What is the latest treatment for multiple myeloma?

Latest Treatment for Multiple Myeloma

The current standard of care for newly diagnosed multiple myeloma is induction therapy with bortezomib, lenalidomide, and dexamethasone (VRd), followed by autologous stem cell transplantation in eligible patients, with continuous lenalidomide maintenance until progression. 1

Frontline Treatment for Transplant-Eligible Patients

For medically fit patients, the treatment algorithm begins with 3-4 cycles of triplet induction therapy, followed by stem cell harvest, high-dose melphalan (200 mg/m²) with ASCT, and continuous lenalidomide maintenance. 2, 1

Induction Regimens

• VRd (bortezomib-lenalidomide-dexamethasone) is the preferred triplet regimen based on superior efficacy and tolerability 1
• Alternative options include bortezomib-cyclophosphamide-dexamethasone (VCD) or bortezomib-thalidomide-dexamethasone (VTD) 2
• Subcutaneous bortezomib is preferred over intravenous administration to prevent peripheral neuropathy 1

Maintenance Therapy

• Continuous lenalidomide maintenance until progression provides median progression-free survival of 41 months 1
• For high-risk cytogenetics (t(4;14), t(14;16), del(17p), gain 1q), bortezomib-based maintenance is preferred over lenalidomide alone as it partially overcomes adverse prognostic effects 1

Frontline Treatment for Transplant-Ineligible Patients

For elderly or medically unfit patients, VRd remains the preferred triplet regimen with dose modifications. 2, 1

Dose Adjustments

• Dexamethasone should be reduced to 20 mg weekly for patients >75 years 2, 1
• Further reduction to 8-20 mg weekly for frail patients 2
• Lenalidomide dose reduction based on creatinine clearance for renal impairment 1

Alternative Regimens

• Bortezomib-melphalan-prednisone (VMP) or melphalan-prednisone-thalidomide (MPT) are acceptable alternatives 2
• Continuous therapy is superior to fixed-duration therapy for both progression-free survival and overall survival 1

Treatment of First Relapse

For first relapse, triplet therapy with a monoclonal antibody-based regimen is preferred, with daratumumab-lenalidomide-dexamethasone (DRd) being the optimal choice. 1, 3

Daratumumab-Based Regimens

• DRd demonstrated median PFS of 61.9 months versus 34.4 months with Rd alone (44% reduction in risk of disease progression) 4
• DRd achieved 92.9% overall response rate with 47.6% complete response or better 4
• 32% reduction in risk of death compared to lenalidomide-dexamethasone alone 4
• Alternative daratumumab combinations include DVd (daratumumab-bortezomib-dexamethasone) 2, 3

Treatment Selection Based on Prior Therapy

• For lenalidomide-refractory patients, use proteasome inhibitor-based regimens (carfilzomib or bortezomib) plus daratumumab and dexamethasone 1, 3
• For proteasome inhibitor-refractory patients, use IMiD-based regimens 3
• For dual-refractory patients, pomalidomide-based regimens (DPd or KPd) are recommended 2, 3

Salvage Transplantation

• Consider second ASCT in fit patients with indolent relapse who had meaningful response to first transplant (median time to progression 19 months versus 11 months with cyclophosphamide) 3

Treatment of Second or Subsequent Relapse

For heavily pretreated patients, treatment selection depends on refractoriness pattern and prior exposures. 2, 3

Triple-Refractory Disease

• For triple-class refractory myeloma (refractory to IMiD, PI, and monoclonal antibody), newer agents include selinexor, venetoclax for t(11;14), or bispecific antibodies 2, 5, 6
• Bispecific T-cell engagers include teclistamab-cqyv (BCMA/CD3), elranatamab-bcmm (BCMA/CD3), and talquetamab-tgvs (GPRC5D/CD3) 7

Novel Immunotherapies

CAR-T cell therapy and bispecific antibodies represent major advances for heavily pretreated patients, though challenges remain with cost, availability, and toxicity. 5, 8, 6

• These therapies are reserved for patients who have exhausted standard options 5, 6
• Bispecific antibodies offer off-the-shelf availability compared to CAR-T cells 6

Critical Supportive Care Measures

All patients on immunomodulatory drugs require thromboprophylaxis, herpes zoster prophylaxis, and bisphosphonates. 1

Monitoring Requirements

• Response monitoring with each treatment cycle using serum and urine protein electrophoresis and serum free light chains 1
• MRD assessment by next-generation flow cytometry or sequencing is recommended for patients in complete remission 2
• Bone marrow studies with FISH at relapse to detect high-risk cytogenetic abnormalities 3

Common Pitfalls to Avoid

• Do not modify therapy based on MRD results outside of clinical trials, except for young patients with high-risk or double/triple-hit myeloma 2
• Ensure adequate thromboprophylaxis when combining IMiDs with dexamethasone or chemotherapy 1
• Monitor for peripheral neuropathy with proteasome inhibitors and adjust route/dose accordingly 1

Risk-Adapted Strategies

High-risk cytogenetics (t(4;14), t(14;16), t(14;20), del(17p), gain 1q, p53 mutation) require more intensive and continuous therapy. 2, 1, 3

• Bortezomib-based therapy partially mitigates poor prognosis in high-risk disease 1
• Continuous treatment is essential as progression-free survival is shorter in high-risk patients 3
• Early relapse should be considered high-risk regardless of cytogenetic profile 3