Rituximab Administration Following Autologous Stem Cell Transplant 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). These clonotypic B cells may be clonogenic cells of MM. We hypothesized that rituximab may be a useful maintenance therapy in MM after autologous stem cell transplant (ASCT). The rationale was that CD20 antibody would deplete the clonotypic and, hence, clonogenic B cells to reduce the risk of disease relapse. ASC were mobilized with Cytoxan (3g/m2) and G-CSF from patients with MM. Two weeks after ASC collection, high dose IV melphalan (200 mg/m2) was administered followed 24 hours later by the infusion of at least 2x106/kg CD34+ cryopreserved ASC. 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 and did not receive any other antimyeloma treatment. A total of 10 patients have been treated. Seven patients who have had post-transplant follow-up periods of >12 months were evaluated. The immunoglobulin recovery and incidence of infections in this group of patients were compared to 6 patients with MM who have undergone an ASCT without rituximab maintenance. The total normal IgM level in all 7 patients was severely depressed following rituximab administration. IgG and IgA were variably affected in these patients. The IgM immunosuppression was prolonged and consistent, being seen in all patients, regardless of the disease status after transplantation. In contrast, the control group showed normalization of the total IgM levels by 3 months after transplant. Two patients treated with rituximab received pneumococcal vaccines 12 months after transplant and neither developed any IgG response to the vaccines. The data indicate that rituximab infusion following ASCT for MM severely impaired B-cell immune reconstitution. Six of the 7 patients developed moderate to severe infections during the first 12 months after initiation of rituximab infusion. There were a total of 23 episodes of infections: 21 pneumonia and 2 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 deficiency 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 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 in CR 12 months and the other 2 have remained in CR 12+ and 18+ months after ASCT. With a follow-up of 29 months after transplant, the progression-free survival was 56.5% and the overall survival 71.4%. Rituximab infusion after ASCT for MM is therefore associated with severe IgM deficiency 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 only be carried out with special attention to the prevention of infection.