12-18 months 1, 6

Risk-Stratified Approach

High-Risk Disease

Patients with del(17p), t(4;14), t(14;16), t(14;20), or karyotypic deletion 13 require bortezomib-based therapy regardless of transplant eligibility. 2, 7, 6

• Bortezomib-based maintenance therapy is recommended over lenalidomide alone for high-risk patients 2
• High-risk patients should receive bortezomib-based triplet induction followed by ASCT and bortezomib-based maintenance 7, 6

Standard-Risk Disease

• Standard-risk patients (including t(11;14), t(6;14), hyperdiploidy) can receive VRd or DRd depending on transplant eligibility 8, 7, 6
• Lenalidomide maintenance should be continued until disease progression in transplant-eligible standard-risk patients 2

Primary Plasma Cell Leukemia (Aggressive Variant)

For primary plasma cell leukemia, the preferred approach is quadruplet therapy including anti-CD38 antibodies, immunomodulatory drugs, proteasome inhibitors, and dexamethasone for 4 cycles, followed by double autologous stem cell transplantation in fit patients ≤70 years. 1

• Treatment must be initiated immediately with short treatment-free intervals to prevent early deaths 1
• Extended consolidation/maintenance with triplets or quadruplets including anti-CD38 antibodies is recommended 1

Essential Supportive Care

• Thromboprophylaxis is mandatory for all patients receiving immunomodulatory drugs (lenalidomide, thalidomide): aspirin for standard-risk, low-molecular-weight heparin for high-risk patients 2, 8
• Herpes zoster prophylaxis is required for all patients on proteasome inhibitors 8
• Bisphosphonates should be administered to reduce skeletal events in stage III or relapsed disease 1
• Pneumocystis jiroveci prophylaxis for patients on dexamethasone 8

Critical Pitfalls to Avoid

• Do not use thalidomide-based regimens in patients with pre-existing neuropathy or POEMS syndrome due to high neurotoxicity risk 1, 9
• Avoid prolonged induction therapy (>4-6 cycles) in transplant-eligible patients as it may impair stem cell collection 8
• Do not delay treatment initiation in primary plasma cell leukemia—immediate multi-phase therapy is essential 1
• Carfilzomib requires careful monitoring for cardiac, renal, and pulmonary toxicities 1, 2