What is the current treatment for recurrent multiple myeloma?

Treatment for Recurrent Multiple Myeloma

For patients with recurrent multiple myeloma, triplet regimens containing a monoclonal antibody combined with an immunomodulatory drug and/or proteasome inhibitor are the preferred treatment approach, with daratumumab-based combinations showing superior outcomes for reducing mortality and improving quality of life. 1

Initial Approach to Recurrent Multiple Myeloma

All patients with recurrent multiple myeloma should undergo complete restaging and risk stratification to determine:

1. Nature of relapse (aggressive vs. indolent)
2. Disease risk category (standard, intermediate, or high-risk)
3. Patient's performance status and comorbidities
4. Previous treatments and response duration
5. FISH cytogenetic data from relapsed bone marrow 2

First Relapse Treatment Algorithm

For Lenalidomide-Naive or Lenalidomide-Sensitive Patients:

• First choice: Daratumumab-lenalidomide-dexamethasone (DRd)

  • Reduces risk of progression by 63% vs. Rd alone 3
  • Median PFS of 45.0 months vs. 17.5 months with Rd 3
  • Median OS of 67.6 months vs. 51.8 months with Rd 3

• Alternative options:

  • Carfilzomib-lenalidomide-dexamethasone (KRd)
  • Ixazomib-lenalidomide-dexamethasone (IRd) - especially for frail patients who benefit from all-oral regimen 2
  • Elotuzumab-lenalidomide-dexamethasone (ERd)

For Lenalidomide-Refractory Patients:

• First choice: Daratumumab-bortezomib-dexamethasone (DVd)

  • Doubles depth of response (VGPR or better: 59% vs. 29%) 3
  • Reduces risk of progression by 61% 3

• Alternative options:

  • Carfilzomib-pomalidomide-dexamethasone (KPd)
  • Daratumumab-pomalidomide-dexamethasone (DPd)
  • Bortezomib-cyclophosphamide-dexamethasone (VCd) 2

Second or Higher Relapse Treatment

Treatment selection should include at least two new drugs that the patient is not refractory to, preferably from different drug classes 2:

1. Quadruplet regimens (adding a monoclonal antibody to a triplet)
2. Selinexor-based regimens
3. Alkylator-based regimens (cyclophosphamide, bendamustine)
4. Panobinostat added to proteasome inhibitor regimens
5. Venetoclax for t(11;14) myeloma
6. Anthracycline-containing regimens 2

Special Considerations

Autologous Stem Cell Transplantation (ASCT)

• Consider salvage ASCT for fit patients with indolent relapse
• Second ASCT is beneficial if first ASCT provided response lasting ≥18 months without maintenance or ≥36 months with maintenance
• NRCI Myeloma X Relapse trial showed median time to progression of 19 months with second ASCT vs. 11 months with cyclophosphamide alone 2

Secondary Plasma Cell Leukemia or Extramedullary Disease

• Fit patients: VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide) followed by ASCT if possible
• Frail patients: Daratumumab or anthracycline-based regimen 2

Treatment Duration

• Most patients continue therapy until disease progression or significant toxicity
• Consider dose reduction of dexamethasone after maximal response to improve quality of life 2
• Consider treatment breaks for patients with indolent relapse who reach a plateau phase 2

Managing Common Toxicities

• Peripheral neuropathy: Switch from bortezomib to carfilzomib if neuropathy becomes significant 2
• Thrombosis risk with IMiDs: Provide thromboprophylaxis (aspirin for average risk; low-molecular-weight heparin or oral anticoagulants for high-risk) 2
• Herpes zoster risk: Consider antiviral prophylaxis, especially with bortezomib (6-11% reactivation rate) 4
• Infusion reactions with daratumumab: Most common with first dose, premedication recommended 3

Pitfalls to Avoid

1. Failing to perform complete restaging at relapse - disease biology may have changed
2. Not considering prior treatment response - previous response duration should guide retreatment decisions
3. Using single agents - combination therapy is superior for depth and duration of response
4. Overlooking salvage transplant - ASCT should be considered at relapse for eligible patients
5. Not adjusting therapy for frail patients - consider doublet regimens or dose modifications for significant comorbidities

The treatment landscape for recurrent multiple myeloma continues to evolve rapidly with new agents and combinations showing improved outcomes. Triplet regimens containing monoclonal antibodies have demonstrated superior efficacy and should be the standard approach when possible, with treatment selection guided by prior therapy exposure and response.