What are the treatment options for a patient experiencing multiple myeloma relapse?

Treatment Options for Multiple Myeloma Relapse

Triple combination therapy should be the standard approach for patients experiencing multiple myeloma relapse, as it provides superior outcomes compared to doublet regimens, with the specific regimen selection based on patient factors, disease characteristics, and prior treatment history. 1

Initial Assessment and Risk Stratification

• All patients should undergo full staging and risk stratification at relapse to determine whether they have aggressive vs indolent relapse and standard-, intermediate-, or high-risk relapsed multiple myeloma 1
• Evaluation should include:
  • FISH data on relapsed bone marrow to detect high-risk cytogenetic abnormalities (del(17p), t(4;14), t(14;16), t(14;20)) 1, 2
  • Assessment of prior treatment response duration and quality 1
  • Evaluation for extramedullary disease and new bone lesions 1
  • Review of previous adverse effects to guide therapy selection 1

First Relapse Treatment Algorithm

Patient and Disease Factors to Consider

• General state of health and frailty status of the patient 1
• Nature of relapse (indolent vs aggressive) 1
• Prior therapies used and response quality/duration 1
• Cytogenetic risk profile 1, 2

Treatment Recommendations

1. For Fit Patients with Indolent Relapse:

   • Consider salvage autologous stem cell transplantation (ASCT) if the patient had a meaningful response to first transplant (response lasting ≥18 months without maintenance or ≥36 months with maintenance) 1
   • The NRCI Myeloma X Relapse trial showed median time to progression of 19 months with second ASCT vs 11 months with cyclophosphamide 1

2. For All Relapsed Patients:

   • Triple combination therapy is preferred when patients can tolerate it 1
   • Options include:
     • Daratumumab-based regimens: DRd (daratumumab, lenalidomide, dexamethasone), DVd (daratumumab, bortezomib, dexamethasone), or DPd (daratumumab, pomalidomide, dexamethasone) 1, 3
     • Carfilzomib-based regimens: KRd (carfilzomib, lenalidomide, dexamethasone) or KPd (carfilzomib, pomalidomide, dexamethasone) 1, 4
     • Ixazomib-based regimens: IRd (ixazomib, lenalidomide, dexamethasone) 1
     • Elotuzumab-based regimens: ERd (elotuzumab, lenalidomide, dexamethasone) 1

3. For Patients with Significant Comorbidities:

   • Doublet therapy may be acceptable: Rd (lenalidomide, dexamethasone), Pd (pomalidomide, dexamethasone), Vd (bortezomib, dexamethasone), or Kd (carfilzomib, dexamethasone) 1

Treatment Selection Based on Prior Therapy Response

For Patients Refractory to Prior Therapies

• Single Refractory (IMiD or PI but not both):

  • If IMiD refractory: Use PI-based regimens (carfilzomib or bortezomib combinations) 1
  • If PI refractory: Use IMiD-based regimens (lenalidomide or pomalidomide combinations) 1

• Dual Refractory (Lenalidomide and Bortezomib/Ixazomib):

  • Pomalidomide-based regimens: KPd or DPd 1
  • Daratumumab-based regimens: DVd or DRd 1, 3

• Triple Refractory:

  • For bortezomib/ixazomib refractory: Daratumumab-based or carfilzomib-based regimens 1
  • For lenalidomide refractory: Alkylator-based or PI with panobinostat combinations 1

Duration of Therapy and Monitoring

• For indolent relapse: Consider treating until plateau is reached, then observe carefully 1
• For aggressive relapse: Continue therapy until progression or significant toxicity 1
• For high-risk disease: Attempt continuous treatment to keep disease burden low and reduce risk of additional mutations 1
• If toxicity develops, consider:
  • Dose adjustments before eliminating agents 1
  • Substituting with complementary drugs with lower toxicity risk (e.g., switching bortezomib to carfilzomib if neuropathy develops) 1
  • Reducing dexamethasone dose after maximal response to improve quality of life 1

Special Considerations

• For High-Risk Cytogenetics: Continuous therapy is recommended as progression-free survival is generally shorter, and keeping disease burden low may reduce risk of additional mutations 1
• For Early Relapse (within first year): Consider as high-risk disease regardless of cytogenetic profile 1
• For Extramedullary Disease: More aggressive approach with combination therapies is needed 1, 5

Pitfalls to Avoid

• Failing to reassess cytogenetic risk at relapse, as disease may evolve to higher risk 1
• Underestimating the importance of triple therapy for optimal outcomes in fit patients 1
• Not considering salvage ASCT in eligible patients with good prior transplant response 1
• Overlooking the need for thromboprophylaxis in patients receiving immunomodulatory drugs 4, 3