Treatment of Multiple Myeloma
For newly diagnosed multiple myeloma, the triplet regimen of bortezomib, lenalidomide, and dexamethasone (VRd) is the standard of care for both transplant-eligible and transplant-ineligible patients, with treatment approach determined by transplant candidacy, age, and cytogenetic risk stratification. 1, 2, 3
Initial Assessment and Risk Stratification
Before initiating treatment, all patients require comprehensive staging including: 1
- Bone marrow examination with FISH for cytogenetic abnormalities to identify high-risk features including del(17p), t(4;14), t(14;16), t(14;20), and gain 1q 1, 4
- Serum and urine protein electrophoresis with immunofixation 1
- Whole-body low-dose CT scan (preferred over conventional skeletal survey) 1
- Frailty assessment in elderly patients to guide dosing modifications 2
Treatment should be initiated only in patients with symptomatic myeloma meeting CRAB criteria (hypercalcemia >11.0 mg/dl, renal insufficiency with creatinine >2.0 mg/dl, anemia with hemoglobin <10 g/dl, or active bone lesions). 5, 3 Asymptomatic or smoldering myeloma does not require immediate treatment. 5
Transplant-Eligible Patients (Age <65 Years or Fit Patients)
Induction Therapy
Administer VRd for 3-4 cycles prior to autologous stem cell transplantation (ASCT): 1, 3, 6
- Bortezomib 1.3 mg/m² subcutaneously on days 1,4,8, and 11 5
- Lenalidomide 25 mg orally on days 1-21 of each 28-day cycle 2
- Dexamethasone 20 mg orally on days 1,2,4,5,8,9,11, and 12 5
For high-risk cytogenetics (del(17p), t(4;14), t(14;16), t(14;20), gain 1q), consider adding daratumumab to VRd (Dara-VRd) as an alternative induction regimen. 4, 6 Alternative triplet regimens include VTD (bortezomib, thalidomide, dexamethasone), VCD (bortezomib, cyclophosphamide, dexamethasone), or PAD (bortezomib, doxorubicin, dexamethasone). 5, 3
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 The overall response rate after VRd induction followed by transplantation reaches 98.5%, with 89.9% achieving very good partial response or better. 7
Maintenance Therapy
Standard-risk patients should receive lenalidomide maintenance until disease progression. 1, 3, 6 High-risk patients require bortezomib-based maintenance (bortezomib plus lenalidomide). 1, 6 This risk-adapted maintenance approach delivers median progression-free survival of 76.5 months for standard-risk patients and 40.3 months for high-risk patients. 7
Transplant-Ineligible Patients (Elderly or Unfit Patients)
Primary Treatment Regimen
Administer VRd for 8-12 cycles followed by lenalidomide maintenance until progression: 1, 2, 6
- Bortezomib 1.3 mg/m² subcutaneously on days 1,8, and 15 of each 28-day cycle 2
- Lenalidomide 25 mg orally on days 1-21, continued until progression 2
- Dexamethasone dosing requires age-based modification 2
An alternative regimen is daratumumab, lenalidomide, and dexamethasone (DRd) until progression. 4, 6
Critical Dosing Modifications for Elderly Patients
Reduce dexamethasone to 20 mg once weekly for patients over 75 years, as standard dosing (40 mg weekly) significantly increases toxicity and mortality. 2 For frail patients, start dexamethasone at 8-20 mg weekly with subsequent titration based on response and tolerability. 2
The ENDURANCE trial demonstrated that carfilzomib-based regimens (KRd) do not improve progression-free survival compared to VRd (median 34.6 vs 34.4 months, HR 1.04, p=0.74) and cause more toxicity, including higher rates of treatment-related deaths (2% vs <1%). 8 Therefore, VRd remains the standard of care for transplant-ineligible patients. 8
European Alternative Regimens
In Europe, melphalan/prednisone/thalidomide (MPT) or bortezomib/melphalan/prednisone (VMP) are approved alternatives. 5 However, avoid melphalan-containing regimens in potentially transplant-eligible patients as they are stem cell toxic. 2 Bendamustine plus prednisone is reserved for patients with clinical neuropathy precluding thalidomide or bortezomib use. 5
Essential Supportive Care Measures
Mandatory herpes zoster prophylaxis with acyclovir is required for all patients receiving bortezomib or proteasome inhibitors. 1, 2
Thromboprophylaxis with full-dose aspirin (or therapeutic anticoagulation for high-risk patients) is required when using lenalidomide-based regimens due to increased risk of deep vein thrombosis. 5, 2
Subcutaneous bortezomib administration is strongly preferred over intravenous to reduce peripheral neuropathy risk. 1 If peripheral neuropathy develops, dose reduction or switching to alternative agents is necessary. 2
Long-term bisphosphonates (oral or IV) should be administered to reduce skeletal-related events. 5, 3
Relapsed/Refractory Disease
At first relapse, triplet therapy should be administered, with regimen selection based on prior treatment response, time to relapse, and cytogenetic risk. 1, 3
For patients previously treated with lenalidomide, pomalidomide, bortezomib, and dexamethasone significantly improves progression-free survival compared to bortezomib and dexamethasone alone (median 11.20 vs 7.10 months, HR 0.61, p<0.0001). 9 Preferred regimens for first relapse include daratumumab-based combinations and carfilzomib/lenalidomide/dexamethasone. 1
Bortezomib retreatment is effective in patients who previously responded, achieving an overall response rate of 38.5% with median duration of response of 6.5 months. 10 Patients must be at least 6 months from prior bortezomib therapy and have no grade ≥2 peripheral neuropathy. 10
Response Assessment and Monitoring
Assess response after every 2 cycles using serum and urine protein electrophoresis with immunofixation and free light chains. 2, 3 Once best response is achieved or during maintenance therapy, assessment frequency can decrease to every 3 months minimum. 1 Complete response requires <5% plasma cells in bone marrow and negative immunofixation. 5, 3
Common Pitfalls to Avoid
- Never use standard dexamethasone dosing (40 mg weekly) in patients over 75 years due to significantly increased toxicity and mortality 2
- Avoid melphalan-containing regimens in potentially transplant-eligible patients as they damage stem cells 2
- Do not treat asymptomatic/smoldering myeloma as immediate treatment provides no benefit 5
- Always provide herpes zoster prophylaxis with proteasome inhibitors to prevent reactivation 1, 2
- Monitor closely for peripheral neuropathy with bortezomib and switch to subcutaneous administration 1, 2