What are the treatment options for relapsed or refractory multiple myeloma (MM)?

Treatment Options for Relapsed or Refractory Multiple Myeloma

For patients with relapsed or refractory multiple myeloma (MM), triplet or quadruplet regimens containing novel agents such as proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies are the preferred treatment options, with specific regimen selection based on prior therapy exposure and refractoriness patterns.

First-Line Treatment Options for Relapsed/Refractory MM

Preferred Regimens Based on Prior Therapy Exposure

For Lenalidomide-Refractory Patients:

• Daratumumab/Pomalidomide/Dexamethasone (DPd)

  • Demonstrated favorable overall survival of 56.7 months in lenalidomide-refractory patients 1
  • Well-tolerated with manageable adverse events profile
  • Category 1 recommendation for patients who have received at least 2 prior therapies

• Daratumumab/Bortezomib/Dexamethasone (DVd)

  • Recommended by NCCN for lenalidomide-refractory disease 2
  • Higher response rates compared to bortezomib/dexamethasone alone

• Carfilzomib/Pomalidomide/Dexamethasone (KPd)

  • Effective option for lenalidomide-refractory patients 3
  • Carfilzomib FDA-approved for relapsed/refractory MM in combination with dexamethasone 4

For Bortezomib-Refractory Patients:

• Daratumumab/Lenalidomide/Dexamethasone (DRd)

  • Category 1, preferred option after 2 prior therapies 2
  • Demonstrated improved PFS (45.0 vs 17.5 months) and OS (67.6 vs 51.8 months) compared to Rd alone 5

• Carfilzomib/Lenalidomide/Dexamethasone (KRd)

  • Effective for bortezomib-refractory disease 3
  • Carfilzomib FDA-approved in combination with lenalidomide and dexamethasone 4

Additional Treatment Options

Immunomodulatory-Based Regimens

• Pomalidomide/Dexamethasone

  • Effective in lenalidomide-refractory patients with median PFS of 12.2 months 6
  • Option for patients who have exhausted lenalidomide benefits

• Lenalidomide/Dexamethasone

  • Higher response rates (~50%) compared to thalidomide alone 2
  • Consider for patients who are lenalidomide-naïve or sensitive

• Lenalidomide Monotherapy

  • Option for steroid-intolerant individuals 2
  • Partial response or better in 26% of heavily pretreated patients 7

Proteasome Inhibitor-Based Regimens

• Carfilzomib/Dexamethasone

  • Superior to bortezomib/dexamethasone with median PFS of 18.7 vs 9.4 months 2
  • FDA-approved for relapsed/refractory MM 4

• Bortezomib/Lenalidomide/Dexamethasone

  • Effective in heavily pretreated patients, including those with prior lenalidomide or bortezomib exposure 2
  • Median PFS of 9.5 months and median OS of 26 months 2

Other Combination Regimens

• Bendamustine-Based Combinations

  • Bendamustine/Carfilzomib/Dexamethasone: 52% PR or better, median PFS 11.6 months 2
  • Bendamustine/Lenalidomide/Dexamethasone: 52% PR, median PFS 6.1 months 2
  • Bendamustine monotherapy: 55% overall response rate, median PFS of 26 weeks 2

• Cyclophosphamide-Based Regimens

  • Cyclophosphamide/Dexamethasone with either lenalidomide or bortezomib 2
  • High-dose or fractionated cyclophosphamide for immediate disease control 2

Treatment for Heavily Pretreated Patients (≥4 prior therapies)

• Selinexor/Dexamethasone

  • For patients who have received at least 4 prior therapies and are refractory to at least 2 PIs, 2 immunomodulatory agents, and an anti-CD38 antibody 2
  • PR or better in 26% of patients 2

• Belantamab Mafodotin-blmf

  • BCMA-targeted antibody-drug conjugate
  • Option for patients after 4 prior therapies including a PI, an IMiD, and an anti-CD38 monoclonal antibody 2

Treatment Selection Algorithm

1. Assess prior therapy exposure and refractoriness pattern:

   • Determine if patient is refractory to lenalidomide, bortezomib, or both
   • Review number of prior lines of therapy

2. For first relapse (1-2 prior therapies):

   • If lenalidomide-refractory: DVd or KPd
   • If bortezomib-refractory: DRd or KRd
   • If neither: Choose based on toxicity profile and patient comorbidities

3. For later relapses (≥3 prior therapies):

   • If lenalidomide-refractory: DPd
   • If double-refractory: Consider carfilzomib-based, pomalidomide-based, or daratumumab-based triplets
   • If quadruple-refractory: Consider selinexor/dexamethasone or belantamab mafodotin

Common Pitfalls to Avoid

1. Underutilizing triplet regimens: Triplet regimens are generally more effective than doublets in relapsed/refractory setting.

2. Ignoring prior drug exposure: Treatment selection should be based on prior therapy exposure and refractoriness patterns.

3. Inadequate supportive care: Ensure appropriate thromboprophylaxis for immunomodulatory drugs and herpes zoster prophylaxis for proteasome inhibitors.

4. Overlooking dose adjustments: Adjust doses for elderly patients, renal impairment, and cytopenias.

5. Premature discontinuation: Continue treatment until disease progression when possible, as continuous therapy is generally superior to fixed-duration therapy.