**3. Reduced immunity in patients with MM**

In patients with MM, causes of immunosuppression include: (1) the immunosuppressive effects of the disease or the direct immunosuppression caused by tumor cells, particularly in advanced stage or refractory disease, (2) therapeutic interventions to control MM, such as corticosteroids, cytotoxic chemotherapy, and the novel therapies such as thalidomide, lenalidomide and bortezomib reduce the immunity further by different mechanisms including neutropenia and mucositis, (3) old age and its immunosuppressive effects, (4) impairment of the capacity of the immune system to mount effective responses or challenges to infection or vaccination, (5) further suppression of the immune system by the administration of HD chemotherapy (melphalan) followed by autologous HSCT, and (6) presence of comorbid medical conditions [14, 27–31].

In patients with MM, the risks of infectious complications and disease progression are enhanced by following forms of dysfunction of the immune system: reduced antigen presentation, high cytokine levels and increased suppressive cells such as CD8 Tregs [32, 33]. Both cellular and humoral components of the immune system are suppressed in patients with MM [28, 34, 35]. Hypogammaglobulinemia or immunoparesis is associated with unfavorable prognosis in newly diagnosed patients with MM [34]. In a Danish study that included 2558 patients with MM, immunoparesis at diagnosis was not confirmed to be an independent prognostic factor for OS, but quantitative immunoparesis was found to be associated with a shorter PFS [34].

Patients with MM have increased susceptibility to infections due to the profound B-cell dysfunction or the depression in humoral immunity [36]. These patients are 10 times more prone to infections than patients with Waldenstrom's macroglobulinemia and 5 times more prone to infections than individuals with monoclonal gammopathy of undetermined significance [36]. MM patients have increased susceptibility to severe pneumococcal infections, and they respond poorly to pneumococcal vaccination [35, 36].

The highest risk of infection occurs within the first month after the diagnosis of MM, particularly in patients with renal failure [14, 36]. The infections that are encountered in patients with MM include urinary tract infection, pneumonia, septicemia, fungal infections, and viral infections such as *influenza virus* and *varicella zoster virus* (VZV) infections [14, 36]. However, bacterial infections predominate particularly those caused by: *Staphylococcus aureus*, *Streptococcus pneumonia*, *Haemophilus influenzae*, and *Escherichia coli* [14, 36]. The advent of autologous HSCT and the introduction of novel therapies in patients with MM have led to a shift in the spectrum of infections with increased incidence of viral and fungal infections [13, 36]. In a recent study, mitogen stimulation of cytokine release profiling for interleukin (IL)-5, IL-13, Th1, and Th2 was used to predict the risk of infections in patients with MM during maintenance therapy, but only IL-5 response was found to be predictive of infection on multivariate analysis [37].
