Measles, rubella, and mumps titers post chemotherapy plus autologous stem cell transplant in multiple myeloma patients
Authors: Mariano Arribas, Greg J. Ahmann, Skye Buckner Petty, Esteban Braggio, Elitza S. Theel, Rafael Fonseca
Journal: American Journal of Hematology (2021)

According to the Centers for Disease Control and Prevention (CDC) of the United States, 1282 cases of measles were confirmed across 31 states in 2019, with most cases found among unvaccinated individuals. This number represents a 341% increase from the previous year and also the greatest number of cases reported in the country since 1992, which highlights the importance of building a safe and strong immunologic response to prevent diseases that viruses like measles, mumps, and rubella (MMR) might cause.1 A common clinical finding among patients with multiple myeloma (MM), a hematological malignancy resulting from the clonal expansion of plasma cells, is the suppression of immune function due to underlying disease and/or chemotherapy-based treatments. Standard of care for newly diagnosed MM consists of one or multiple lines of induction therapy combining steroids, proteasome inhibitors (PI), and immunomodulatory agents (IMiD), followed by an autologous stem cell transplant (ASCT) in all eligible candidates.2 Furthermore, we are likely to add monoclonal antibodies that target CD38 as part of four drug regimens. It is known that ASCT recipients experience a decline in antibody titers to vaccine-preventable illnesses post-transplant, particularly those who have previously received multiple lines of chemo-immunotherapy.3 Additionally, prior studies have demonstrated that MMR revaccination among these patients is necessary, effective, and safe after the procedure, even when followed by lenalidomide or bortezomib maintenance therapy.4 Current guidelines recommend revaccination with live attenuated vaccines such as MMR 2 years after ASCT. A primary objective of this study is to evaluate whether the advent of novel therapeutics, which has greatly improved disease outcomes and duration of disease control, followed by ASCT would result in decreased humoral immunity against common childhood diseases. If so, earlier post-ASCT vaccination boost would likely be indicated. Furthermore, studying the effects of therapy plus ASCT on long-lasting immunity will be of relevance to understand the effects of ASCT on COVID-19 immunity. We analyzed 110 patients diagnosed with MM (age range from 25 to 75 years old, median 60 years) that had been seen at Mayo Clinic Arizona (MCA). Of these, 60% were male (66) and 57.3% (63) were born before 1957 (Table S1), which makes them presumably immune against MMR due to natural infection. The vaccination status of the remaining patients was unknown. All patients had received one or multiple lines of therapy and subsequently underwent ASCT between 2014 and 2019. We selected one sample per individual within approximately 100 days after ASCT (median 92 days, range 24–255 days), from the MCA tissue bank and extracted 800 microliters (μL) of plasma that was used for serologic testing (after Institutional Review Board approval). In the relapsed patients who had received a second salvage transplantation (N = 14), the analysis was performed in the sample collected after the most recent ASCT. The predominant MM subtype, found in 32 patients (29.1%), was IgG Kappa. The main chemotherapy regimens received immediately prior to ASCT were VRd (bortezomib + lenalidomide + dexamethasone) in 44 patients (40%), CyBorD (cyclophosphamide + bortezomib + dexamethasone) in 22 (20%) and KRd (carfilzomib + lenalidomide + dexamethasone) in 14 (12.7%). Additional induction therapies, including monoclonal antibodies such as daratumumab and isatuximab, were provided depending on risk stratification of the disease, stage, tolerance, toxicity, and other prognostic factors. As a control, we utilized an assay from the clinical laboratory representing fully vaccinated health care workers (HCWs) ranged in age from 21 to 51 years old (median, 37 years), a population younger than our MM patients, with presumed immunity to MMR, and evaluated for presence of MMR IgG antibodies.5 The serum samples for subjects in the MM patient group and the HCW group were tested using the same laboratory, equipment, and method (see below). Additionally, pre-ASCT samples were available in 45 of the 110 MM patients (median number of days prior to ASCT of 130; range 7–1925) and the IgG antibody levels were compared with the post-ASCT samples. We performed the IgG multiplex flow immunoassay (MFI) using the Bio-Rad MMRV (measles, mumps, rubella, and varicella zoster virus) on the Bio-Rad BioPlex 2200 system (Bio-Rad Laboratories, Hercules, CA). This assay is FDA approved and was used according to manufacturer instructions for the simultaneous detection of IgG antibodies to MMRV in plasma samples as described previously.6 Flow cytometry is used to determine whether IgG antibodies are present against each of the viral targets and a fluorescence ratio (FR) is established by dividing the sample relative fluorescence intensity (RFI) by the internal standard bead fluorescence signal. The FR is subsequently compared to the assay-specific calibration curve to establish an analyte-specific antibody index (AI). For measles and mumps, AI values of ≤ 0.8, 0.9–1.1, and ≥ 1.1 are interpreted as negative, equivocal, and positive for the presence of IgG-class antibodies to these viruses, respectively. The interpretive criteria for IgG-class antibodies to rubella are as follows: ≤ 0.7 AI, negative; 0.8–0.9 AI, equivocal; and ≥ 1.0 AI, positive. Differences in the presence of IgG-class antibodies from pre-ASCT to post-ASCT where assessed via McNemar's chi-squared test. Differences in antibody presence among those born before 1957 versus those born in or after 1957 was assessed via Pearson's chi-squared test. p-values less than .05 were considered statically significant. All analyses were completed in R version 3.6. Of 110 MM patients, 77 had positive measles titers after ASCT (Table 1). This represents 70% prevalence, versus 77.4% (154 out of 199) of the HCWs with a documented 2-dose measles vaccination history. With mumps, 49.1% (54/110) of the MM population showed positive IgG-class antibodies versus 84.8% (167/197) of the presumptively immune HCWs. Finally, 64.5% (71/110) of the MM cohort tested positive for IgG anti-rubella in comparison with 83.7% (175/209) of the HCWs who received at least one dose of rubella vaccine. The comparison of the pre-ASCT samples versus post-ASCT in 45 MM patients showed mild variations in the overall number of individuals with positive IgG antibodies detected against any of the three viruses, despite the effects of induction therapy plus transplant (Table 1). There are very few discrepancies in equivocal results becoming negative after ASCT (one case in measles, three in mumps and one in rubella). Finally, we found statistical significance (Pearson's chi-squared test) among the MM patients seropositive for anti-measles, post ASCT, based on their year of birth (Table S2). Of the 63 patients born before 1957 and presumably immune after natural exposure to the virus, 82.5% (52) showed positive IgG antibodies versus 53.2% (25 of 47) born in 1957 or after (p = .001). The same tendency is observed in mumps (p value not significant) and rubella (p = .01), with higher prevalence in those born before 1957 (55.6% and 76.2%, respectively) versus the rest (40.4% and 48.9%, respectively). In conclusion, our findings show sustained immunity in most patients and no ubiquitous decrease in titers levels that could presumably be attributed to the immunosuppressive effect of novel MM treatments plus ASCT. Consequently, there is no strong evidence to contemplate earlier revaccination. Consideration to measure viral titers individually might be appropriate to better ascertain the need for repeating vaccination. This study has some limitations. Initially, the assay is not calibrated to the World Health Organization standard to detect protective levels of immunity against measles and mumps, but rather whether any antibodies to these viruses are present. The anti-rubella IgG it is the only assay referenced against the true level of protective antibodies. Second, as mentioned, we did not know, nor did we have access to documentation of the patients' vaccination status during their childhood. At the same time, we recognize that the incidence of measles, mumps, and rubella in a resource-rich nation such as the United States is exceedingly low, and that MM patients represent an even smaller fraction of those that may potentially be impacted by these illnesses. However, our study is important as it relates more to enduring immunity and supports persistence of immunity post-transplant. Additional studies are needed to establish the level at which detected antibodies confer protective immunity for both measles and mumps viruses, and whether the statistical significance of birth year variances in IgG durability is further borne out. Furthermore, we found a remarkable variance in the seropositive percentages for anti-mumps and anti-rubella in MM patients after transplant versus the control population that might require further investigation. At first glance, our results suggest a more durable immunity associated with infection, versus the resulting from immunization, an observation that will be of relevance as well for COVID-19 and other infections. While our cohort cannot test for SARS-CoV2 antibodies, based on our observations, it is likely that those who have been vaccinated or who have recovered from infection will remain protected if they undergo an ASCT. RF: consulting: Amgen, BMS, Celgene, Takeda, Bayer, Janssen, Novartis, Pharmacyclics, Sanofi, Merck, Juno, Kite, Aduro, OncoTracker, Oncopeptides, GSK, AbbVie. Scientific Advisory Board: Adaptive Biotechnologies, Caris Life Sciences and OncoTracker. EST: consulting: Roche Diagnostics, Euroimmun. Scientific advisory board: Oxford Immunotec, Serimmune. Data available on request from the authors. Data available on request from the authors. 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