Rituximab administration following autologous stem cell transplantation for multiple myeloma is associated with severe IgM deficiency

Clonotypic B cells are frequently isolated from the peripheral blood of patients with multiple myeloma (MM).¹  These clonotypic B cells may be the clonogenic cells of MM. We have hypothesized that rituximab, a chimeric CD20 monoclonal antibody, may be a useful maintenance therapy in MM after autologous hematopoietic stem cell transplantation (HSCT). The rationale was that CD20 antibody would deplete the clonotypic and, possibly, clonogenic B cells, in the setting of major malignant plasma cell eradication, to reduce the risk of disease relapse. Furthermore, CD20 has been shown in recent studies to be expressed on malignant plasma cells in up to 20% of patients with MM.^2,3  CD20 antibody has previously been used with limited success to treat patients with MM in a phase 2 study.² 

Autologous hematopoietic stem cells (HSCs) were mobilized with cyclophosphamide (3 g/m²) and granulocyte colony-stimulating factor (G-CSF; 10 μg/kg per day) from patients with MM. Two to 3 weeks after stem cell collection, high-dose melphalan (200 mg/m²) was administered intravenously followed 24 hours later by the infusion of at least 2 × 10⁶/kg CD34⁺ cryopreserved autologous stem cells. Rituximab infusion (375 mg/m²) was started on day +30. Each patient received one antibody infusion every 3 months for 2 years or until disease progressed. All patients continued on monthly zoledronate (4 mg) and did not receive any other antimyeloma treatment.

A total of 10 patients have been treated. However, only the 7 patients who have had posttransplantation follow-up periods of more than 12 months were evaluated. One of the 3 patients with follow-up periods of less than 12 months has achieved a complete remission (CR; defined by negative serum protein electrophoresis and immunofixation electrophoeresis) and the other 2 patients achieved a partial remission. The immunoglobulin recovery and incidence of infections in this group of patients were compared to 6 patients with MM who have undergone an autologous stem cell transplantation but without the administration of rituximab.

The total normal immunoglobulin M (IgM) level in all 7 patients was severely depressed following rituximab administration (Figure 1A). Unlike patients with non-Hodgkin lymphoma who received rituximab infusions after autologous stem cell transplantation in which IgG recovery was depressed,⁴  the immunosuppression in patients with MM was observed primarily in IgM and only variably in IgG and IgA (data not shown). The IgM immunosuppression was prolonged and consistent, being observed in all 10 treated patients, regardless of the disease status after transplantation. In contrast, the control group showed normalization of the total IgM levels by 3 months after transplantation. Two patients treated with rituximab received pneumococcal vaccines 12 months after transplantation and neither developed any IgG response to the vaccine. The data indicate that rituximab infusion following autologous transplantation for MM severely impaired B-cell immune reconstitution.

The clinical significance of the IgM immunodeficiency was next examined. Six of the evaluated 7 patients developed moderate to severe infection during the first 12 months after initiation of rituximab infusion. The cumulative infection episodes in these 6 patients are shown in Figure 1B. There were a total of 23 episodes of infection: 21 episodes of pneumonia and 2 episodes of septicemia (one pneumococcus and one Pseudomonas). A patient died in CR due to pneumonia. In contrast, only one episode of pneumonia was observed in the control group during the same follow-up period. Therefore, the IgM immunodeficiency probably predisposed the patients to infection.

Of the 7 patients who have had more than 12 months of follow-up periods, 4 had disease refractory to standard induction chemotherapy. Of all the 10 patients treated, 6 achieved CR (2 were in CR before treatment, 2 achieved CR 3 months after treatment, and 2 achieved CR 6 months after starting rituximab). All 4 patients with refractory MM (all had a follow-up of more than 12 months) achieved CR, one before and 3 after starting rituximab. One of the refractory patients has since relapsed, one died of pneumonia 12 months after transplantation, and the other 2 have remained in CR 12+ and 18+ months after transplantation. With a follow-up of 29 months after transplantation, the progression-free survival was 56.5% and the overall survival 71.4%.

Rituximab infusion after autologous stem cell transplantation for MM is therefore associated with severe IgM immunodeficiency and an increased risk of infection. Further works are needed to determine the antitumor activities of rituximab in MM in the setting of minimal residual disease, but this should probably only be carried out with special attention to the prevention of infection.