Objective:

To report a case of HLH as the initial manifestation of multiple myeloma, highlighting its complications, including EBV reactivation and the development of aggressive B-cell lymphoma.

Key Findings:

• HLH can present as the initial manifestation of multiple myeloma, complicating diagnosis and treatment.
• EBV reactivation was associated with HLH relapse despite effective control of multiple myeloma.
• PD-1 blockade had limited and transient efficacy in controlling EBV viremia, highlighting treatment challenges.
• Aggressive B-cell lymphoma emerged in the context of EBV-related immune dysregulation, complicating patient management.

Interpretation:

The case illustrates the complexities of diagnosing and managing HLH in the context of multiple myeloma and EBV reactivation.

Limitations:

• Lymphoma classification relied on bone marrow findings due to the infeasibility of tissue biopsy, which may affect diagnostic accuracy.
• EBER positivity alone was insufficient to establish a direct pathogenic role of EBV in lymphoma development, indicating a need for further research.

Conclusion:

This case underscores the diagnostic and therapeutic challenges in managing HLH and associated lymphoid neoplasms, particularly in the context of EBV-related immune dysregulation.