What are the treatment guidelines for high-risk smoldering multiple myeloma, such as light chain IgA Kappa, using JNJ Daratumumab (daratumumab) and hyaluronidase?

Treatment Guidelines for High-Risk Smoldering Multiple Myeloma

For patients with high-risk smoldering multiple myeloma (HR-SMM), including IgA kappa light chain type, daratumumab-based therapy is now recommended over observation alone based on recent evidence showing significant reduction in progression to active multiple myeloma. 1

Risk Stratification for Smoldering Multiple Myeloma

High-risk SMM is defined by specific criteria that predict a higher likelihood of progression to active multiple myeloma:

• High-risk features include:
  • Serum monoclonal protein ≥3 g/dL for IgG or ≥2 g/dL for IgA
  • Urinary Bence Jones protein >1 g/24h
  • Abnormal serum free light chain ratio (≥100 involved kappa or ≤0.01 involved lambda)
  • Bone marrow plasma cell infiltration 10-60% with ≥95% phenotypically aberrant plasma cells

  • 1 focal lesion on MRI studies ≥5 mm

  • Cytogenetic abnormalities such as del(17p), t(4;14), t(14;16), t(14;20), and gain(1q)

Treatment Recommendations for High-Risk SMM

Daratumumab-Based Therapy

The AQUILA phase 3 trial demonstrated that subcutaneous daratumumab monotherapy significantly reduced the risk of progression to active multiple myeloma or death by 51% compared to active monitoring (HR 0.49; 95% CI, 0.36-0.67) with 5-year progression-free survival of 63.1% versus 40.8% with observation alone. Overall survival at 5 years was also improved (93.0% vs 86.9%) 1.

Recommended regimen:

• Subcutaneous daratumumab monotherapy for 36 months or until disease progression

Alternative Approaches

For patients unable to receive daratumumab:

• Lenalidomide plus dexamethasone has shown improved time to progression and overall survival compared to observation in high-risk SMM 2
• Clinical trial enrollment should be strongly considered 2

Monitoring During Treatment

• CBC, serum chemistry (creatinine, albumin, LDH, calcium, beta2 microglobulin)
• Serum quantitative immunoglobulins, SPEP, SIFE, and serum FLC assay
• 24-hour urine for total protein, UPEP, and UIFE
• Bone marrow aspiration and biopsy as clinically indicated
• Imaging studies with MRI and/or CT and/or PET/CT as clinically indicated
• Annual bone survey or as clinically indicated 2

Important Considerations and Pitfalls

1. Accurate diagnosis is critical: Ensure the patient truly has high-risk SMM and not active multiple myeloma requiring standard myeloma therapy. The 2014 updated criteria for multiple myeloma reclassified ultra-high risk SMM as active myeloma 2.

2. Risk assessment should be comprehensive: Multiparameter flow cytometry can help individualize the follow-up strategy by measuring abnormal cells in the bone marrow and providing information about progression risk 2.

3. Daratumumab administration considerations:

   • Subcutaneous administration is preferred over IV for patient convenience and reduced infusion reactions
   • Infusion-related reactions typically occur at first infusion and are generally grade 1/2 3
   • Consider herpes zoster prophylaxis during treatment

4. Monitoring for progression: Despite treatment, patients should be monitored regularly for progression to active multiple myeloma, which would require transition to standard myeloma therapy 2.

5. Treatment duration: The optimal duration of therapy remains under investigation, but current evidence supports treatment for up to 36 months 1.

The treatment landscape for high-risk SMM is rapidly evolving, with ongoing clinical trials evaluating various treatment approaches. While observation has traditionally been the standard approach, recent evidence strongly supports early intervention with daratumumab to delay progression to symptomatic disease and potentially improve overall survival.