Complement Abnormalities in Multiple Myeloma

Purpose: Patients with multiple myeloma have been shown to have defective opsonization and C3 deposition. Previous studies have suggested that defective C3 deposition may be related to a failure of C3 activation in myeloma serum, the mechanism of which is unknown. We therefore decided to in- vestigate the underlying mechanism responsible for the failure in C3 activation and deposition. Patients and methods: The study consisted of 10 patients from whom a total of 12 serum speci- mens were obtained. Normal serum was prepared from a pool of serum specimens in four healthy male donors. We evaluated, in vitro, the kinetics of C3 deposition onto zymosan using radiolabeled C3 under various conditions. We also measured the se- rum levels of a variety of complement components using standard methods. Results: Five of 10 patients' sera demonstrated poor C3 deposition onto zymosan at all time points, whereas an additional two showed poor C3 deposi- tion at early time points but a rebound to normal by 30 minutes. Multiple components of the classical and alternative complement pathways were de- creased in many patients, with the most striking abnormalities occurring in those with the poorest C3 deposition. No single complement component abnormality was found to be common to the group. Elevations in Bb fragment concentration strongly suggest in vivo activation as the likely mechanism for depletion of alternative pathway components; the mechanism for classical pathway abnormalities is less clear. There was an inverse correlation be- tween paraprotein concentration and abnormal C3 deposition (p <0.0001) and C3 (p <0.0005) and C4 (p <0.0001) concentrations. However, no consistent ev- idence of fluid-phase complement consumption was present. Conclusion: The defect in C3 activation and de- position in multiple myeloma cannot be explained on the basis of a single complement component ab- normality but rather is due to a heterogeneous group of complement abnormalities. Although no correlation between in vitro abnormalities and clinical status was identified in this small group of patients, it is likely that the described complement defects play an important role in defective host de- fense in multiple myeloma.