Infections are a major cause of morbidity and mortality in multiple myeloma (MM), a cancer of the immune system. Vaccination clinical efficacy endpoints have not been demonstrated, and there are limited data on surrogate markers of efficacy. This pilot study evaluated sequential immunologic markers after standard pneumococcal vaccination (PV) in patients with MM and non-MM controls. Vaccination was standard for PV (PCV13 or PPV23), with laboratory testing at baseline and at 2, 4, 12 and 24 weeks after vaccination. Immunoglobulin G (IgG) antibodies to pneumococcal antigens were detected by ELISA. Prevaccination total IgG levels and IgG subclass levels were also measured by ELISA. Four of 6 controls responded with at least a 2-fold increase in antibody concentration; only 2 controls had a sustained increase in concentration. Six of 8 patients with MM had at least a 2-fold antibody increase; however, only 2 of these patients showed a sustained increase of antipneumococcal antibody. Response rate differences were not statistically significant in this small pilot, and there was no relationship between responsiveness to PV and initial serum total IgG levels or IgG subclasses at study entry. Future prospective studies are needed to ascertain the immunological and clinical efficacy and effectiveness of various vaccines and vaccination strategies in MM.