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

Initial Treatment for Multiple Myeloma

For newly diagnosed multiple myeloma, initiate treatment with the triplet regimen bortezomib, lenalidomide, and dexamethasone (VRd), which is the standard of care for both transplant-eligible and transplant-ineligible patients. 1, 2, 3

Treatment Algorithm by Transplant Eligibility

Transplant-Eligible Patients

Induction Phase:

• Administer 4-6 cycles of VRd (bortezomib 1.3 mg/m² subcutaneously on days 1,4,8,11; lenalidomide 25 mg orally days 1-14; dexamethasone 20 mg orally on days 1,2,4,5,8,9,11,12 in 21-day cycles) 1, 3, 4
• Bortezomib should be given subcutaneously rather than intravenously to significantly reduce peripheral neuropathy risk 5
• Collect peripheral blood stem cells after induction (preferred over bone marrow) 2, 3

Consolidation Phase:

• Proceed to high-dose melphalan 200 mg/m² with autologous stem cell transplantation (ASCT) 2, 3
• ASCT provides median progression-free survival of 50 months versus 36 months with delayed transplant 3

Maintenance Phase:

• Continue lenalidomide maintenance until disease progression 1, 2, 3
• For standard-risk patients, lenalidomide maintenance provides median progression-free survival of 41 months 2, 3
• For high-risk patients (del 17p, t(14;16), t(14;20)), bortezomib-based maintenance is preferred over lenalidomide alone 2, 3

Transplant-Ineligible Patients

Initial Treatment:

• VRd triplet therapy remains the preferred regimen 1, 2
• Alternative option: Daratumumab plus bortezomib plus melphalan plus prednisone (D-VMP) 1
• Continuous therapy should be offered over fixed-duration therapy when initiating immunomodulatory drug or proteasome inhibitor-based regimens 1

Dosing Adjustments:

• Initial dosing must be individualized based on age, renal function, comorbidities, functional status, and frailty status 1, 2
• For patients >75 years with standard-risk disease, lenalidomide-dexamethasone with lenalidomide maintenance (Rd-R) may be better tolerated than VMP 6

Risk-Stratified Approach

Risk Assessment Required:

• All patients must undergo cytogenetic testing by FISH to identify high-risk features: del(17p), t(4;14), t(14;16), t(14;20) 1, 2
• High-risk patients comprise 20% of cases with median overall survival of 3 years without optimal therapy 1
• Standard-risk patients comprise 60% of cases with median overall survival of 8-10 years 1

High-Risk Patients (del 17p, t(4;14), t(14;16), t(14;20)):

• Bortezomib-containing regimens are mandatory as bortezomib overcomes adverse prognostic effects of high-risk cytogenetics, particularly t(4;14) 1, 2
• VRd induction followed by ASCT (if eligible) and bortezomib-based maintenance therapy 1, 2
• High-risk patients benefit most from achieving complete response, so therapy should be intensified to achieve this goal 1
• VMP improved progression-free survival and overall survival in high-risk patients irrespective of age compared to lenalidomide-dexamethasone 6

Standard-Risk Patients:

• VRd induction followed by ASCT (if eligible) and lenalidomide maintenance 1, 2
• VMP and Rd-R are equally effective in younger (≤75 years) standard-risk patients 6

Important Note on t(11;14):

• t(11;14) is classified as standard-risk, NOT high-risk cytogenetics 5
• Standard VRd induction is appropriate for t(11;14) patients 5
• Venetoclax-based regimens are reserved for relapsed/refractory disease, not initial treatment 5

Essential Supportive Care Measures

Mandatory for All Patients:

• Thromboprophylaxis: Full-dose aspirin or therapeutic anticoagulation for all patients receiving immunomodulatory drugs (lenalidomide) 2, 3, 5
• Herpes zoster prophylaxis: Acyclovir or valacyclovir for all patients on proteasome inhibitors 3
• Bisphosphonates: Administer to reduce skeletal-related events 1, 2, 5
• Pneumocystis jiroveci prophylaxis: For patients receiving high-dose glucocorticosteroids 3

Renal Failure Management:

• Bortezomib-based regimens are preferred due to primarily non-renal clearance 1
• Avoid nephrotoxic drugs and maintain euvolemia 1
• Start induction therapy immediately in patients with renal failure from myeloma 1

Response Monitoring

Frequency:

• Assess response with each treatment cycle using serum and urine protein electrophoresis and serum free light chains 1, 2, 3, 5
• Once best response is attained or on maintenance therapy, assess at minimum every 3 months 1, 3

Imaging:

• Whole-body low-dose CT is superior to skeletal survey with plain x-rays and is the preferred method for baseline and routine bone surveillance 1, 2, 5
• PET/CT or MRI may be used as alternatives at baseline or in select situations 1

Complete Response Criteria:

• Requires <5% plasma cells in bone marrow and negative immunofixation 2, 3, 5

Critical Evidence Comparison

The ENDURANCE trial (2020) directly compared carfilzomib-lenalidomide-dexamethasone (KRd) to VRd in 1,087 newly diagnosed patients without immediate transplant intent 7. VRd demonstrated equivalent progression-free survival (34.4 vs 34.6 months) with significantly less toxicity, including lower rates of dyspnea (2% vs 7%), thromboembolic events (2% vs 5%), and treatment-related deaths (<1% vs 2%) 7. This high-quality randomized trial definitively establishes VRd as the standard triplet regimen over KRd.

Common Pitfalls to Avoid

• Do not use lenalidomide-based regimens alone in high-risk patients—bortezomib must be included to overcome adverse cytogenetics 1, 2
• Do not delay ASCT in transplant-eligible patients—early ASCT provides superior progression-free survival compared to delayed approach 3
• Do not use single or doublet therapy when triplet combinations are tolerated—triplet regimens consistently demonstrate superior outcomes 1, 3
• Do not administer bortezomib intravenously when subcutaneous route is available—subcutaneous administration significantly reduces peripheral neuropathy 5, 4
• Do not overlook thromboprophylaxis—all patients on lenalidomide require anticoagulation to prevent thromboembolic events 2, 3, 5