What are the management strategies for patients with multiple sclerosis (MS) who develop low Immunoglobulin M (IgM) levels while on Kesimpta (ofatumumab)?

Management of Low IgM Levels in MS Patients on Kesimpta (Ofatumumab)

For patients with multiple sclerosis who develop low IgM levels while on Kesimpta (ofatumumab), monitoring immunoglobulin levels regularly and considering immunoglobulin replacement therapy for those with recurrent infections is recommended, while maintaining Kesimpta treatment unless serious infections occur.

Monitoring Recommendations

• Regular monitoring of immunoglobulin levels is essential for MS patients on Kesimpta, with particular attention to both IgM and IgG levels 1, 2
• Monthly monitoring of immunoglobulin levels is recommended if immunoglobulin replacement therapy is initiated 1
• Baseline immunoglobulin levels should be obtained before starting Kesimpta treatment to establish reference values 3
• Low IgM levels alone without clinical manifestations do not necessarily require intervention, as there is no clear association between isolated IgM reduction and infection risk in ofatumumab-treated patients 4, 5

Clinical Significance of Low IgM

• Low IgM levels increase the risk of infections, particularly with encapsulated bacteria 1, 2
• The most common cause of discontinuation in patients treated with Kesimpta in clinical trials was low immunoglobulin M (3.3%), defined as IgM at 10% below the lower limit of normal 3
• Unlike IgG levels which tend to remain stable, IgM levels commonly decrease during Kesimpta treatment 5, 6
• In clinical studies, mean IgM levels decreased but remained above the lower limit of normal in most patients with up to 3.5 years of ofatumumab exposure 5

Management Strategies

When to Consider Immunoglobulin Replacement Therapy

• Consider immunoglobulin replacement therapy for patients who have experienced ≥2 severe recurrent infections by encapsulated bacteria, regardless of IgG level 1, 2
• Consider immunoglobulin replacement for patients with life-threatening infections 1
• Consider immunoglobulin replacement for patients with documented bacterial infection with no or insufficient response to antibiotic therapy 1
• Monthly IVIG treatment is recommended for the duration of immunoparesis until Ig levels recover to acceptable levels 1

Continuing or Discontinuing Kesimpta

• The FDA label recommends considering discontinuation of Kesimpta if a patient develops a serious opportunistic infection or recurrent infections if immunoglobulin levels indicate immune compromise 3
• In most cases, Kesimpta dosing should be maintained during immunoglobulin replacement therapy 1, 2
• Temporary discontinuation of Kesimpta may be considered during treatment of active viral infections until clinical resolution of infection symptoms 1

Special Considerations

• IgG and IgM serology tests for diagnosis of viral infections may be used routinely but should be interpreted with caution in patients on Kesimpta 1, 2
• Patients may have false negative results in response to IgG and IgM serology tests due to failure to mount antibody responses to pathogens 1
• Serum immunoglobulin levels alone are not adequate to inform on an individual's capacity to mount an antibody response against various pathogens; monitoring the frequency of infections is more important 1
• Prophylactic measures against common infections should be considered, including acyclovir or valacyclovir against HSV and VZV in all patients 1

Algorithm for Management

1. Baseline Assessment:

   • Obtain baseline immunoglobulin levels before starting Kesimpta 3
   • Screen for hepatitis B virus and other infections 3

2. Regular Monitoring:

   • Monitor immunoglobulin levels periodically during treatment 1, 2
   • Pay particular attention to infection frequency and severity 1

3. If Low IgM is Detected:

   • Continue monitoring if no infections are present 5
   • If patient develops infections, assess frequency and severity 1

4. Intervention Thresholds:

   • Initiate monthly IVIG if patient has experienced ≥2 severe recurrent infections 1
   • Consider IVIG for life-threatening infections or infections not responding to antibiotics 1
   • Continue Kesimpta during IVIG treatment unless serious opportunistic infections develop 1, 3

5. Follow-up:

   • Monitor immunoglobulin levels monthly during IVIG treatment 1
   • Continue IVIG until immunoglobulin levels recover 1
   • Consider discontinuing Kesimpta only if serious opportunistic infections or recurrent infections occur despite IVIG 3

Practical Considerations

• Case reports suggest that patients can maintain disease control on ofatumumab despite low IgM levels, with careful monitoring 7
• Real-world data indicate that infection rates may increase over time with anti-CD20 therapies, requiring vigilance particularly in older patients and those with comorbidities 8
• Unlike some other anti-CD20 therapies, ofatumumab has shown relatively stable IgG levels over time, which may be advantageous for long-term treatment 6