What is the typical treatment regimen for multiple myeloma?

Treatment Regimens for Multiple Myeloma

The standard treatment regimen for multiple myeloma is based on transplant eligibility, with transplant-eligible patients receiving induction therapy with bortezomib, lenalidomide, and dexamethasone (VRd) followed by autologous stem cell transplantation (ASCT) and maintenance therapy, while transplant-ineligible patients receive similar combination therapies without transplantation. 1, 2

Initial Risk Stratification

• Risk stratification is essential using the International Staging System and cytogenetic analysis to identify high-risk features such as del(17p), t(4;14), t(14;16), t(14;20), or gain 1q 3
• Patients with two high-risk factors are considered to have double-hit myeloma, while those with three or more have triple-hit myeloma 1

Treatment Approach Based on Transplant Eligibility

Transplant-Eligible Patients (<65 years)

• Induction therapy: Bortezomib, lenalidomide, and dexamethasone (VRd) for 3-4 cycles 4, 2
• For high-risk patients, daratumumab, bortezomib, lenalidomide, dexamethasone (Dara-VRd) is an alternative to VRd 2
• Stem cell collection: Peripheral blood progenitor cells are preferred over bone marrow as the source of stem cells 4
• Conditioning regimen: High-dose melphalan (200 mg/m²) is the standard preparative regimen before ASCT 4, 5
• Maintenance therapy: Lenalidomide until progression for standard-risk patients; bortezomib-based maintenance for high-risk patients 4, 2

Transplant-Ineligible Patients (>65 years)

• Induction therapy: VRd for approximately 8-12 cycles followed by maintenance 2
• Alternative regimen: Daratumumab, lenalidomide, dexamethasone (DRd) until progression 2
• Bortezomib-melphalan-prednisone (VMP) is another effective option 4
• For frail elderly patients, doublet regimens such as lenalidomide-dexamethasone (Rd) may be considered 4

Continuous vs. Fixed-Duration Therapy

• Continuous therapy should be offered over fixed-duration therapy when initiating an immunomodulatory drug or proteasome inhibitor-based regimen 4
• Continuous lenalidomide-dexamethasone has shown improvement in progression-free survival and overall survival compared to fixed-duration regimens 4

Treatment of Relapsed/Refractory Disease

First Relapse

• If relapse occurs >6 months after stopping therapy, the initial treatment regimen can be reinstituted 4
• Preferred options for first relapse include 4:
  • Daratumumab-lenalidomide-dexamethasone (DRd)
  • Carfilzomib-lenalidomide-dexamethasone (KRd)
  • Ixazomib-lenalidomide-dexamethasone (IRd)
  • Elotuzumab-lenalidomide-dexamethasone (ERd)

For Lenalidomide-Refractory Patients

• Daratumumab-bortezomib-dexamethasone (DVd) 4, 6
• Carfilzomib-pomalidomide-dexamethasone (KPd) 4
• Daratumumab-pomalidomide-dexamethasone (DPd) 4

Second or Higher Relapse

• Consider regimens with at least 2 new drugs that the patient is not refractory to 4
• Options include quadruplet regimens, selinexor-based regimens, bendamustine-based regimens, or panobinostat added to proteasome inhibitor-containing regimen 4
• Venetoclax for t(11;14) myeloma 4

Response Assessment

• Evaluation of response is based on serum and urine electrophoresis 4
• In patients with no M-component in serum and urine, complete remission assessment requires bone marrow aspiration (<5% plasma cells) and immunofixation 4
• Evaluation of free light chains and/or their ratio may be helpful 4

Supportive Care

• Thromboprophylaxis is essential for patients on immunomodulatory drugs 4
• Bisphosphonates should be administered to reduce skeletal-related events 4
• Herpes zoster prophylaxis is recommended for patients treated with proteasome inhibitors 4

Common Pitfalls and Considerations

• Exposure to myelotoxic agents (including alkylating agents and nitrosoureas) should be limited to avoid compromising stem cell reserve prior to stem cell harvest in transplant candidates 4
• There appears to be an increased risk for secondary cancers, especially with lenalidomide maintenance following transplant 4
• Subcutaneous bortezomib is the preferred method of administration for patients with pre-existing or high-risk peripheral neuropathy 4, 7
• Triplet regimens should be used as the standard therapy; however, elderly or frail patients may be treated with doublet regimens 4

Efficacy of Standard Regimens

• VRd induction therapy followed by ASCT and maintenance has shown a median progression-free survival of 65 months for the entire cohort (40.3 months for high-risk patients and 76.5 months for standard-risk patients) 8
• The median overall survival with this approach is 126.6 months for the entire cohort 8
• A recent randomized trial showed that VRd remains the standard of care for induction therapy compared to KRd, which did not improve progression-free survival and had more toxicity 9