What is the recommended management approach for multiple myeloma?

Management of Multiple Myeloma

The management of multiple myeloma requires immediate risk stratification followed by a three-phase treatment approach (induction, consolidation, maintenance) that differs fundamentally based on transplant eligibility, with bortezomib-lenalidomide-dexamethasone (VRd) as the preferred induction regimen for transplant-eligible patients and bortezomib-based combinations for transplant-ineligible patients. 1, 2

Initial Risk Stratification (Mandatory Before Treatment)

All patients must undergo cytogenetic risk assessment using FISH to guide treatment intensity 1:

Standard-risk features:

• Hyperdiploidy, t(11;14), t(6;14)
• ISS stage I-II 1, 3

High-risk features requiring intensified therapy:

• t(4;14), t(14;16), t(14;20), del(17p), 1q amplification/del(1p)
• ISS stage III
• High LDH levels
• Plasma cell labeling index >3%
• Extramedullary disease or plasma cell leukemia 1

Critical point: Bortezomib-based regimens can overcome some high-risk features, particularly t(4;14) and del(17p), making proteasome inhibitor inclusion essential for these patients 1

Transplant-Eligible Patients (Age <65-70, No Major Comorbidities)

Induction Therapy (4-6 cycles maximum)

Preferred regimen: VRd (bortezomib/lenalidomide/dexamethasone) achieves 58% VGPR or better and 52% complete response rates 2, 4

Alternative regimens:

• VTd (bortezomib/thalidomide/dexamethasone): 94% response rate, 33% CR rate 1, 2
• VCD (bortezomib/cyclophosphamide/dexamethasone): 47% CR rate with modified dosing 1
• DVTd (daratumumab/bortezomib/thalidomide/dexamethasone): 29% sCR rate at day 100 post-transplant, superior to VTd alone 5

Critical limitation: Do not exceed 4-6 cycles of induction to preserve stem cell collection capacity 1

Administration modifications to reduce toxicity:

• Subcutaneous bortezomib significantly reduces peripheral neuropathy versus intravenous 2
• Weekly bortezomib dosing reduces neuropathy while maintaining efficacy 2

Consolidation: Autologous Stem Cell Transplantation

High-dose melphalan (200 mg/m²) with ASCT remains standard of care and provides superior progression-free survival (50 months vs 36 months without transplant, HR 0.65, p<0.001) 1, 6

Tandem (double) ASCT should be considered specifically for:

• Patients with high-risk cytogenetics (del 17p, t(4;14), t(14;16)) 4
• Patients not achieving excellent response after first ASCT 1

Maintenance Therapy

Lenalidomide maintenance is mandatory and continues until disease progression, providing:

• Extended progression-free survival (45 months vs 17.5 months without maintenance) 5
• 27% reduction in risk of death (HR 0.73, p=0.0044) 5
• Improved overall survival at 4 years 1, 2

For high-risk patients (del 17p, t(4;14), t(14;16), t(14;20)): Bortezomib-based maintenance is preferred over lenalidomide alone 2

Important caveat: Discuss the 7% risk of second primary malignancies with lenalidomide maintenance before initiating therapy 1

Transplant-Ineligible Patients (Age >70 or Significant Comorbidities)

Preferred Regimens

VMP (bortezomib/melphalan/prednisone): 24% CR rate, standard of care 1

MPT (melphalan/prednisone/thalidomide): 13% CR rate, alternative option 1

MPR (melphalan/prednisone/lenalidomide) with lenalidomide maintenance: Improves progression-free survival but overall survival data still maturing 1

DVMp (daratumumab/bortezomib/melphalan/prednisone): Recently approved, provides enhanced efficacy 5, 7

Lenalidomide-low-dose dexamethasone (Rd): Demonstrated statistically significant improvement in progression-free survival versus MPT in the MM-020/IFM 07-01 trial 1

Special Clinical Situations Requiring Immediate Action

Renal Failure from Myeloma

Start bortezomib-dexamethasone regimens immediately without dose adjustment, as bortezomib can be administered safely in severe renal impairment and dialysis 1, 3

Specific regimens with proven renal benefit:

• VMP: 40% renal improvement rate 1
• VCd (bortezomib/cyclophosphamide/dexamethasone): Preferred for acute renal failure from light-chain cast nephropathy 3

Avoid nephrotoxic drugs and maintain euvolemia 1

Plasmapheresis or high cut-off dialysis role remains unclear and should only be used within clinical trials 1

Symptomatic Bone Disease

Initiate bisphosphonates immediately for painful bone lesions and hypercalcemia 1

Consult orthopedic oncology for lesions at high risk of fracture 1

Local radiotherapy for prompt pain relief of localized bone lesions 1

Hypercalcemia

Manage with intravenous fluids and bisphosphonates 1

Essential Supportive Care (Non-Negotiable)

Thromboprophylaxis (Mandatory for All Patients on Immunomodulatory Drugs)

Standard-risk patients: Aspirin 3, 2

High-risk patients (prior thrombosis, immobility, concurrent erythropoietin, multiple myeloma therapy): Low-molecular weight heparin, warfarin, or direct thrombin inhibitors 3

Antimicrobial Prophylaxis

Herpes zoster prophylaxis: All patients on proteasome inhibitors 3

Pneumocystis jiroveci prophylaxis: Patients on high-dose dexamethasone 3

Levofloxacin: During first two cycles for all newly diagnosed patients 3

Common Pitfalls to Avoid

Do not use carfilzomib/lenalidomide/dexamethasone (KRd) instead of VRd for standard/intermediate-risk patients: The ENDURANCE trial demonstrated no progression-free survival benefit (34.6 months vs 34.4 months, HR 1.04, p=0.74) with significantly more toxicity including 2% treatment-related deaths versus <1% with VRd 8

Do not delay stem cell collection beyond 4-6 cycles in transplant-eligible patients, particularly those receiving lenalidomide-based regimens 1

Do not omit risk stratification: High-risk patients require bortezomib-containing regimens to overcome adverse cytogenetics 1

Monitor carfilzomib patients closely for cardiac, renal, and pulmonary toxicities 2

Do not use thalidomide maintenance long-term: 60% discontinuation rate due to peripheral neuropathy and quality of life impairment 1