What are the considerations for using Trintelix (lenalidomide) as an add-on therapy in multiple myeloma treatment?

Lenalidomide (Trintelix) as an Add-On Therapy in Multiple Myeloma

Triplet therapy including lenalidomide is strongly recommended over doublet therapy for multiple myeloma patients at first relapse due to improved clinical outcomes, including progression-free survival and overall survival. 1

Role of Lenalidomide in Multiple Myeloma Treatment

Lenalidomide is an immunomodulatory drug (IMiD) with well-defined anti-inflammatory, immunomodulatory, anti-proliferative, and anti-angiogenic properties 2. It works through dual mechanisms:

1. Direct antitumor effects by inhibiting proliferation and inducing apoptosis of myeloma cells
2. Enhancement of immune system function by activating T cells and natural killer cells

Optimal Combinations with Lenalidomide

For First Relapse:

• Preferred approach: Triplet therapy containing two novel agents plus steroids 1
• Most effective triplets include lenalidomide combined with:
  • Proteasome inhibitors (bortezomib, carfilzomib, ixazomib) plus dexamethasone
  • Monoclonal antibodies (daratumumab, elotuzumab) plus dexamethasone

A network meta-analysis identified daratumumab-lenalidomide-dexamethasone as the most efficacious treatment option among 16 different regimens for relapsed multiple myeloma 1.

Considerations Based on Prior Therapy:

1. For patients relapsing >1 year after treatment:

   • May respond to repeat course of previous therapy 1

2. For patients relapsing during therapy or within 1 year:

   • If progressing on lenalidomide maintenance: Consider bortezomib with a monoclonal antibody
   • If bortezomib-refractory: Consider lenalidomide with a monoclonal antibody
   • If double-refractory: Consider pomalidomide combinations with monoclonal antibodies or cyclophosphamide 1

Dosing and Administration

• Standard dose: 25 mg once daily for 21 days of 28-day cycles 2
• Dose adjustments may be needed for:
  • Renal impairment
  • Cytopenias (most common adverse events)
  • Elderly or frail patients

Managing Adverse Events

The most common grade 3/4 adverse events with lenalidomide are:

1. Hematologic toxicity:

   • Neutropenia (60%)
   • Thrombocytopenia (39%)
   • Anemia (20%) 3

2. Non-hematologic toxicity:

   • Fatigue
   • Diarrhea (often due to bile acid malabsorption, treatable with bile acid sequestrants) 1

3. Thrombosis risk:

   • All patients should receive thromboprophylaxis
   • Aspirin for average-risk patients
   • Low-molecular-weight heparin or oral vitamin K antagonists for high-risk patients 1

Special Considerations

Infection Risk

• Routine antibiotic prophylaxis should be considered for the first three months of therapy, particularly for:
  • Patients with aggressive disease
  • History of infectious complications
  • Neutropenia 1

Cytogenetic Risk Status

• Lenalidomide may partly overcome adverse effects of del(17p) but has limited impact on t(4;14) 1
• For high-risk cytogenetics, consider combining lenalidomide with bortezomib 1

Renal Impairment

• Lenalidomide requires dose adjustment in renal impairment
• Consider thalidomide as an alternative in severe renal insufficiency 1

Lenalidomide Monotherapy vs. Combination Therapy

While lenalidomide monotherapy shows activity in relapsed/refractory multiple myeloma (26% partial response or better) 3, combination therapy with dexamethasone or other agents significantly improves outcomes:

• Lenalidomide + dexamethasone is superior to dexamethasone alone in terms of:

  • Time to progression
  • Response rate
  • Overall survival 4

• Adding a third agent (proteasome inhibitor or monoclonal antibody) further improves outcomes 1

Conclusion for Clinical Practice

When considering lenalidomide as add-on therapy in multiple myeloma:

1. First-line approach: Use lenalidomide as part of a triplet regimen with a proteasome inhibitor or monoclonal antibody plus dexamethasone
2. Consider patient factors: Prior therapies, cytogenetic risk, comorbidities, and toxicity profile
3. Monitor for: Hematologic toxicity, thrombosis risk, and infections
4. Continue treatment: Until disease progression or unacceptable toxicity

The addition of lenalidomide to existing regimens has significantly improved outcomes in multiple myeloma patients, making it a cornerstone of modern myeloma therapy.