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To systematically review all dosimetric studies investigating the impact of deep inspiration breath hold (DIBH) compared with free breathing (FB) in mediastinal lymphoma patients treated with proton therapy as compared to IMRT (intensity-modulated radiation therapy)-DIBH.We conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline using the PubMed database to identify studies of mediastinal lymphoma patients with dosimetric comparisons of proton-FB and/or proton-DIBH with IMRT-DIBH. Parameters included mean heart (MHD), lung (MLD), and breast (MBD) doses, among other parameters. Case reports were excluded. Absolute differences in mean doses 1 Gy between comparators were considered to be clinically meaningful.As of April 2021, eight studies fit these criteria (n = 8), with the following comparisons: proton-FB vs IMRT-DIBH (n = 5), proton-DIBH vs proton-FB (n = 5), and proton-DIBH vs IMRT-DIBH (n = 8). When comparing proton-FB with IMRT-DIBH in 5 studies, MHD was reduced with proton-FB in 2 studies, was similar (1 Gy difference) in 2 studies, and increased in 1 study. On the other hand, MLD and MBD were reduced with proton-FB in 3 and 4 studies, respectively. When comparing proton-DIBH with proton-FB, MHD and MLD were reduced with proton DIBH in 4 and 3 studies, respectively, while MBD remained similar. Compared with IMRT-DIBH in 8 studies, proton-DIBH reduced the MHD in 7 studies and was similar in 1 study. Furthermore, MLD and MBD were reduced with proton-DIBH in 8 and 6 studies respectively. Integral dose was similar between proton-FB and proton-DIBH, and both were substantially lower than IMRT-DIBH.Accounting for heart, lung, breast, and integral dose, proton therapy (FB or DIBH) was superior to IMRT-DIBH. Proton-DIBH can lower dose to the lungs and heart even further compared with proton-FB, depending on disease location in the mediastinum, and organ-sparing and target coverage priorities.

An estimated 30-40% of patients with diffuse large B cell lymphoma (DLBCL) will either relapse or have refractory disease with first-line chemoimmunotherapy. The standard approach for relapsed/refractory disease is salvage chemotherapy followed by autologous stem cell transplantation, but this approach cures fewer than 20% of patients in the modern era. This low cure rate is a result of refractory disease despite salvage therapy, medical ineligibility for transplantation, or relapse following transplantation. CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment paradigm for patients with relapsed or refractory disease, leading to response rates that range between 52% to 93%, and overall survival rates at one year between 48% and 83%. However, the time from apheresis to infusion of CAR T-cell therapy currently takes several weeks, leaving many patients in need of bridging therapy to control disease progression. Radiation therapy (RT) has been utilized as a bridging therapy prior to CAR T infusion in select patients, with some remarkable responses in chemorefractory disease. Furthermore, the potential synergy between RT and CAR T-cells due to immunomodulatory mechanisms has generated considerable excitement, as it has been hypothesized that RT could also be considered as a salvage therapy following CAR T failure, based on limited case series published to date. Prospective trials are warranted to validate the significance of this modality following CAR T-cell therapy.

The NCCN Guidelines for Survivorship are intended to help healthcare professionals working with cancer survivors to ensure that each survivor’s complex and varied needs are addressed. The Guidelines provide screening, evaluation, and treatment recommendations for consequences of adult-onset cancer and its treatment; recommendations to help promote healthful lifestyle behaviors, weight management, and immunizations in survivors; and a framework for care coordination. This article summarizes the recommendations regarding employment and return to work for cancer survivors that were added in the 2021 version of the NCCN Guidelines.

The NCCN Guidelines for Survivorship provide screening, evaluation, and treatment recommendations for consequences of adult-onset cancer and its treatment, with the goal of helping healthcare professionals who work with survivors, including those in primary care. The guidelines also provide recommendations to help clinicians promote physical activity, weight management, and proper immunizations in survivors and facilitate care coordination to ensure that all of the survivors’ needs are addressed. These NCCN Guidelines Insights summarize additions and changes made to the guidelines in 2020 regarding cardiovascular disease risk assessment and screening for subsequent primary malignancies.

Purpose Radiotherapy is an effective palliative treatment modality for cutaneous T-cell lymphomas such as mycosis fungoides (MF) due to its sensitivity to radiation. For patients with extensive skin involvement of the limbs, it is challenging to accommodate a number of clinical concerns: providing homogeneous dose to an irregular surface, minimizing the treatment time, and maintaining reproducible setups for multiple treatments. We utilized water as a tissue compensator to address all of these concerns. Case presentation A 66-year-old man with a history of stage IB mycosis fungoides previously treated with multiple prior therapies, including surface applicator high dose rate (HDR) brachytherapy. The disease then progressed to involve the right upper extremity distal to the prior treatment and much of the left upper extremity. In addition, he had recurrence of the prior right posterior thigh plaque, and face without scalp involvement. In order to avoid prolonged treatment time and inhomogeneous dose delivery, external beam radiation therapy using a water bath for tissue compensation was used to treat the upper extremities. We used a water tank and aligned each extremity to the center of the tank with custom-fit immobilization devices. A dose of 10 Gy in 2.5 Gy per fraction using 6 mega-voltage photons was prescribed to the mid-plane of the water tank. Two opposed lateral beams were used to obtain homogeneous dose across the water tank. Results The patient tolerated the treatment without toxicities. A complete response was observed during follow-ups at 6 and 12 weeks after treatment. Conclusions The patient reported improved function and cosmesis following treatment of his upper extremities with the water bath technique radiation therapy. Using a water bath as a tissue compensator was a fast and reproducible method for treatment of MF with circumferential cutaneous involvement of the extremity.

Purpose/objective(s) Painful osteolytic bone lesions are common in patients with multiple myeloma (MM). Radiotherapy (RT) is effective in providing pain relief from MM bone lesions in over 80% of patients. There is no consensus as to the most effective dose or fractionation for palliation. Shorter courses of RT are not only more convenient for patients and their families, but they also have less impact on timing of systemic therapies. There is precedent for using 2 Gy x 2 for palliation of lymphomas, which have similar radiosensitivity to myeloma. The primary objective is to determine whether treatment with 2 Gy x 2 to painful myeloma bone lesions achieves patient-reported pain reduction comparable to historical controls at 4 weeks. Secondary objectives will assess QOL endpoints, use of analgesia and time to pain relief, and duration of pain relief. Materials/methods Patients who consent to participation will complete quality of life and pain questionnaires (Brief Pain Index, EORTC QLQ-BM22, and EORTC QLQ-C30) prior to treatment and at 2,4,8 weeks and 6 months following treatment. Pain response, as defined by the international consensus on palliative RT for bone metastases, will be measured based on BPI and daily oral morphine equivalent. Reirradiation at standard dose can be considered at ≥4 weeks following initial treatment for indeterminate pain response or pain progression. Cytogenetics and International Myeloma Working Group risk stratification and response criteria are recorded, when available, but are not required for patient participation. Results This trial, supported by ILROG, has opened at 7 institutions with one more in process of opening. Prior to COVID, accrual was 1.5 patients per month. Since COVID, enrollment has been at 0.7 patients per month. A total of 18 patients have been accrued. The median age of patients accrued is 65.5 years with 7/18 female patients. Fourteen patients are Caucasian. Twelve patients have an ECOG performance score of 1-2. Thirteen patients had pain response captured at 4 weeks following RT. Of the 5 patients that did not complete questionnaires at 4 weeks post-RT, 2 expired, 1 was lost to follow-up, 1 had a missed evaluation and 1 had pain progression). The most common site of treatment was the shoulder (4/18). Conclusion This ongoing prospective trial in palliation of multiple myeloma bone lesions is feasible and able to accrue at multiple institutions and will provide valuable information as to the role of low-dose RT in this population.

Low-dose total skin electron beam therapy provides a durable treatment response for skin lesions caused by cutaneous T-cell lymphoma. We prospectively assessed the durability of response and quality of life for patients receiving low-dose total skin electron beam therapy using a novel rotational technique and dosing regimen.Patients completed baseline Skindex-29 quality-of-life surveys and had baseline Modified Severity-Weighted Assessment Tool score recorded. Patients received 12 Gy in 12 fractions with a dual-field rotational technique. The primary outcome was overall response rate, with the secondary outcomes being time to treatment response, duration of clinical benefit, and quality-of-life change.We enrolled 20 patients and recorded an overall response rate of 90%. The median time to treatment response was 6.5 weeks. The baseline Modified Severity-Weighted Assessment Tool score was 55.6 and it declined to a median of 2.2 at last follow-up (P .001). The median duration of clinical benefit was 21 months. There was a decline in the Skindex-29 total score and every subdomain when each follow-up visit was compared (P = .004).This prospective study demonstrated a very high overall response rate and improvement in skin-related quality of life. Low-dose rotational total skin electron beam therapy can be implemented routinely in clinical practice.

Purpose Despite high response rates, there has been reluctance to use radiation therapy for patients with relapsed/refractory (r/r) Hodgkin (HL) or aggressive non-Hodgkin lymphoma (NHL) given concerns for subacute and late toxicities. Symptomatic pneumonitis, a subacute toxicity, has an incidence of 17% to 24% (≥grade 2) even with intensity modulated radiation therapy. Proton therapy (PT), which has no exit radiation dose, is associated with a lower dose to lung compared with other radiation techniques. As risk of radiation pneumonitis is associated with lung dose, we evaluated whether pneumonitis rates are lower with PT. Methods and Materials Within an international, multi-institutional cohort, we retrospectively evaluated the incidence and grade of radiation pneumonitis (National Cancer Institute Common Terminology Criteria for Adverse Events v4) among patients with r/r HL or NHL treated with PT. Results A total of 85 patients with r/r lymphoma (66% HL, 34% NHL; 46% primary chemorefractory) received thoracic PT from 2009 to 2017 in the consolidation (45%) or salvage (54%) setting. Median dose was 36 Gy(RBE). Before PT, patients underwent a median of 1 salvage systemic therapy (range, 0-4); 40% received PT within 4 months of transplant. With a median follow-up of 26.3 months among living patients, 11 patients developed symptomatic (grade 2) pneumonitis (12.8%). No grade 3 or higher pneumonitis was observed. Dose to lung, including mean lung dose, lung V5, and V20, significantly predicted risk of symptomatic pneumonitis, but not receipt of brentuximab, history of bleomycin toxicity, sex, or peritransplant radiation. Conclusions PT for relapsed/refractory lymphoma was associated with favorable rates of pneumonitis compared with historical controls. We confirm that among patients treated with PT, pneumonitis risk is associated with mean lung and lung V20 dose. These findings highlight how advancements in radiation delivery may improve the therapeutic ratio for patients with relapsed/refractory lymphoma. PT may be considered as a treatment modality for patients with relapsed/refractory lymphoma in the consolidation or salvage setting.

Purpose To determine the effect of treatment changes over time on all-cause mortality risk in patients with early-stage Hodgkin lymphoma (HL) after radiation therapy. The long-term survivorship of those with HL necessitates quantification of the late risk of mortality from HL and other causes. Methods and Materials An institutional review board–approved retrospective study was conducted using a multi-institutional database of 1541 stage I and II HL patients treated from 1968 to 2007 with radiation therapy alone or combined-modality treatment. The analytic methods included cumulative incidence function, Kaplan-Meier estimates and log-rank tests for overall survival (OS) differences, and Cox proportional hazards modeling. Results The median age at diagnosis was 27 years. At a median follow-up of 15.2 years (35% of patients with >20 years of follow-up), 395 patients had died of all causes, including 85 HL, 168 second malignancy (25 hematologic and 143 nonhematologic), 70 cardiovascular, and 21 pulmonary deaths. The cumulative incidence of non-HL mortality had surpassed HL mortality at 8.3 years. For patients treated from 1968 to 1982, 1983 to 1992, and 1993 to 2007, the 15-year OS rates were 78%, 85%, and 88%, respectively (P=.0016). On Cox proportional hazards analysis, age, B symptoms, and number of disease sites were significantly associated with all-cause mortality in the first decade of follow-up, with a trend toward significance for radiation field extent. Conclusions The all-cause mortality risk was significantly lower for patients treated in the most recent era during the first decade of follow-up, likely due to improved HL therapy resulting in a higher cure rate and lower treatment-related toxicity from smaller radiation fields. Current efforts toward radiation treatment reduction might further reduce the long-term mortality risk for these patients.

To investigate the determinants of radiation therapy refusal in pediatric cancer, we used the Surveillance, Epidemiology, and End Results registry to identify 24,421 patients who met the eligibility criteria, diagnosed between 1974 and 2012. Patients had any stage of cancer, were aged 0 to 19, and received radiation therapy or refused radiation therapy when it was recommended. One hundred twenty-eight patients (0.52%) refused radiation therapy when it was recommended. Thirty-two percent of patients who refused radiation therapy ultimately died from their cancer, at a median of 7 months after diagnosis (95% confidence interval, 3-11 mo), as compared with 29.0% of patients who did not refuse radiation therapy died from their cancer, at a median of 17 months after diagnosis (95% confidence interval, 17-18 mo). On multivariable analysis, central nervous system (CNS) site, education, and race were associated with radiation refusal. The odds ratio for radiation refusal for patients with CNS disease was 1.62 (P=0.009) as compared with patients without CNS disease. For patients living in a county with ≥10% residents having less than ninth grade education, the odds ratio for radiation refusal was 1.71 (P=0.008) as compared with patients living in a county with

Purpose In studies evaluating the benefit of adjuvant therapies, immortal time bias (ITB) can affect the results by incorrectly reporting a survival advantage. It does so by including all deceased patients who may have been planned to receive adjuvant therapy within the observation cohort. Given the increase in National Cancer Database (NCDB) analyses evaluating postoperative radiation therapy (PORT) as an adjuvant therapy, we sought to examine how often such studies accounted and adjusted for ITB. Methods and Materials A systematic review was undertaken to search MEDLINE and EMBASE from January 2014 until May 2019 for NCDB studies evaluating PORT. After appropriate exclusion criteria were applied, 60 peer-reviewed manuscripts in which PORT was compared with postoperative observation or maintenance therapy were reviewed. The manuscripts were reviewed to evaluate whether ITB was accounted for, the method with which it was adjusted for, impact factor, year of publication, and whether PORT was beneficial. Results Of the 60 publications reviewed, 23 studies (38.3%) did not include an adjustment for ITB. Most studies that did adjust for ITB employed a single landmark (LM) time (n = 31), 4 used a sequential landmark analyses, and 2 used a time-dependent Cox model. In 23 of 31 studies (74.2%) that did adjust for ITB via a single LM time, the rationale behind why the specified LM time was chosen was not clearly explained. There was no relationship between adjusting for ITB and year of publication (P = .074) or whether the study was published in a high-impact journal (P = .55). Conclusions Studies assessing adjuvant radiation therapy by analyzing the NCDB are susceptible to ITB, which overestimates the effect size of adjuvant therapies and can provide misleading results. Adjusting for this bias is essential for accurate data representation and to better quantify the impact of adjuvant therapies such as PORT.

Decorin is a small, leucine-rich proteoglycan found in the extracellular matrix of various connective tissues with potential effective tumor suppressive properties. Recent data suggest low levels of decorin in multiple myeloma (MM) patients compared to healthy volunteers, as well as in patients with osteolytic bone lesions compared to non-osteolytic lesions. In the present report, we investigated the role of decorin in the MM microenvironment or niche. Our data suggests that decorin is produced by osteoblasts (OBs) but not by MM cells. Furthermore, MM cells decrease OB-induced decorin secretion and this effect is mediated by CCL3. Importantly, neutralizing CCL3 from MM cells restores decorin levels in OBs as does proteasome inhibitors such as carfilzomib. These findings indicate that decorin may indirectly act as an antagonist to MM cell survival and that the interplay between MM and decorin may be an important target to explore in manipulating the tumor niche to inhibit tumorigenesis.

To assess the utilization and outcomes of adjuvant monotherapy with hypofractionated radiation (RT) among elderly patients not receiving traditional adjuvant chemoradiotherapy (cRT) for glioblastoma multiforme (GBM). A retrospective analysis using the National Cancer Data Base with GBM patients aged 65 years or older treated between 2005 and 2012 was conducted. Patients who underwent hypofractionated RT (40 Gy), conventional RT (60 Gy), chemotherapy, or best supportive care alone were included. Statistical methods included logistic regression for utilization and Cox regression for survival analysis. A total of 9556 patients were analyzed. On multivariate analysis (compared to those receiving conventional RT), patients more likely to be treated with hypofractionated RT were older (75-84 years old OR 2.05; p 0.01 and ≥ 85 years old OR 3.32; p 0.01), with a Charlson/Deyo score of 2 or higher (OR 1.80; p = 0.05), from communities 50 miles from their treatment facility (50-100 miles OR 8.03; p 0.01 and 100 miles OR 7.16; p 0.01), treated at an Academic/Research facility (OR 2.85; p = 0.04), and diagnosed between 2011 and 2012 (OR 4.15; p 0.01). On Cox regression, hypofractionated RT (HR 0.65; p 0.01), conventional RT (HR 0.60; p 0.01), and chemotherapy alone (HR 0.69; p 0.01) were all associated with decreased risk of death compared to no adjuvant therapy. Among patients receiving adjuvant treatment, utilization of hypofractionated RT increased from 7 to 19% during the study period. Among elderly patients with GBM not receiving cRT, the utilization of adjuvant monotherapy with hypofractionated RT has increased over time. Retrospective evidence suggests it may be better than best supportive care alone and as good as conventionally fractionated RT alone.

Background: Patients with multiple myeloma may be susceptible to osteonecrosis of the jaw (ONJ) and stress fractures due to long-term aminobisphosphonate (aBP) therapy. However, it is unknown whether urinary N-telopeptide (NTX) or other bone biomarkers are predictive of skeletal-related events (SRE) or the impact of cessation of aBP therapy on bone remodeling. Methods: We studied markers of bone turnover over a 6-month period after a single dose of zoledronic acid in 29 patients with multiple myeloma in remission who previously received 8 to 12 doses of pamidronate or zoledronate (NCT00577642). Our primary objective was to determine the duration of time urinary NTX levels remain suppressed after a single dose of zoledronate. A secondary objective was to identify and correlate other markers of bone remodeling with NTX changes. Thirty cytokines, based on their possible role in bone remodeling, were tested using cytokine arrays. Candidates were confirmed by ELISA. Results: All patients had continued suppression of NTX levels, except 1 patient who had an increase in NTX levels associated with an SRE. GDF-15 and decorin were found to decrease, whereas bone-specific alkaline phosphatase (BSALP) increased. Although not significant in aggregate, osteopontin and osteoprotegerin levels increased in at least half of the patients. Conclusion: Our data show that NTX levels continue to be suppressed after aBP therapy, and suggest that suppressed NTX levels may be predictive of freedom from SRE in this patient population. Furthermore, osteoblast suppression by aBP may be reversible in myeloma. These data provide the basis for less frequent dosing of aBPs. Clin Cancer Res; 20(15); 3955–61. ©2014 AACR.

Context The role of adjuvant chemotherapy remains poorly defined for the management of muscle-invasive bladder cancer (MIBC). The last meta-analysis evaluating adjuvant chemotherapy, conducted in 2005, had limited power to fully support its use. Objective To update the current evidence of the benefit of postoperative adjuvant cisplatin-based chemotherapy compared with control (ie, surgery alone) in patients with MIBC. Evidence acquisition A comprehensive literature review was performed to identify all randomized controlled trials (RCTs) comparing adjuvant cisplatin-based chemotherapy with control for patients with MIBC. The search included the Medline, Embase, Cochrane Central Register of Controlled Trials databases, and abstracts from the American Society of Clinical Oncology meetings up to May 2013. An updated systematic review and meta-analysis was performed. Evidence synthesis A total of 945 patients included in nine RCTs (five previously analyzed, one updated, and three new) were examined. For overall survival, the pooled hazard ratio (HR) across all nine trials was 0.77 (95% confidence interval [CI], 0.59–0.99; p =0.049). For disease-free survival, the pooled HR across seven trials reporting this outcome was 0.66 (95% CI, 0.45–0.91; p =0.014). This disease-free survival benefit was more apparent among those with positive nodal involvement ( p =0.010). Conclusions This updated and improved meta-analysis of randomized trials provides further evidence of an overall survival and disease-free survival benefit in patients with MIBC receiving adjuvant cisplatin-based chemotherapy after radical cystectomy.

Drug targeting of adult stem cells has been proposed as a strategy for regenerative medicine, but very few drugs are known to target stem cell populations in vivo. Mesenchymal stem/progenitor cells (MSCs) are a multipotent population of cells that can differentiate into muscle, bone, fat, and other cell types in context-specific manners. Bortezomib (Bzb) is a clinically available proteasome inhibitor used in the treatment of multiple myeloma. Here, we show that Bzb induces MSCs to preferentially undergo osteoblastic differentiation, in part by modulation of the bone-specifying transcription factor runt-related transcription factor 2 (Runx-2) in mice. Mice implanted with MSCs showed increased ectopic ossicle and bone formation when recipients received low doses of Bzb. Furthermore, this treatment increased bone formation and rescued bone loss in a mouse model of osteoporosis. Thus, we show that a tissue-resident adult stem cell population in vivo can be pharmacologically modified to promote a regenerative function in adult animals.

Decorin is a small leucine rich proteoglycan found in the extracellular matrix of various connective tissues with potential effective tumor suppressor properties. Recently, it has been shown that decorin decreases in multiple myeloma (MM) patients compared to healthy volunteers, and also in patients with osteolytic bone lesions than non-osteolytic lesions. By using a cytokine array analysis we showed that decorin is down regulated in patients withdrawn from aminobisphosphanates for six months. These results led us to focus on decorin and its role in the bone marrow micro environment. We looked at the expression of decorin in MM cell lines. The mRNA expression of decorin in MM cells (OPM1, OPM2, RPMI, INA6, U266, KMS18 and KMS20) was not detectable when compared to MG63, an osteosarcoma cell line that constitutively produces decorin. Consistent with the mRNA expression, decorin protein secretion was also very low in the MM cell lines as demonstrated by ELISA. A 48 hour MTT assay on OPM1, OPM2, RPMI, MM1.S and CD138+ patient myeloma cells with increasing concentrations (0, 5, 10, 20 and 40μg/ml) of exogenous decorin did not show a significant decrease in cell viability. These results indicate that decorin is not produced by MM cells and does not have a direct effect on MM cell viability. Having looked at decorin in the tumor, we then observed its expression in the stromal compartment. We investigated decorin mRNA and protein expression in bone marrow stromal cells (BMSC), osteoclasts (OC) and osteoblats (OB) differentiated from MM patients. BMSC and OB, differentiated for 4 and 7 days, showed a significantly higher expression of decorin compared to the OC. Decorin secretion was more pronounced by differentiating OB than BMSCs. Consistent with previously reported data, we also found that decorin protein levels were higher in BMSCs and OB differentiated for 4 and 7 days from healthy volunteers than MM patients. Moreover, addition of exogenous decorin (at 5 and 10 μg/ml) to OB increased OB differentiation as seen by increased mRNA expression for markers of OB differentiation (alkaline phosphatase and RUNX2) suggesting that decorin plays a role in OB differentiation. Given the significance of the interaction between the MM tumor and its micro-environment we next evaluated the effect of decorin in the stroma when co-cultured with MM cells. Decorin mRNA levels were down regulated when OPM2 cells were co-cultured without direct cell contact with BMSC and OB differentiated for 4 and 7 days suggesting that MM cells decreased decorin and the effect is probably cytokine mediated. Having studied the effect of decorin on OB in the stromal compartment, we then focused on the OCs. When exogenous decorin was added at 5 and 10mg/ml to peripheral blood mononuclear cells from MM patients in OC differentiation media for 7, 14 and 21 days of differentiation, there was a significant decrease in OC number as observed by TRAP staining (80% decrease in OC number in 5mg/ml and 95% decrease in 10mg/ml compared to control). Decorin at the same concentrations greatly decreased the area of pits as compared to the control (43% decrease in area of pit in 5mg/ml and 67% decrease in 10mg/ml compared to control) suggesting that exogenous decorin inhibited OC differentiation and function. TRAP staining and MTT assays on 14 day mature OCs with decorin treated for 48 hours after maturation, did not show a decrease in cell number and viability of OC indicating that decorin does not affect mature OCs. In conclusion, our data suggests that decorin secreted by stromal cells and in particular differentiating OBs, does not directly affect the viability of MM cells. It inhibits OC differentiation and function and promotes OB differentiation. Importantly, decorin levels decreased significantly in the BMSC and OB when co-cultured with MM cells. We speculate that this decrease is a result of decreased OB differentiation by MM cells. Since, all the above lines of evidence point to decorin modulating the myeloma microenvironment with potential indirect anti-tumor effects without acting as a direct antagonist to the tumor, ongoing studies that understand mechanisms to stimulate decorin secretion can prove to be useful with respect to MM microenvironment interactions. Disclosures: Raje: Celgene: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Amgen: Consultancy; Acetylon: Consultancy, Research Funding; Eli Lilly: Research Funding.

Abstract 3965 Background: Aminobisphosphonates (aBP) are standard of care for myeloma-related bone disease and are recommended every 3–4 weeks. Multiple myeloma patients may be susceptible to osteonecrosis of the jaw (ONJ) and stress fractures secondary to altered bone remodeling due to long-term aBP therapy. Monthly dosing of aBP is based on early studies that documented the suppression of N-telopeptide (NTX), a marker of bone resorption, for 4–8 weeks following a single dose of aBP. However, it is unclear whether NTX or other bone biomarkers are predictive of skeletal related events (SRE) or what the impact of cessation of aBP therapy has on bone remodeling. Methods: We studied markers of bone turnover after a single dose of zoledronic acid in myeloma patients in remission (NCT00577642). All patients had received 8–12 doses of aBP (pamidronate/zoledronic acid) prior to study inclusion. Patients were not receiving active anti-myeloma therapy besides maintenance therapy. Our primary objective was to determine the duration of time urinary NTX levels remain suppressed after a single dose of zoledronic acid on study. A secondary objective was the identification and correlation of other markers of bone remodeling with NTX changes. High throughput cytokine arrays of validated and potential surrogate markers of bone remodeling were performed. Bone marrow biopsies at start and end of protocol during which time aBPs were not administered were performed. Patients were removed from study if NTX crossed a threshold value (50 nMol), based on correlation of NTX levels with bone-related morbidity and mortality. Results: Twenty-nine patients were enrolled in a 6-month period. Cytokine array data is available in 28 patients. All patients had suppressed NTX levels, except one patient who had an increase in NTX levels associated with a SRE and disease progression. To identify other surrogate as yet unexplored cytokines that may serve as better markers in addition to NTX to monitor aBP activity, thirty cytokines were curated from the literature based on their possible role in bone remodeling and tested using custom designed cytokine arrays. Positive hits were confirmed by ELISA. GDF-15, which correlates with poor prognosis in myeloma and is thought to be produced by bone marrow mesenchymal stem cells, decreased in 24 of 28 patients (two-sided paired T test, p Conclusion: Our data suggest that suppressed NTX levels are predictive of freedom from SRE in this patient population. Furthermore, osteoblast suppression by aBP is reversible in myeloma. Importantly, the role of other surrogates such as decorin and GDF-15 need further validation and are the subject of ongoing studies. Taken together, this evidence may provide rationale for less frequent aBP dosing in multiple myeloma patients to help lower the incidence of long term toxicities such as ONJ and stress fractures, by allowing limited recovery of bone remodeling without adverse effects on multiple myeloma progression. Disclosures: Richardson: Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Ghobrial:Bristol Myers Squibb: Advisory Board, Advisory Board Other; Millennium: Advisory Board, Advisory Board Other; Onyx: Advisory Board, Advisory Board Other; Novartis: Advisory Board Other. Schlossman:Celgene: Membership on an entity's Board of Directors or advisory committees. Anderson:Onyx: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Raje:Onyx: Consultancy; Celgene: Consultancy; Millenium: Consultancy; Acetylon: Research Funding; Amgen: Research Funding; Eli-Lilly: Research Funding.

Abstract 2491 While much has been discovered in the laboratory regarding the mechanisms of multidrug resistance (MDR), based on phase III clinical trials of ATP-binding cassette (ABC) transporter modulators, these findings have not resulted in appreciable clinical benefit in acute myeloid leukemia (AML) patients. In this pilot study, we investigated the clinical relevance of 380 genes related to MDR in 31 samples from AML patients who had undergone conventional treatment, with 11 patients contributing samples at diagnosis and relapse, using TaqMan Low Density Arrays (TLDA). We and others have shown that the TaqMan-based qRT-PCR is superior to microarrays and SYBR-green-based qRT-PCR because of higher sensitivity and specificity in determining expression of highly homologous gene family members, such as the ABC transporters. 380 genes involved in metabolism, signal transduction, DNA repair, stress response, tumor suppressor activity, oncogenic transformation, apoptosis, and drug uptake or efflux were curated based on their potential role in MDR in the current literature. We found expression of four genes previously unreported in AML in both diagnostic and relapsed patient samples to correlate with duration of complete remission (CR) of induction chemotherapy: SLC7A8 and HSPE1 correlate negatively while GBP1 and ABCD2 correlate positively with CR duration (>2-fold change relative to the median, p2-fold change relative to the median, p2 fold change compared to diagnosis, p2 fold change compared to diagnosis, p Disclosures: No relevant conflicts of interest to declare.

Abstract 1789 Poster Board I-815 Understanding the pathogenesis of cancer-related bone disease is critical to the discovery of new therapies. The development of osteolytic lesions in multiple myeloma (MM) results from unopposed osteoclast activity due to decreased osteoblast (OB) function. We recently demonstrated that activin A contributes to MM-mediated OB inhibition. The availability of a clinical-grade activin A inhibitor that reduces tumor burden by restoring the bone structure in vivo, underscores the relevance of this pathway in the development of MM-bone disease. Here, we characterize the signaling pathway mediating OB inhibition by activin A. Activin A secretion by bone marrow stromal cells (BMSC) is enhanced in the presence of MM cells which was completely abrogated and using a transwell system. To identify the receptors and pathways involved in activin A secretion, we used neutralizing antibody against several integrins, CD40 and osteopontin. Only VLA4 neutralizing antibodies partially inhibited activin secretion by about 20% (range 10-30%, p Disclosures Chauhan: Nereus Pharmaceuticals, Inc: Consultancy. Seehra:Acceleron Pharma: Employment. Anderson:Celgene : Research Funding; Novartis: Research Funding; Millennium: Research Funding. Scadden:Fate Therapeutics: Consultancy. Raje:Astrazeneca, Novartis, Celgene: Research Funding.

Multiple studies have shown the importance of PI3K/Akt/mTOR pathway in the pathogenesis of multiple myeloma (MM). Specifically, it mediates cell proliferation and development of drug resistance. Identifying mTOR as a key kinase acting downstream of Akt led to the prediction that rapamycin, a universal inhibitor of mTORC1-dependent S6K1 phosphorylation, may be useful in the treatment of MM. Cumulative evidence support the hypothesis that rapamycin-induced cytotoxicity is predominantly triggered as a consequence of autophagy (programmed cell death type II) via excessive cell digestion. Therefore activated Akt can be a key upstream inhibitor of two cell death-inducing events: autophagy via mTOR activation and apoptosis via phosphorylation of BAD and inhibition of the catalytic subunit of caspase-9. Importantly, recent studies have demonstrated the existence of strong positive feedback loops from mTOR/S6K1 to Akt, resulting in Akt activation in some cancer types. We confirmed that suppression of mTOR signaling by rapamycin was associated with upregulation of Akt phosphorylation, which may reduce sensitivity to rapamycin. We therefore hypothesized that inhibition of this positive feedback by a potent Akt inhibitor perifosine could augment rapamycin-induced cytotoxicity in MM cells. As expected, perifosine inhibited rapamycin-induced p-Akt, associated with synergistic cytotoxicity, even in the presence of IL-6, IGF-1 or bone marrow stromal cells. Synergism was confirmed by the Chou-Talalay model, demonstrating that a combination index was < 1 over a range of doses evaluated. We further examined the molecular mechanisms whereby this combination treatment induced synergistic cytotoxicity. We first studied its effect on ultrastructure in MM cells assessed by electron microscopy, demonstrating that rapamycin-induced autophagy was augmented by perifosine in MM.1S cells. We also confirmed autophagy by immunofluorescent staining of LC3, an autophagosome membrane-associated protein. Interestingly, both autophagy and apoptosis were observed when cells were cultured for longer periods with rapamycin and perifosine co-treatment. The apoptotic effect of the combination was further assessed by Annexin/PI flow cytometric analysis and caspase/PARP cleavage. Neither inhibition of autophagy by 3-MA, nor the blockade of apoptosis by Z-VAD-FMK rescued MM cell death from the combination treatment. Finally, we demonstrate that the combination of nanoparticle albumin-bound (nab) -rapamycin and perifosine had significant antitumor activity in an in vivo human MM cell xenograft murine model, associated with prolonged survival. We observed pAkt upregulation induced by rapamycin, which was inhibited by perifosine evidenced by immunohistochemical analyses on tumor tissue from the xenograft model. Importantly, autophagy and apoptosis were also confirmed by LC3 and caspase 3 staining on tumor tissue. Collectively our data suggest that mutual suppression of the PI3K/Akt/mTOR pathway by rapamycin and perifosine co-treatment induces autophagy and apoptosis, resulting in synergistic cytotoxicity in MM, providing the rationale for use of this combination in future clinical trial in patients with MM.

A distinct feature of multiple myeloma (MM) is the tight interaction between malignant plasma cells and their bone microenvironment, creating a niche suitable for MM growth. In particular, MM cells inhibit osteoblast (OB) differentiation and stimulate osteoclast (OC) function, resulting in imbalanced bone remodeling and osteolytic bone disease. Here we studied a novel cytokine, activin A, identified from a broad range of cytokines, in the development of MM bone disease. We next asked whether activin A inhibition could restore bone balance and suppress tumor growth. Activin, a member of the TNF-α superfamily, is a pleiotropic cytokine involved in bone remodeling. Here, we observed, that MM patients with multiple osteolytic lesions had a 4-fold increase in activin A expression levels in bone marrow plasma compared to MM patients with one or less osteolytic lesions and non-MM patients (average 123.6 ± 136 vs 26.4 ± 21.4 vs 30.6 ± 25.1 pg/ml respectively, p

Bortezomib is a first-in-class proteasome inhibitor approved for the therapy of relapsed, refractory multiple myeloma (MM). Two large registration trials (SUMMIT and APEX) of bortezomib in MM revealed an increase in the serum levels of bone-specific alkaline phosphatase (b-ALP) and osteocalcin (ocn) in bortezomib-responsive patients, raising the prospect that bortezomib may influence the bone marrow (BM) microenvironment in association with its anti-myeloma effect,. However, the precise cellular target of bortezomib within the BM milieu remains unknown. We hypothesized that the observed rise in b-ALP and ocn was the result of direct effects of bortezomib on osteoblast-lineage committed cells. The effect of bortezomib on osteoblastic cells was first evaluated in in vitro. When bortezomib was added to freshly isolated primary BM mononuclear cells, the CFU-Ob (osteoblastic colony-forming units) was unchanged, but the colony size was increased, with a maximum effect observed at 1 nM. In particular, bortezomib increased the number of CD45−/CD51+ cells 1.8 fold (P