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

Treatment Regimen for Multiple Myeloma

For newly diagnosed multiple myeloma, the recommended treatment regimen is bortezomib, lenalidomide, and dexamethasone (VRd) for both transplant-eligible and transplant-ineligible patients, with treatment duration and maintenance strategies determined by transplant candidacy and risk stratification. 1, 2, 3

Initial Assessment Requirements

Before initiating therapy, all patients require comprehensive staging including: 1

• Bone marrow examination with FISH to identify high-risk cytogenetic abnormalities: del(17p), t(4;14), t(14;16), t(14;20), gain 1q, or p53 mutation 1, 4
• Serum and urine protein electrophoresis with immunofixation and free light chain analysis 1, 3
• Whole-body low-dose CT scan (preferred over conventional skeletal survey) 1
• Frailty assessment in elderly patients to guide dosing modifications 2

Treatment should only be initiated in patients meeting CRAB criteria: hypercalcemia (>11.5 mg/dl), renal insufficiency (creatinine >2 mg/dl), anemia (hemoglobin <10 g/dl), or active bone lesions. 5, 3

Transplant-Eligible Patients (Age <65 or Fit)

Induction Therapy

VRd triplet regimen for 3-4 cycles: 1, 3, 6

• Bortezomib 1.3 mg/m² subcutaneously on days 1,4,8,11 5, 7
• Lenalidomide 25 mg orally on days 1-21 of each 28-day cycle 1
• Dexamethasone 20 mg orally on specified days 5

For high-risk patients (presence of del(17p), t(4;14), t(14;16), t(14;20), gain 1q), consider adding daratumumab to VRd (Dara-VRd). 4

Alternative triplet regimens include VTD (bortezomib-thalidomide-dexamethasone), VCD (bortezomib-cyclophosphamide-dexamethasone), or PAD (bortezomib-doxorubicin-dexamethasone), though VRd remains preferred. 5, 3

Autologous Stem Cell Transplantation

• High-dose melphalan 200 mg/m² IV is the standard preparative regimen 5, 3
• Peripheral blood progenitor cells should be used rather than bone marrow 5
• Transplantation should occur after achieving optimal response to induction 1

Maintenance Therapy

• Lenalidomide maintenance should be continued until disease progression for standard-risk patients 1, 3
• Bortezomib plus lenalidomide maintenance is recommended for high-risk patients 1, 4

Transplant-Ineligible Patients (Elderly or Unfit)

Primary Treatment Regimen

VRd for 8-12 cycles followed by lenalidomide maintenance: 1, 2

• Bortezomib 1.3 mg/m² subcutaneously on days 1,8,15 of each 28-day cycle 2
• Lenalidomide 25 mg orally on days 1-21 2
• Dexamethasone dosing requires age-based modification (see below) 2

Alternative regimen: Daratumumab, lenalidomide, and dexamethasone (DRd) until progression 4

Critical Dosing Modifications for Elderly Patients

Dexamethasone dose reduction is mandatory in patients over 75 years: 2

• Reduce to 20 mg once weekly (not the standard 40 mg weekly) 2
• For frail patients, start at 8-20 mg weekly with subsequent titration based on tolerability 2
• Standard dexamethasone dosing (40 mg weekly) significantly increases toxicity and mortality in elderly patients 2

Historical Alternatives (No Longer Preferred)

Melphalan-based regimens (MPT: melphalan-prednisone-thalidomide or VMP: bortezomib-melphalan-prednisone) were previously standard but are now avoided due to stem cell toxicity and inferior outcomes compared to VRd. 5, 2

Essential Supportive Care Measures

Mandatory Prophylaxis

• Herpes zoster prophylaxis with acyclovir for all patients receiving bortezomib or proteasome inhibitors 1, 2
• Thromboprophylaxis with full-dose aspirin (or therapeutic anticoagulation in high-risk patients) when using lenalidomide-based regimens 1, 2
• Bisphosphonates (oral or IV) to reduce skeletal-related events 5, 3

Neuropathy Prevention

Subcutaneous bortezomib is strongly preferred over intravenous administration for patients with pre-existing peripheral neuropathy or high-risk factors. 1, 2

Response Assessment and Monitoring

• Assess response after every 2 cycles using serum protein electrophoresis, immunofixation, and free light chains 2
• Monitor for peripheral neuropathy closely with each bortezomib dose 2
• Once best response is achieved or on maintenance therapy, assessment frequency can decrease to every 3 months minimum 1

Treatment of Relapsed Disease

At first relapse, triplet therapy is required: 1, 3

• Preferred regimens include daratumumab-based combinations (daratumumab-lenalidomide-dexamethasone or daratumumab-bortezomib-dexamethasone) 1
• Carfilzomib-lenalidomide-dexamethasone (KRd) is an alternative, though the ENDURANCE trial showed no superiority over VRd in newly diagnosed patients 8
• Treatment selection should consider prior therapy exposure, time to relapse, and cytogenetic risk 1, 3

For patients previously exposed to anti-CD38 antibodies (daratumumab), consider alternative mechanisms of action such as carfilzomib-based or pomalidomide-based regimens. 2

Common Pitfalls to Avoid

• Never use melphalan-containing regimens (MPT, VMP) in potentially transplant-eligible patients due to stem cell toxicity 2
• Never use standard-dose dexamethasone (40 mg weekly) in patients over 75 years—this significantly increases mortality 2
• Never omit herpes zoster prophylaxis in patients receiving proteasome inhibitors—reactivation risk is substantial 1, 2
• Never skip thromboprophylaxis when using immunomodulatory drugs (lenalidomide, thalidomide)—venous thromboembolism risk is markedly elevated 5, 1, 2

Evidence Quality Note

The VRd regimen has the strongest evidence base with the longest follow-up data, demonstrating median progression-free survival of 65 months and 10-year overall survival rates of 58% in standard-risk patients. 6 The ENDURANCE trial definitively established that carfilzomib-based regimens (KRd) offer no progression-free survival advantage over VRd in standard-risk patients while causing more toxicity, including higher rates of cardiotoxicity and treatment-related deaths. 8