Why is daratumumab (Darzalex) avoided immediately before CAR‑T cell therapy for multiple myeloma?

Why Daratumumab Should Be Avoided Immediately Before CAR-T Cell Therapy

Daratumumab (Darzalex) should be avoided immediately before CAR-T cell therapy for multiple myeloma because it can profoundly deplete normal B-cells and potentially compromise the collection, expansion, and persistence of CAR-T cells, similar to the mechanism observed with other B-cell depleting therapies in acute lymphoblastic leukemia.

Mechanistic Rationale Based on Analogous Therapies

While the provided evidence does not directly address daratumumab before CAR-T in multiple myeloma, the principles are extrapolated from well-documented effects of B-cell depleting therapies in other settings:

Impact of Prior Targeted Immunotherapy on CAR-T Outcomes

• Emerging data from B-ALL demonstrate that prior therapy with agents causing profound B-cell depletion can compromise CAR-T expansion and persistence 1
• Specifically, inotuzumab ozogamicin (INO) exposure resulted in death from progressive B-ALL after CAR-T therapy in 7 of 11 pediatric patients, with profound INO-induced B-cell depletion potentially compromising CAR-T expansion and persistence 1
• Prior blinatumomab exposure in B-ALL patients was associated with lower complete response rates (64.5% vs 93.5% in blinatumomab-naïve patients) and significantly lower 6-month event-free survival rates (27.3% vs 72.6%) 1, 2

Extrapolation to Daratumumab and Multiple Myeloma CAR-T

• Daratumumab targets CD38, which is expressed not only on myeloma cells but also on normal immune cells including T-cells, NK cells, and regulatory T-cells 3
• The immunomodulatory effects of daratumumab include depletion of CD38+ immune effector cells through ADCC, ADCP, and CDC mechanisms 3
• This broad immune cell depletion could theoretically impair the quality and quantity of T-cells collected during leukapheresis for CAR-T manufacturing, analogous to the mechanism seen with other B-cell depleting agents 1

Practical Considerations for Leukapheresis Timing

Pre-Collection Requirements

• Absolute lymphocyte count must be ≥0.2 × 10⁹/L before proceeding with leukapheresis to ensure adequate T-cell collection 4
• Performance status should be ECOG <2 or Karnofsky >60% 4
• Corticosteroids must be avoided before leukapheresis as they are lymphocytotoxic and reduce collection yield 4

Critical Timing Window

• Adequate marrow recovery from prior therapy is essential before attempting T-cell collection 4
• Given daratumumab's mechanism of depleting CD38+ cells (including T-cell subsets), a washout period would be prudent to allow immune reconstitution before leukapheresis
• The goal is to collect high-quality T-cells with adequate central memory and stem cell memory populations, which are critical for CAR-T persistence and long-term efficacy 1

Bridging Therapy Considerations

Optimal Bridging Strategy

• Bridging regimens should be selected carefully to maintain disease control during CAR-T manufacturing while minimizing toxicities that might compromise T-cell quality or disqualify patients from proceeding to infusion 5, 4
• For multiple myeloma patients, alternative bridging options that don't deplete CD38+ immune cells would be preferable during the manufacturing window
• Monitor for tumor lysis syndrome and provide antimicrobial prophylaxis during bridging therapy 4

Clinical Algorithm for Sequencing

Recommended Approach:

1. If daratumumab is part of the treatment plan, complete daratumumab-based therapy well in advance of planned CAR-T cell therapy
2. Allow adequate time for immune reconstitution (specific duration not established in guidelines, but extrapolating from B-ALL data suggests several weeks minimum) 1
3. Verify absolute lymphocyte count ≥0.2 × 10⁹/L before scheduling leukapheresis 4
4. Use alternative bridging therapy (not daratumumab-based) during the CAR-T manufacturing period 5, 4
5. Ensure patient meets all eligibility criteria including absence of active infection and adequate performance status before proceeding 5

Common Pitfalls to Avoid

• Do not underestimate the impact of prior immunotherapy on CAR-T cell collection quality and subsequent expansion 1
• Do not proceed with leukapheresis if lymphocyte counts are inadequate, as this compromises manufacturing success 4
• Do not use lymphocytotoxic agents (including corticosteroids or potentially daratumumab) immediately before or during the collection window 4
• Do not assume that all bridging therapies are equivalent—select regimens that preserve T-cell function and quantity 5, 4

Evidence Limitations and Clinical Judgment

While direct evidence specifically addressing daratumumab timing before BCMA-targeted CAR-T in multiple myeloma is not provided in these guidelines, the mechanistic parallels with B-cell depleting therapies in B-ALL provide strong biological rationale for avoiding daratumumab immediately before CAR-T therapy 1. The principle of preserving adequate T-cell quantity and quality for successful CAR-T manufacturing is well-established across all CAR-T applications 1, 5, 4.