Infectious Complications of Daratumumab-Containing Therapy for Multiple Myeloma

Introduction

Over the past several years, new drug therapies have transformed the treatment approach in multiple myeloma. Amongst these, daratumumab (a monoclonal antibody directed against CD38) has been a clear breakthrough in relapsed myeloma and is currently being studied in frontline regimens. It is known that multiple myeloma patients are inherently immunosuppressed by functional hypogammaglobulinemia and decreased T-cell counts, but the impact of anti-CD38 monoclonal antibodies on the remaining innate immunity and infection rates is unclear. In this study, we measured infection rates and immune cell subset populations in multiple myeloma patients treated with daratumumab-containing regimens.

Methods

We conducted a retrospective analysis of multiple myeloma patients who received daratumumab at our institution from October 2015 to December 2016. Patients were divided into four groups based on administration regimen of daratumumab: (1) single agent with dexamethasone; (2) double therapy with another agent (proteasome inhibitor (PI), immune-modulating drug (IMiD), mitogen-activated protein kinase (MEK) inhibitor or mAB) (3) triple therapy with IMiD ± PI ± mAB or cyclophosphamide; (4) combination therapy with high-dose chemotherapy. We evaluated the incidence of infection, hospitalization, and 90-day survival.

Results

We studied a total of 170 subjects, 108 (64%) were male and 62 (36%) female. The median age was 67 years (range: 40-87).

They received a total of 340 different daratumumab regimens: single therapy (n=99, 29%), double therapy (n=171, 50%), triple therapy (n=52, 15%) and combination therapy (n=18, 5%).

An infection event occurred in 124 of the regimens (36.5%). The causative agent was found in 114 cases (92%): 79 viral (69%) and 53 bacterial (46%). Our study found that patients who developed an infection had statistically significant lower nadir ANC (1007 ± 1034 vs 1459 ± 1248), t(256) = 3.047, p = 0.003; and lower nadir ALC (529 ± 544 vs 769 ± 588), t(332) = 3.698, p < 0.001 compared to patients who didn't develop an infection. There were no differences in the absolute CD4 and absolute CD 56 between patients who developed viral vs bacterial infections.

Patients who developed a viral infection had statistically significant lower nadir ALC (529 ± 569 vs 717 ± 583), t(332) = 2.108, p = 0.036 compared to patients who didn't develop a viral infection.

A hospitalization event occurred in 82 cases (24%). The reason for the hospital admission was an infection process in 38 (51%) of the cases. No statistically significant differences in the rates of hospitalization were seen in the different daratumumab regimen groups.

The overall 90-day overall survival for this cohort was 96 % (n=327). In patients who didn't achieve 90-d survival, the cause of death was related to an infection in 62% (n=8).

Conclusion

Multiple myeloma patients treated with daratumumab-containing regimens had a relatively high rate of infectious complications (36.5%), which were identifiable and most often viral. Infections were associated with significantly lower nadir ANC and ALC, and viral infections were associated with a significantly lower ALC than in patients who did not develop viral infections. No differences were appreciated in absolute CD4 or absolute CD56 in viral vs. bacterial infections, or in infected vs. non-infected patients. Further studies are needed to elucidate the entire immunomodulatory effects of daratumumab therapy in patients with multiple myeloma. Increased awareness of its associated risk of infection is important to permit clinical recognition and appropriate anti-infective measures.