Thalidomide–Containing Regimens Induce Recovery of Normal Immunoglobulins in Newly Diagnosed Patients with Multiple Myeloma; Recovery of Normal Immunoglobulins Improves Survival.
Authors: Katodritou Eirini , Verrou Evgenia , Banti Anastasia , Mihou Dimitra , Gastari Vassiliki , Hadjiaggelidou Christina , Markala Dimitra , Lazaridou Anna , Terpos Evangelos , Zervas Konstantinos 
Published: October 2019

Abstract
Normal immunoglobulins, which are important for the host defense, are often decreased in Multiple myeloma (MM), either at the time of diagnosis or even after achieving response. Thalidomide, which is an immunomodulatory drug, in combination with other chemotheraputic drugs is effective for the treatment of newly diagnosed multiple myeloma (MM) patients, yielding 60–80% response rate. The purpose of this study was to examine, if the addition of Thalidomide to standard regimens, in newly diagnosed MM patients, induces recovery of normal immunoglobulins and whether this normalization has any impact on time to progression and overall survival. Two hundred twenty–six newly diagnosed symptomatic MM patients were evaluated. One hundred sixty–nine patients, 95 males and 74 females, with a median age of 66 years (range 29–90) who presented with normal immunoglobulins’ value below the minimum normal limit at the time of diagnosis, were selected for analysis. One hundred twenty-seven patients (group 1) received standard regimens not containing Thalidomide (93 received Vincristine /Adriamycin /Dexamethasone and 34 received Melphalan /Prednisone). Forty-two patients (group 2) received regimens containing Thalidomide (27 patients received Vincristine /Adriamycin /Dexamethasone /Thalidomide, 10 patients Dexamethasone /Thalidomide and 5 patients Melphalan /Prednisone /Thalidomide). All patients were evaluated after at least 4 cycles of treatment (median time of evaluation 6mo, range 4-8mo) for recovery of normal immunoglobulins (defined as the return of the normal immunoglobulins within the normal range). Statistical analysis was performed with the Pearson’s chi square test, Mann Whitney-U test and binary logistic regression analysis. The patients in both groups were well-balanced concerning age, sex, ISS score, B2-micriglobulin, creatinine and LDH (p<0.05). Recovery of normal immunoglobulins was achieved in 14,2% in group 1 and 33,3% in group 2 (p=0.006). The multivariate analysis, including age, ISS, type of myeloma and addition of Thalidomide in the first line treatment regimens, showed that the addition of Thalidomide in first line treatment was the only factor predicting for recovery of normal immunoglobulins (p=0.04). With a median follow up of 32mo (range 4–231mo), the median overall survival of patients in whom recovery of normal immunoglobulins was observed and of patients without any immunoglobulin recovery, was 35mo (SD=23mo) and 31mo (SD=31,6mo), respectively (p=0.004) and the median time to progression was 16mo (SD=23mo) and 6mo (SD=22mo), respectively (p=0.005). These results suggest that, Thalidomide-containing regimens used as first–line treatment, induce significant recovery of normal immunoglobulins compared to regimens without Thalidomide and that, the recovery of normal immunoglobulins overall, positively influences time to progression and overall survival. Conclusively, this study highlights the important role of normal immunoglobulins in MM biology and outcome and may suggest that the recovery of normal immunoglobulins could be possibly another criterion for defining complete remission.