Bone Marrow Research depletion of Tregs by low-dose CYC resulted in upregulated numbers of IFN-γ producing NKT cells that are capable of controlling tumor growth in vivo [60] and are aﬀected reciprocally by Tregs [61, 62]. The antitumor properties of NKT cells are linked to their ability to produce large amounts of IFN-γ upon activation of NKT cells [63–65]. Further, the expression of MHC class II and CD86 stimulatory molecules in DCs was up-regulated, which enhanced their function as antigen presenting cells [4, 66–68]. Once the concept of low- dose CYC was proven feasible for potentially enabling an eﬀective immune response against MM cells, it was essential to ﬁnd the most eﬀective protocol of treatment by means of satisfactory and durable antimyeloma eﬀects. 5.2. Optimal Time Schedules of CYC Treatments Aﬀecting MM Progression. The initial cytotoxic eﬀect of CYC reduced markedly tumor load, thereby eliminating the acute disease and prolonging the survival of 5T2MM-bearing mice into a chronic phase. Further, reduced MM incidence during the prolonged latency was accomplished by repeated adminis- trations of low-dose CYC at intervals coinciding with the timing before complete Treg restoration occurred. Kinetic studies on Treg depletion and recovery to pretreatment levels following low-dose CYC injection of 5T2MM-bearing mice showed that it lasted beyond 45 after CYC administration [4]. This period of Treg recovery provided a “window of opportunity” involving a speciﬁc balance between depletion of Tregs and activation of eﬀector T cell responses resulting in lysis of tumor cells and reduction of tumor load (Figure 1). More frequent administrations of low-dose CYC at 7- or 21- day intervals did not improve the therapeutic eﬀect, since these mice developed MM in a higher incidence [4]. These shorter time intervals limited the “window of opportunity” by preventing recruitment of eﬀector T cells, NKT, or DCs required for the reduction of MM incidence. Continuous low-dose CYC treatments at 45-day intervals were shown to be most eﬀective in reducing and/or preventing MM development [4, 59]. Moreover, even when the initial injection of a high-dose CYC was chosen, further repeated injections of low-dose CYC at 45-day intervals prevented the disease [59]. Less frequent administrations of low-dose CYC enabled recruitment of compatible immune-derived cells that reduced tumor load and prolonged survival with minimal residual disease. Thus, issues of doses and schedules are crucial. 6. Concluding Remarks The development of MM is associated with humoral and cellular immune deﬁciencies. Immunological active com- ponents that promote tumor cell survival are produced by MM cells. Increased numbers of functional Tregs correlate with MM progression and severity of disease. Thus, the eﬀectiveness of antitumor therapy could be enhanced by the removal of Treg suppressive activity. In this regard, CYC has a broad antitumor spectrum including lymphoablation in addition to a direct tumoricidal eﬀect. CYC-induced disruption of Tregs as a means for reducing the progression 5 of MM depends on dosing and time schedule of drug administration. The use of high-dose of CYC is less eﬀective in preventing the disease, since the cytotoxic eﬀect then is less selective, reducing both tumor cells as well as immune cells with potential antitumor properties. In contrast, treatment with low-dose CYC is associated with selective Treg deple- tion, which leads to the restoration of peripheral eﬀector T cell proliferation and immune function and to a reduction in MM incidence. 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