What is the role of daratumumab (Darzalex) in the treatment of systemic lupus erythematosus (SLE)?

Daratumumab in Systemic Lupus Erythematosus: Emerging Experimental Therapy

Daratumumab is not included in current EULAR or ACR treatment guidelines for SLE and remains an experimental, off-label therapy reserved only for life-threatening, refractory disease after exhaustion of all standard and approved biologic options. 1

Current Guideline-Recommended Treatment Hierarchy

The most recent EULAR 2023 guidelines establish a clear treatment algorithm that does not include daratumumab 1:

First-Line Approved Therapies

• Hydroxychloroquine (≤5 mg/kg real body weight) for all patients 2, 3
• Glucocorticoids minimized to <7.5 mg/day for maintenance 2, 3
• Conventional immunosuppressants: mycophenolate mofetil, azathioprine, methotrexate, cyclophosphamide for organ-threatening disease 2, 3

Approved Biologic Options (Before Considering Daratumumab)

• Belimumab for persistently active extrarenal SLE and lupus nephritis 1, 2
• Anifrolumab for moderate-to-severe extrarenal SLE 1, 2
• Voclosporin for lupus nephritis 1, 2
• Rituximab for refractory cases, particularly hematological manifestations 2, 4

Experimental Evidence for Daratumumab

Mechanism and Rationale

Daratumumab is an anti-CD38 monoclonal antibody approved for multiple myeloma that targets and depletes long-lived plasma cells—the source of pathogenic autoantibodies in SLE 5. Unlike rituximab (which targets CD20+ B-cells but spares plasma cells), daratumumab directly eliminates the plasma cell population that persists despite conventional immunosuppression 5, 6.

Published Clinical Experience

The only peer-reviewed evidence consists of a 2020 New England Journal of Medicine case report describing two patients with life-threatening, refractory SLE 5:

• Both patients achieved substantial clinical responses after daratumumab treatment 5
• Responses were sustained with maintenance belimumab 5
• Documented mechanisms included plasma cell depletion, reduced type I interferon activity, and down-regulation of inflammatory T-cell transcripts 5
• Both patients had exhausted all standard therapies including cyclophosphamide, rituximab, and other biologics before daratumumab 5

Critical Limitations

• No randomized controlled trials exist for daratumumab in SLE 1
• Evidence limited to case reports in life-threatening disease 5
• Not mentioned in any systematic literature review informing current guidelines 1
• Safety profile in SLE unknown beyond myeloma data 5

Clinical Decision Algorithm

When to Consider Daratumumab (Off-Label, Experimental):

1. Life-threatening organ involvement (severe nephritis, neuropsychiatric lupus, cytopenias) 5
2. Documented failure of all the following 5:
   • High-dose glucocorticoids
   • Cyclophosphamide
   • Mycophenolate mofetil
   • Rituximab
   • Belimumab
   • Other approved biologics (anifrolumab, voclosporin if applicable)
3. Evidence of plasma cell-driven pathology (persistent high-titer autoantibodies despite B-cell depletion) 5
4. Institutional review board approval or compassionate use authorization given lack of regulatory approval 5

Dosing Strategy (Extrapolated from Case Report):

• Use myeloma dosing: 16 mg/kg intravenously 1, 5
• Consider maintenance therapy with belimumab after daratumumab response 5

Important Caveats

Why Guidelines Exclude Daratumumab

The 2024 EULAR systematic review covering 2018-2022 literature included 439 studies but found insufficient evidence to recommend daratumumab 1. The research agenda specifically calls for "optimisation of clinical trial design" and testing of new drugs, but daratumumab has not undergone this process for SLE 1.

Comparison to Failed Biologics

Multiple biologics have failed in SLE trials despite promising mechanisms 7, 8. The single case report for daratumumab, while published in a prestigious journal, does not meet the evidentiary threshold established by recent successful trials (e.g., BLISS-LN for belimumab, AURORA for voclosporin) that enrolled hundreds of patients 1.

Practical Barriers

• Cost: Daratumumab is extremely expensive (myeloma indication) 1
• Insurance coverage: Unlikely without documented failure of all approved options 5
• Monitoring requirements: Intensive infusion protocols and infection surveillance needed 1
• Plasma cell depletion effects: Long-term consequences of eliminating plasma cells in autoimmune disease unknown 5

In summary, daratumumab should only be considered as a last-resort experimental therapy in tertiary referral centers for patients with life-threatening SLE who have exhausted all guideline-recommended options, and only after multidisciplinary discussion and appropriate regulatory approval. 5