Promising new drugs are being evaluated for treatment of multiple myeloma (MM), but their impact should be measured against the expected outcome in patients failing current therapies. However, the natural history of relapsed disease in the current era remains unclear. We studied 286 patients with relapsed MM, who were refractory to bortezomib and were relapsed, refractory, or ineligible, to an IMiD (Immunomodulatory Drug), with measurable disease and ECOG PS of 0, 1 or 2. The date patients satisfied the entry criteria was defined as time zero (T0). The median age at diagnosis was 58 years and time from diagnosis to T0 was 3.3 years. Following T0, 213 (74%) patients had a treatment recorded with one or more regimens (median=1; range 0-8). The first regimen contained bortezomib in 55 (26%) patients and an IMiD in 70 (33%). A minor response or better was seen to at least one therapy after T0 in 94 patients (51%) including >=partial response in 69 (38%). The median overall survival and event free survival from T0 were 9 and 5 months respectively. This study confirms the poor outcome once patients become refractory to current treatments. The results provide context for interpreting ongoing trials of new drugs.

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Hypoxia is associated with increased metastatic potential and poor prognosis in solid tumors. In this study, we demonstrated in the murine 5T33MM model that multiple myeloma (MM) cells localize in an extensively hypoxic niche compared with the naive bone marrow. Next, we investigated whether hypoxia could be used as a treatment target for MM by evaluating the effects of a new hypoxiaactivated prodrug TH-302 in vitro and in vivo. In severely hypoxic conditions, TH-302 induces G 0 /G 1 cell-cycle arrest by down-regulating cyclinD1/2/3, CDK4/6, p21 cip-1 , p27 kip-1 , and pRb expression, and triggers apoptosis in MM cells by upregulating the cleaved proapoptotic caspase-3, -8, and -9 and poly ADP-ribose polymerase while having no significant effects under normoxic conditions. In vivo treatment of 5T33MM mice induces apoptosis of the MM cells within the bone marrow microenvironment and decreases paraprotein secretion. Our data support that hypoxia-activated treatment with TH-302 provides a potential new treatment option for MM. (Blood. 2010;116(9):1524-1527) IntroductionMultiple myeloma (MM) is an incurable clonal B-cell malignancy characterized by the accumulation of neoplastic plasma cells in the bone marrow (BM). 1 Studies have shown that the intimate reciprocal relationship between tumor cells and the cellular and noncellular microenvironment plays a pivotal role in MM growth and survival. 2,3 Hypoxia, one of the important microenvironmental factors, is well known to be highly associated with increased angiogenesis and metastatic potential as well as poor prognosis in solid tumors. More recently, hypoxia has been demonstrated to be crucial for normal marrow hematopoiesis. [4][5][6] However, the role of hypoxia in the etiology, pathogenesis, and possible treatment of hematologic malignancies, such as MM, is still unknown.Given very low oxygen levels, as found in tumors, are rarely observed in normal tissues, the presence of hypoxic tumor cells is therefore regarded not only as an adverse prognostic factor but also as a potential target for tumor-specific treatment. Currently, several hypoxia-targeted therapeutics are under development. 7-12 TH-302 is a new hypoxia-activated prodrug that is being evaluated in phase 1/2 clinical trials for the treatment of solid tumors as a monotherapy and in combination with 4 chemotherapeutic agents (gemcitabine, pemetrexed, doxorubicin, and docetaxel). TH-302 is a 2-nitroimidazole prodrug of the cytotoxin bromo-isophosphoramide mustard, with a favorable physicochemical, metabolic, and pharmacokinetic profile and exhibits hypoxiaselective cytotoxicity across a broad spectrum of human cancer cell lines in vitro and in vivo efficacy in a large panel of human tumor xenografts. 13,14 The doses used in the clinical studies are in the same range as the doses demonstrating efficacy in both in vitro and in vivo preclinical models.In this study, we investigated the hypoxic nature of MM by staining the BM of naive and 5T33MM mice with the exogenous hypoxia marker pimonidazole and endogenou...

Previous studies have demonstrated that mesenchymal stem cells from multiple myeloma (MM) patients (MM-hMSCs) display a distinctive gene expression profile, an enhanced production of cytokines and an impaired osteogenic differentiation ability compared to normal donors (ND-hMSCs). However, the underlying molecular mechanisms are unclear. In the present study, we observed that MM-hMSCs exhibited an abnormal upregulation of miR-135b, showing meanwhile an impaired osteogenic differentiation and a decrease of SMAD5 expression, which is the target of miR-135b involved in osteogenesis. By gain and loss of function studies we confirmed that miR-135b negatively regulated hMSCs osteogenesis. We also found that MM cell-produced factors stimulated ND-hMSCs to upregulate the expression of miR-135b. Importantly, treatment with a miR-135b inhibitor promoted osteogenic differentiation in MM-hMSCs. Finally, we observed that MM cell-derived soluble factors could induce an upregulation of miR-135b expression in ND-hMSCs in an indirect coculture system and the miR-135b expression turned to normal level after the removal of MM cells. Collectively, we provide evidence that miR-135b is involved in the impaired osteogenic differentiation of MSCs derived from MM patients and might therefore be a promising target for controlling bone disease.

Multiple myeloma (MM) is a malignant B-cell disorder characterized by a monoclonal expansion of plasma cells (PC) in the bone marrow (BM). During the main course of disease evolution, MM cells depend on the BM microenvironment for their growth and survival. Reciprocal interactions between MM cells and the BM mediate not only MM cell growth, but also protect them against apoptosis and cause bone disease and angiogenesis. A striking feature of MM represents the predominant localization and retention of MM cells in the BM. Although BM PC indeed represent the main neoplastic cell type, small numbers of MM cells can also be detected in the peripheral blood circulation. It can be assumed that these circulating cells represent the tumour-spreading component of the disease. This implicates that MM cells have the capacity to (re)circulate, to extravasate and to migrate to the BM (homing). In analogy to the migration and homing of normal leucocytes, the BM homing of MM cells is mediated by a multistep process of extravasation with adhesion to the endothelium, invasion of the subendothelial basement membrane, followed by further migration within the stroma, mediated by chemotactic factors. At the end stage of disease, MM cells are thought to develop autocrine growth supporting loops that enable them to survive and proliferate in the absence of the BM microenvironment and to become stroma-independent. In this stage, the number of circulating cells increases and growth at extramedullary sites can occur, associated with alteration in adhesion molecule and chemokine receptor expression. This review summarizes the recent progress in the study of the extravasation and homing mechanisms of MM cells.