Morbidity In Multiple Myeloma Patients Research Articles

TAK1-inhibitors are cytotoxic for multiple myeloma cells alone and in combination with melphalan.

Multiple myeloma (MM) is an incurable cancer caused by malignant transformation of plasma cells. Transforming growth factor-β activated kinase 1 (MAP3K7, TAK1) is a major regulator of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) signaling. Both NF-κB and MAPK control expression of genes with vital roles for drug resistance in MM. TAK1 is an attractive drug target as it switches these survival pathways to cell death. Our analysis showed that patients with high MAP3K7 expression in the tumor had shorter overall and progression free survival. The TAK1-inhibitors NG25 and 5Z-7-oxozeaenol (5Z-7) were cytotoxic to MM cell lines and patient cells. NG25 reduced expression of MYC and E2F controlled genes, involved in tumor cell growth, cell cycle progression and drug resilience. TAK1 can be activated by genotoxic stress. NG25 and 5Z-7 induced both synergistic and additive cytotoxicity in combination with the alkylating agent melphalan. Melphalan activated TAK1, NF-κB, and the MAPKs p38 and c-Jun N-terminal kinase (JNK), as well as a transcriptional UV-response. This was blocked by NG25, and instead apoptosis was activated. MM induce elevated bone-degradation resulting in myeloma bone disease (MBD), which is the main cause of disability and morbidity in MM patients. NG25 and 5Z-7 reduced differentiation and viability of human bone degrading osteoclasts, suggesting that TAK1-inhibition can have a double beneficial effect for patients. In sum, TAK1 is a promising drug target for MM treatment.

A Radiographic Assessment of Dental Morbidity in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplant: A Retrospective Study

Aim: To assess the dental and oral morbidity in multiple myeloma patients as expressed in dental radiographs before autologous stem cell transplant. Materials and Methods: A retrospective study involving 79 multiple myeloma patients was designed to collect data prior to their autologous stem cell transplant. Patients were seen at the oral medicine clinic at the University of Florida College of Dentistry during the years 2010–2013. Through available patient data and interpretation of radiographs, the following variables were recorded: age, gender, carious lesions, periodontal disease, and periapical radiolucency. In addition, the incidence of root fragment retention and the presence of punched-out osteolytic lesions were recorded. Cochran–Mantel–Haenszel (CMH) tests and logistic regression were performed for descriptive analysis and presentation of the data. Results: Seventy-nine multiple myeloma patients were recruited for this study. Ages ranged from 28 to 79 years (mean = 61, SD = 9.6), including 41 (51.9%) females and 38 (48.1%) males. The results demonstrated dental decay in 64.56% of patients, periodontal disease in 62.03%, apical rarefying osteitis in 13.92% of patients, and punched-out lesions in 24.05% of patients. Conclusion: Our study indicates high dental morbidity in multiple myeloma patients prior to autologous stem cell transplant. The elimination of foci of infection is highly recommended prior to autologous stem cell transplant for this high-risk population because of the potential risk of bacteremia/septicemia from oral bacteria associated with dental morbidity.

Ixazomib Modulates Bone Remodeling and Actives Sonic Hedgehog Pathways

Multiple myeloma (MM) is a clonal B-cell malignancy characterized by an accumulation of clonal plasma cells (PC) in the bone marrow (BM) leading to bone destruction and BM failure. Osteolytic bone disease is a common manifestation of MM that leads to progressive skeleton destruction and is the most severe cause of morbidity in MM patients. Pathogenetic mechanisms of MM bone destruction are closely linked to MM PC and osteoclasts (OCs) hyperactivity coupled with defective osteoblast (OB) function unable to counteract bone resorption. We recently demonstrated that the proteasome inhibitor (PI) Bortezomib, commonly used to treat MM, was capable to inhibit osteoclastic differentiation modulating chitinase family genes. In this work we investigated the effect of Ixazomib (IXA), a third generation PI, on osteoclastogenesis and osteogenic differentiation. Human monocytes were differentiated in OCs in presence of OC medium (supplemented with RANKL and M-CSF), and/or 10nM IXA. We observed that IXA was able to inhibit the expression of different OCs markers such as RANK, CTSK, TRAP, and MMP9 when added in OC medium in respect to OC medium alone (p<0.001). In addition, IXA treatment reduced CHIT1 enzymatic activity and downregulated CHIT1 and YKL40 (both mRNA and proteins). Immunofluorescence evaluation confirmed that IXA inhibited the mature OCs formation with five or more nuclei. Moreover, IXA was able to stimulate osteogenic differentiation of human mesenchymal stromal cells (MSCs). After 21 days of treatment, IXA alone or added to osteogenic medium increased the osteogenic markers genes (BMP2, RUNX2, Osteocalcin and Osteonectin). Immunofluorescence assay confirmed the increase of BMP2 after IXA treatment alone or in combination with osteogenic medium. Sonic Hedgehog (Shh) is one of the intricate signal transduction mechanisms that govern the precisely regulated developmental processes of multicellular organisms. Its signaling cascade plays an important role in bone homeostasis, and reducing Shh pathway protects against age-related bone loss. In this work we observed that IXA, but not Bortezomib, was able to bind the Smoothened (Smo) receptor which is the transducing molecule of the extracellular signal of Shh. Interestingly, using cellular thermal shift assay (CETSA), we demonstrated that IXA was able to bind directly Smo receptor activating the Shh cascade that leads to the nuclear translocation of Gli1 an effector of this pathway. Inhibiting Shh signaling by using an inhibitor of Smo activation (Cyclopamine), IXA-activated ostegenic differentiation-related genes were down-regulated. In conclusion, our data demonstrated that IXA regulates bone remodeling decreasing osteoclastogenesis and promoting osteogenic differentiation and therefore represents a good therapeutic option to improve the complex pathological condition of patients with MM. Disclosures Conticello: Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Palumbo:Amgen: Honoraria; Celgene: Honoraria; Hospira: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Teva: Honoraria. Di Raimondo:Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Celgene: Consultancy, Honoraria, Research Funding.

External Validation of the Impede VTE Risk Score in Newly Diagnosed Multiple Myeloma (MM) Patients

Background: Venous thromboembolism (VTE) is a prevalent cause of morbidity in MM patients. The IMPEDE VTE score was recently proposed by Sanfilippo KM et al. in 2018 ASH annual meeting to predict VTE in MM. Herein, we report on the external validation of this score. Methods: We reviewed consecutive newly diagnosed MM patients who were treated at the Cleveland Clinic between 2010 and 2012. All treatment variables were collected as time-varying variables. Poor cytogenetic features were defined as monosomy 13 or 17, t(4;14), or t(4;16). We calculated the total IMPEDE VTE score for each patient as previously defined; immunomodulatory drug (IMiD) use (+3), BMI >25 kg/m2 (+1), pathologic pelvis/femur fracture (+2), erythropoiesis-stimulating agent use (+1), low/high dexamethasone use (+2/+4), doxorubicin use (+2), Asian race (-3), history of VTE (+3), central venous catheter use (+2), prophylactic aspirin or enoxaparin (-2), therapeutic anticoagulation (-5). Patients with IMPEDE VTE score of <3, 3 to 6, and >6 were defined as low-, intermediate-, and high-risk groups, respectively. Cumulative incidence of symptomatic VTE after initiation of systemic treatment was calculated with death as competing risk and compared with the Gray's test. Overall survival (OS) was estimated by the Kaplan-Meier method and compared with the log-rank test. Multivariable Cox analysis was used to identify independent predictors of OS. Results: We identified 210 MM patients, 102 (49%) were female, 31 (15%) were black, and median age at diagnosis was 63 years (range: 30 - 91). Fifteen (7%) patients had VTE prior to MM diagnosis and 30 (14%) patients had pathologic pelvic or femur fracture at or after MM diagnosis. Poor cytogenetic features were seen in 65 (31%) patients. ECOG performance status at diagnosis was ≥2 for 33 (16%) patients. Sixty-seven (32%), 65 (31%), and 57 (27%) patients had ISS stage I, II, and III disease, respectively. MM subtypes were IgG, IgA, and light-chain disease for 109 (52%), 46 (22%), and 52 (25%) patients, respectively. IMiDs and low-dose dexamethasone were given to 145 (69%) and 205 (98%) patients, respectively. Seventy-seven (37%) patients underwent autologous hematopoietic cell transplant. Patient and treatment characteristics were compared between patients with and without VTE after MM diagnosis in Table 1. Twenty-two (10%) patients had symptomatic VTE within 6 months after initiation of systemic treatment for MM. When IMPEDE VTE score was calculated based on the risk factors during this time period, 37 (18%), 157 (75%), and 16 (8%) patients were in low-, intermediate- and high-risk groups, respectively. Six-months cumulative incidence of VTE in low-, intermediate- and high-risk groups were 2.7% (95% CI: 0 - 7.9), 10.8% (95% CI: 6.0 - 15.7), and 25% (95% CI: 3.8 - 46.2), respectively (p=0.011) (Figure 1A). Whereas, 39 (19%) patients were diagnosed with symptomatic VTE during median follow-up of 86 months. When the highest IMPEDE VTE score for each patient was calculated based on the risk factors at any time after initiation of treatment, 16 (8%), 151 (72%), and 43 (20%) patients were in low-, intermediate-, and high-risk groups, respectively. Seven-year cumulative incidence of VTE in low-, intermediate- and high-risk groups were 9.0% (95% CI: 0 - 25.7), 16.3% (95% CI: 10.3 - 22.3), and 29.3 (95% CI: 15.2 - 43.3), respectively (p=0.014) (Figure 1B). Seven-year OS of patients with and without VTE within 6 months after initiation of treatment was 50% (95% CI: 32% - 79%) and 46% (95% CI: 39% - 55%), respectively (p=0.4). On multivariable analysis, VTE vs no VTE within 6 months after initiation of treatment did not predict OS (HR 1.10, 95% CI: 0.46 - 2.66, p=0.8), whereas each 1-year increase in age (HR 0.99, 95% CI: 0.96 - 1.02, p=0.61), each 1 increase in ECOG performance status (HR 1.77, 95% CI: 1.24 - 2.53, p=0.002) and ISS stage (HR 1.50, 95% CI: 1.06 - 1.14, p=0.024), poor vs non-poor cytogenetics features (HR 4.38, 95% CI: 2.25 - 8.57, p<0.0001), high vs normal LDH (HR 1.94, 95% CI: 1.05 - 3.60, p=0.035), IMiD use vs non-use at first induction (HR 0.52, 95% CI: 0.29 - 0.43, p=0.026), and transplant vs no transplant (HR 0.40, 95% CI: 0.20 - 0.79, p=0.008) were statistically significant predictors of OS (Table 2). Conclusion: In this cohort of MM patients, we showed that IMPEDE VTE score was able to stratify patients into distinct risk groups and can be a helpful tool to provide personalized strategies for thromboprophylaxis. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Valent:Takeda pharmaceuticals: Speakers Bureau; Amgen corporation: Speakers Bureau; Celgene corporation: Speakers Bureau.

Ixazomib inhibits osteoclastogenesis and promotes osteogenic differentiation in vitro

Multiple myeloma (MM) is a clonal B-cell malignancy characterized by an accumulation of clonal plasma cells (PC) in the bone marrow (BM) leading to bone destruction and BM failure. Osteolytic bone disease is a common manifestation of MM that leads to progressive skeleton destruction and is the most severe cause of morbidity in MM patients. Proteasome inhibitors (PIs) are the most important drugs for the treatment of multiple myeloma. Pathogenetic mechanisms of MM bone destruction are closely linked to MM PC and osteoclasts (OCs) hyperactivity coupled with defective osteoblast (OB) function unable to counteract bone resorption.

An Increased Number of Cybord Induction Cycles Does Not Increase Peri-Transplant Morbidity in Multiple Myeloma Patients

Introduction:Despite a plethora of novel therapies, autologous stem cell transplant (ASCT) continues to offer a progression free survival benefit to multiple myeloma patients. At our institution, standard of care for transplant-eligible patients remains induction with cyclophosphamide, bortezomib, and decadron (CyBorD) for 4 cycles, followed by ASCT. However, limited resources for collection and the logistics of receiving late referrals from outside centers often result in patients receiving additional cycles of treatment prior to transplant. We sought to determine whether the administration of additional induction chemo led to increased peri-transplant morbidity.Methods:With REB approval, chart review was done for myeloma patients receiving an ASCT between 2007 and 2017. Only patients receiving induction with CyBorD or bortezomib-decadron on a like schedule were included in analysis. Patients received pre-ASCT conditioning of high-dose melphalan (93.5%) or busulfan-melphalan (6.5%). Data collected included patient's age, gender, myeloma subtype, ISS score, and cytogenetics, as well as the number of induction cycles received and hematopoietic cell transplantation-specific co-morbidity index (HCT-CI). The primary endpoint assessed was median length of hospital stay (LOS) post-infusion. Secondary end-points included time to engraftment, ICU transfer rate, infection rate, organ-specific toxicity, 100-day mortality, and response as measured by VGPR rate at 100 days. Patients were grouped into those who received 2-4 cycles vs. 5-9 cycles of induction.Results:Fifty-three patients received 2-4 cycles of induction and 54 received 5-9. Median age was 61 for both groups, gender was well-matched (53% vs. 57% male), and HCT-CI ≥ 3 was similar (26% vs. 31%).The only significant difference between groups was the subtype of myeloma, with the 2-4 group having 30.1% light chain disease (vs. 14.8%) and 39.6% IgG subtype (vs. 61.1%) (p = 0.026). Median LOS post-infusion was 20 days in the 2-4 group and 17 days in the 5-9 group. Median time to engraftment was 12 days in both (range 9-21 in 2-4 group, 10-20 in 5-9 group). ICU transfer was needed in 4 (7.5%) and 6 (11.1%) patients in the respective groups, and there were two deaths in the 5-9 group (one of sepsis at d+16 and one of multi-organ failure at d+46). Both patients had HCT-CI scores of 5, and the differences in ICU and mortality rates were not statistically significant. There were no significant differences in measurable toxicity. Documented infection or febrile neutropenia occurred in 92.5% vs. 88.9% (p = 0.53); acute kidney injury in 20.8% vs. 11.1% (p= 0.17); and acute liver injury in 24.5% vs. 14.8% (p = 0.21). Among evaluable patients, 84.6% achieved VGPR or better in the 2-4 group and 78.4% in the 5-9 group, although the latter had a higher number of patients with high-risk cytogenetics by FISH (6 vs. 10 with t(4;14) or 17p-).Discussion:Evidence for a precise number of cycles of induction prior to ASCT is scarce. A recent study by Charaborty et. al.(BJHJul 2018) showed that median PFS and OS were similar between patients who received ≤ 4 months vs. > 4 months of induction. 39% of their patients received bortezomib-based induction without lenalidomide, akin to our regimen. Likewise, our study showed no significant difference in VGPR rates at 100 days, an endpoint used at our center as one criterion for determining the need for tandem transplant and potential increased chemotherapy exposure for the patient. Our overall VGPR rate for the group of 81.6% is comparable to previously published results, suggesting our population is representative of a typical myeloma cohort. Most importantly, our data suggests no increase in peri-transplant toxicity as a result of the additional induction chemotherapy burden. In fact, there was a surprising trend towards decreased organ toxicity and shorter hospital stay, and the only two early deaths occurred in high-risk patients. Among the 17 patients who received the heaviest induction burden (7-9 cycles), there were no deaths and only 1 ICU transfer. While there did not appear to be any long-term benefit to greater induction length, our study provides reassurance that it is safe to continue CyBorD induction past the intended 4 cycles without compromising patient safety at the time of transplant. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Bortezomib modulates CHIT1 and YKL40 in monocyte-derived osteoclast and in myeloma cells.

Osteolytic bone disease is a common manifestation of multiple myeloma (MM) that leads to progressive skeleton destruction and is the most severe cause of morbidity in MM patients. It results from increased osteolytic activity and decrease osteoblastic function. Activation of mammalian chitinases chitotriosidase (CHIT1) and YKL40 is associated with osteoclast (OCs) differentiation and bone digestion. In the current study, we investigated the effect of two Bortezomib’s concentration (2.5 and 5 nM) on osteoclastogenesis by analyzing regulation of chitinase expression. OCs exposition to bortezomib (BO) was able to inhibit the expression of different OCs markers such as RANK, CTSK, TRAP, and MMP9. In addition BO-treatment reduced CHIT1 enzymatic activity and both CHIT1 and YKL40 mRNA expression levels and cytoplasmatic and secreted protein. Moreover, immunofluorescence evaluation of mature OCs showed that BO was able to translocate YKL40 into the nucleus, while CHIT1 remained into the cytoplasm. Since MM cell lines such as U266, SKM-M1 and MM1 showed high levels of CHIT1 activity, we analyzed bone resorption ability of U266 using dentin disk assay resorption pits. Silencing chitinase proteins in U266 cell line with specific small interfering RNA, resulted in pits number reduction on dentine disks. In conclusion, we showed that BO decreases osteoclastogenesis and reduces bone resorption in OCs and U266 cell line by modulating the chitinases CHIT1 and YKL40. These results indicate that chitinases may be a therapeutic target for bone disease in MM patients.

Bone disease in multiple myeloma: pathophysiology and management.

Myeloma bone disease (MBD) is a devastating complication of multiple myeloma (MM). More than 80% of MM patients suffer from destructive bony lesions, leading to pain, fractures, mobility issues, and neurological deficits. MBD is not only a main cause of disability and morbidity in MM patients but also increases the cost of management. Bone destruction and lack of bone formation are main factors in the development of MBD. Some novel factors are found to be involved in the pathogenesis of MBD, eg, receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG) system (RANKL/OPG), Wingless (Wnt), dickkopf-1 (Wnt/DKK1) pathway. The addition of novel agents in the treatment of MM, use of bisphosphonates and other supportive modalities such as radiotherapy, vertebroplasty/kyphoplasty, and surgical interventions, all have significant roles in the treatment of MBD. This review provides an overview on the pathophysiology and management of MBD.

Erythropoietin Treatment in Multiple Myeloma – Friend or Foe?

AbstractAbstract 5013Erythropoietin (Epo), mainly produced by the adult kidney, is the major hormone that promotes erythropoiesis. As such, clinical introduction of recombinant human Epo (rHuEpo) and its derivatives (Epoetins), has been a breakthrough in treating patients with anemia, mainly those with chronic kidney failure and cancer patients on chemotherapy. In contrast to 'red flags' suggesting possible detrimental effects of Epo in certain cases of cancer, the hormone was found by numerous studies to have beneficial effects such as neuroprotective and cardio-protective effects. Immune-mediated anti-cancer effects were also documented, as exemplified in multiple myeloma (MM) patients and mouse models. These effects, at least in part, are mediated by Epo receptors (EpoRs) present on cells other than the erythroid lineage. In this respect, we have recently identified functional EpoRs in murine bone marrow-derived macrophages.MM is characterized by clonal proliferation of malignant plasma cells that produce a pathological paraprotein, accompanied by a decrease in the levels of the normal immunoglobulins. Typically this disease is associated with lytic bone lesions. In 5T33 MM, an experimental murine model of MM (producing an IgG2bk paraprotein), mice that were treated with rHuEpo, displayed a 50% decrease in the levels of the pathological K light chain. Notably, the decline in the levels of normal IgA, typically observed in the MM mice, was attenuated in the Epo-treated MM mice. Administration of rHuEpo led to increased levels of liver (three fold increase) and splenic (ten fold increase) macrophages as determined by the number of F4/80/CD11b expressing cells. These findings were associated with an increase in the transcript levels of the Th1 cytokine IFN-g in the bone marrow of Epo-treated 5T33 MM mice as compared to diluent-treated 5T33 MM mice. As MM is typically associated with a Th2 response, Epo may have a beneficial effect in MM, by shifting the balance towards a Th1 response.Myeloma-associated bone disease is considered a major cause of morbidity in MM patients. Using high-resolution computed tomography analysis of recovered femurs we confirmed that the 5T33 MM mice indeed exhibit bone disease. Femur trabecular bone density (bone volume/total volume) of 5T33 MM mice was 43% lower (p=0. 04) than that of their healthy control counterparts (3. 1%±0. 003 versus 4. 4%±0. 008, respectively). This decrease in bone density reflects a 38% increase (p=0. 001) in the total femur volume (4. 38mm3±0. 13 and 2. 72mm3±0. 95 in the 5T33 MM mice, compared to that of healthy mice) and no significant change in trabecular bone volume. Unexpectedly, Epo treatment of the MM mice induced a 34% reduction (p=0. 004) in trabecular bone density compared to the diluent-treated MM mice (2%±0. 007 and 3. 1%±0. 003, respectively) and 41% (p=1E-6) reduction in trabecular number (1. 54mm−1±0. 266 and 2. 62mm−1±0. 23, respectively). This was accompanied by a 19% increase (p=0. 006) in trabecular bone thickness in the Epo-treated MM mice (0. 043mm±0. 005 and 0. 036mm±0. 003, respectively), suggesting a mechanical compensatory mechanism in response to the extensive bone loss.Taken together, our data demonstrate that Epo's impact extends well beyond erythropoiesis. The administration of rHuEpo may be considered as an adjunct treatment to specific anti-MM therapy in cases which require elevation of the erythrocyte counts and an enhancement of the immune system. Yet, a bone protection regimen (bisphosphonates?) should be considered.This study is supported by the Multiple Myeloma Research Foundation, to DN. Disclosures:No relevant conflicts of interest to declare.

Developing In Vivo Model for Studying Mechanisms of Osteoblast Suppression in Multiple Myeloma.

Multiple myeloma (MM) is an incurable neoplastic disease characterized by an accumulation of plasma cells in bone marrow. Osteolytic bone lesions are the major source of morbidity in MM patients and are associated with bone pain and fractures and hypercalcemia. The bone lesions result from increased osteoclastic bone destruction in areas adjacent to the myeloma cells. New bone formation that normally happens at sites of previous bone resorption still occurs in early stages of the disease but is absent in advanced MM. Although the molecular basis for the increased osteoclastic activity has been intensely investigated, the basis for the decreased osteoblast activity is just beginning to be understood. Recently, inhibitors of WNT signaling pathway, Dickkorpf1 (DKK1) and secreted Frizzle-Related Protein-2 (sFRP2) have been identified as factors involved in osteoblast suppression in MM. In addition, IL-3 and IL-7 are increased in plasma of MM patients and suppress osteoblastogenesis in cell culture models. However, the role of those factors in the osteoblastic activity in MM patients is unclear. Studies in patients are confounded by cytotoxic therapy as well as bisphosphonates, which are standard therapy for MM patients. Therefore, preclinical in vivo models are required to delineate the mechanisms responsible for the profound osteoblast suppression in MM. We have developed a mouse model of myeloma bone disease in which genetically modified myeloma cells can be selectively ablated without the confounding effects of cytotoxic therapies and allows us to tract the growth of MM cells. The 5TGM1 cell line which is the most common version of murine MM, was stably transfected with the thymidine kinase (TK) gene from herpes simplex virus, which permits eradication of myeloma cells with ganciclovir, as well as GFP and luciferase genes to detect the presence of MM cells. One ug/ml ganciclovir treatment in culture results in 100% death of the transfected 5TGM1 cells in 4 days. Importantly, ganciclovir treatment of primary marrow cell cultures had no effect on growth and differentiation of osteoblast and hematopoietic progentitors. Co-culturing of primary marrow cells with 5TGM1 expressing TK has no bystander effect on osteoblast differentiation with ganciclovir treatment. Subcutaneously implanted 5TGM1 cells into SCID mice were eradicated by intraperitoneal injection of 20mg/kg ganciclovir/d for 2 weeks. The dose of ganciclovir did not affect osteoblast differentiation of primary marrow culture from the mice treated with ganciclovir. Then we injected the 5TGM1 cells into tibia of SCID nude mice (n=4 per group). After measuring the increase of serum IgG2b level, half of the mice were treated with ganciclovir for 2 weeks and the other with saline. Our preliminary data show that osteogenic cultures of bone marrow from the ganciclovir treated mice had significantly higher alkaline phosphatase activity than cultures derived from the saline treated group (p=0.03). In addition, the ganciclovir treated mice had tendency of higher trabecular bone volume than the saline-treated group (p=0.08). These results demonstrate that this model should be useful for studying mechanisms of osteoblast suppression in MM.