Hindawi Publishing Corporation Bone Marrow Research Volume 2011, Article ID 269519, 7 pages doi:10.1155/2011/269519 Review Article Immune Recovery after Cyclophosphamide Treatment in Multiple Myeloma: Implication for Maintenance Immunotherapy Amir Sharabi1, 2 and Nechama Haran-Ghera1 1 Department of Immunology, the Weizmann Institute of Science, Rehovot 76100, Israel 2 Department of Internal Medicine B, the Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel Correspondence should be addressed to Amir Sharabi, amir.sharabi@weizmann.ac.il Received 13 December 2010; Accepted 7 February 2011 Academic Editor: David A. Rizzieri Copyright © 2011 A. Sharabi and N. Haran-Ghera. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Multiple myeloma (MM) is a progressive B-lineage neoplasia characterized by clonal proliferation of malignant plasma cells. Increased numbers of regulatory T cells (Tregs) were determined in mouse models and in patients with MM, which correlated with disease burden. Thus, it became rational to target Tregs for treating MM. The eﬀects of common chemotherapeutic drugs on Tregs are reviewed with a focus on cyclophosphamide (CYC). Studies indicated that selective depletion of Tregs may be accomplished following the administration of a low-dose CYC. We report that continuous nonfrequent administrations of CYC at low doses block the renewal of Tregs in MM-aﬀected mice and enable the restoration of an eﬃcient immune response against the tumor cells, thereby leading to prolonged survival and prevention of disease recurrence. Hence, distinctive time-schedule injections of low-dose CYC are beneﬁcial for breaking immune tolerance against MM tumor cells. 1. Introduction Multiple myeloma (MM) is a progressive B lineage neoplasia characterized by clonal proliferation of malignant plasma cells that localize in the bone marrow (BM) replacing the normal BM population. A reduced level of polyclonal immunoglobulins is a consistent feature of active MM reﬂecting the suppression of CD19+ lymphocytes that corre- late inversely with the disease stage. The relationship between myeloma plasma cells and the BM microenvironment is critical for the maintenance of the disease. Tumor cells and stromal cells interact via adhesion molecules and cytokine networks to simultaneously promote progression of the disease leading to bone destruction, vertebral collapse, hypercalcemia, renal failure, hypogammaglobulinemia, and peripheral neuropathy. The disease is associated with both cellular and humoral immune deﬁciencies [1]. Recent studies have revealed that CD4+CD25highFoxp3+ regulatory T cells (Tregs), which are physiologically engaged in the mainte- nance of immunological self-tolerance, play critical roles for the control of antitumor immune responses. Increased num- bers of Tregs were documented in peripheral blood, tumor mass, and draining lymph nodes from patients of a wide spectrum of cancers. A strong correlation exists between Treg levels and the progression of cancer. The increased number of Tregs was reported to reﬂect poor prognosis [2] and is associated with suppression of T cell proliferation, down- regulation of proinﬂammatory cytokines, and involvement in tumor tolerance to self antigens. Thus, new anticancer strategies involving interference in Treg biology by means of functional disruption or numerical depletion are of critical importance. Treg depletion can lead to decreased tumor cell growth both directly by enabling anti cancer cytotoxic eﬀects or indirectly by inducing cellular immune responses against cancerous cells. General strategies to reduce Treg functions include depletion of Tregs by chemotherapeutic drugs, blockade of Treg function by target known receptors, blockade of Treg traﬃcking, and combing depletion of Tregs with tumor vaccination. Recently, we showed a correlation between increased ratios of functional Tregs and disease progression in a unique mouse model of MM that mimics the human disease [3, 4]. Low-dose cyclophosphamide (CYC) that selectively depletes Tregs reduced MM progression. Treatment of tumor-bearing