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, perform 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 Initiation Criteria

Treatment should be initiated in all patients with active myeloma fulfilling 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 of each 21-day cycle 5, 2
• Lenalidomide 25 mg orally on days 1-14 5, 2
• Dexamethasone 20 mg orally on days 1,2,4,5,8,9,11,12 5

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

Autologous Stem Cell Transplantation

• High-dose melphalan 200 mg/m² IV is the standard preparative regimen before ASCT 5, 3
• Peripheral blood progenitor cells should be used rather than bone marrow 5
• After ASCT, overall response rates reach 98.5% with 89.9% achieving very good partial response or better 6

Maintenance Therapy

• Standard-risk patients: Lenalidomide maintenance continued until disease progression 1, 3
• High-risk patients: Bortezomib plus lenalidomide maintenance 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 for cycles 1-8, then days 1,8 for cycles 9-12 2, 7
• Lenalidomide 25 mg orally on days 1-21 of each 28-day cycle 2, 7
• Dexamethasone dosing requires age-based modification (see below) 2

Critical Age-Based Dexamethasone Modifications

This is a critical safety consideration that directly impacts mortality: 2

• Patients >75 years: Reduce dexamethasone to 20 mg once weekly (standard dosing increases toxicity and mortality) 2
• Frail patients: Start dexamethasone at 8-20 mg weekly with subsequent titration based on tolerability 2
• Never use standard dexamethasone dosing (40 mg weekly) in patients over 75 years 2

Alternative Regimens for Elderly Patients

If VRd is not tolerated: 5

• Melphalan/prednisone/thalidomide (MPT) or bortezomib/melphalan/prednisone (VMP) are approved alternatives 5
• Bendamustine plus prednisone for patients with baseline neuropathy precluding bortezomib or thalidomide 5
• Avoid melphalan-containing regimens in potentially transplant-eligible patients due to stem cell toxicity 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 for 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 IV administration for patients with pre-existing or high-risk peripheral neuropathy 1

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 bortezomib therapy 2
• Once best response is attained or on maintenance therapy, assessment may be less frequent but at minimum every 3 months 1

Treatment of Relapsed Disease

At first relapse, triplet therapy should be administered: 1, 3

• Preferred regimens include daratumumab-based combinations and carfilzomib/lenalidomide/dexamethasone 1
• Treatment selection should consider prior therapy response, time to relapse, cytogenetic risk, and patient tolerance 1
• Bortezomib and lenalidomide are equally effective at first relapse in terms of progression-free survival and overall survival 8
• For patients refractory to anti-CD38 therapy (daratumumab), consider alternative mechanisms of action such as carfilzomib-based or pomalidomide-based regimens 2

Evidence Quality and Comparative Effectiveness

The VRd regimen has demonstrated exceptional long-term outcomes with median progression-free survival of 65 months and median overall survival of 126.6 months in the largest cohort reported to date. 6 A head-to-head comparison showed that carfilzomib-based regimens (KRd) did not improve progression-free survival compared to VRd (34.6 vs 34.4 months, HR 1.04, p=0.74) and had more toxicity including higher rates of treatment-related deaths (2% vs <1%). 7 This definitively establishes VRd as the standard of care for induction therapy in standard-risk and intermediate-risk newly diagnosed multiple myeloma. 7

Common Pitfalls to Avoid

• Never use melphalan-containing regimens in potentially transplant-eligible patients as they cause stem cell toxicity 2
• Never use standard-dose dexamethasone (40 mg weekly) in elderly patients over 75 years due to significantly increased mortality 2
• Never omit herpes zoster prophylaxis in patients receiving proteasome inhibitors 1, 2
• Never omit thromboprophylaxis in patients on immunomodulatory drug-based therapy 1, 2