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Thursday, September 22, 2016 10:00 AM|An, G., Acharya, C., Feng, X., Wen, K., Zhong, M., Zhang, L., Munshi, N. C., Qiu, L., Tai, Y.-T., Anderson, K. C.|Blood current issue|Labels: MM

The number and activity of osteoclasts (OCs) are strongly enhanced by myeloma cells, leading to significant bone lesions in patients with multiple myeloma (MM). Mechanisms remain elusive as to whether myeloma-supporting OCs also induce suppressive immune bone marrow (BM) microenvironment. Here, we first show that OCs significantly protect MM cells against T-cell–mediated cytotoxicity via direct inhibition of proliferating CD4+ and CD8+ T cells. The immune checkpoint molecules programmed death ligand 1 (PD-L1), Galectin-9, herpesvirus entry mediator (HVEM), and CD200, as well as T-cell metabolism regulators indoleamine 2, 3-dioxygenase (IDO), and CD38 are significantly upregulated during osteoclastogenesis. Importantly, the levels of these molecules, except CD38, are higher in OCs than in MM cells. Anti–PD-L1 monoclonal antibody (mAb) and IDO inhibitor partly overcome OC-inhibited T-cell responses against MM cells, confirming their roles in OC-suppressed MM cell lysis by cytotoxic T cells. In addition, Galectin-9 and a proliferation-induced ligand (APRIL), secreted by OCs, are significantly upregulated during osteoclastogenesis. Galectin-9 specifically induces apoptosis of T cells while sparing monocytes and MM cells. APRIL induces PD-L1 expression in MM cells, providing additional immune inhibition by OCs. Moreover, CD38 is significantly upregulated during osteoclastogenesis. When targeted by an anti-CD38 mAb, suppressive T-cell function by OCs is alleviated, associated with downregulation of HVEM and IDO. Taken together, these results define the expression of multiple immune proteins and cytokines in OCs essential for suppressive MM BM milieu. These results further support the combination of targeting these molecules to improve anti-MM immunity.

Thursday, September 22, 2016 7:00 AM|PR Newswire Association LLC.|PR Newswire: Medical Pharmaceuticals|Attachments|Labels: MM, regulatory

http://photos.prnewswire.com/prnc/20150203/727958-bMADRID, September 22, 2016 /PRNewswire/ -- PharmaMar (MSE:PHM) has announced today the submission to the European Medicines Agency (EMA) of the Marketing Authorization Application (MAA) for Aplidin® (plitidepsin) in combination with dexamethasone for the treatment of...


Monday, September 19, 2016 11:57 AM|Nijhof, I. S., Franssen, L. E., Levin, M.-D., Bos, G. M. J., Broijl, A., Klein, S. K., Koene, H. R., Bloem, A. C., Beeker, A., Faber, L. M., van der Spek, E., Ypma, P. F., Raymakers, R., van Spronsen, D.-J., Westerweel, P. E., Oostvogels, R., van Velzen, J., van Kessel, B., Mutis, T., Sonneveld, P., Zweegman, S., Lokhorst, H. M., van de Donk, N. W. C. J.|BLOOD First Edition Papers|Labels: MM, clinical trial

The prognosis of multiple myeloma (MM) patients who become refractory to lenalidomide and bortezomib is very poor, indicating the need for new therapeutic strategies for these patients. Next to the development of new drugs, the strategy of combining agents with synergistic activity may also result in clinical benefit for patients with advanced myeloma. We have previously shown in a retrospective analysis that lenalidomide combined with continuous low-dose cyclophosphamide and prednisone (REP) had remarkable activity in heavily pretreated, lenalidomide-refractory MM patients. To evaluate this combination prospectively, we initiated a phase 1/2 study to determine the optimal dose and to assess its efficacy and safety in lenalidomide-refractory MM patients. The maximum tolerated dose (MTD) was defined as 25 mg lenalidomide (days 1-21/28 days), combined with continuous cyclophosphamide (50 mg/day) and prednisone (20 mg/day). At the MTD (n=67 patients), the overall response rate was 67%, and at least minimal response was achieved in 83% of the patients. Median PFS and OS were 12.1 and 29.0 months, respectively. Similar results were achieved in the subset of patients with lenalidomide- and bortezomib-refractory disease as well as in patients with high-risk cytogenetic abnormalities, defined as t(4;14), t(14;16), del(17p), and/or ampl(1q) as assessed by FISH. Neutropenia (22%) and thrombocytopenia (22%) were the most common grade 3-4 hematologic adverse events. Infections (21%) were the most common grade 3-5 non-hematologic adverse events. In conclusion, the addition of continuous low-dose oral cyclophosphamide to lenalidomide and prednisone offers a new therapeutic perspective for multidrug refractory MM patients. This trial was registered at www.clinicaltrials.gov as #NCT01352338.

Monday, September 19, 2016 6:00 AM|PR Newswire Association LLC.|PR Newswire: Medical Pharmaceuticals|Attachments|Labels: MM, clinical trial, NHL

SAN FRANCISCO, Sept. 19, 2016 /PRNewswire/ -- Sutro Biopharma Inc. today announced that it has presented findings from two studies of investigational antibody drug conjugates, or ADCs, that it developed to target CD74, a protein highly expressed in hematologic malignancies.  The...


Monday, September 19, 2016 1:28 AM|Business Wire Health: Pharmaceutical News|Labels: MM, clinical trial, patent
LUND, Sweden--(BUSINESS WIRE)--Regulatory News: BioInvent International (STO:BINV) announces that it has been granted additional patent protection in Japan, Russia and China for BI-505, its lead immune-oncology programme currently in Phase II for the treatment of multiple myeloma. These patents cover the use of BI-505 in the treatment of patients previously treated for cancer that have either not responded or subsequently relapsed. The patents now granted, add to patents previously granted in t

Thursday, September 15, 2016 7:42 AM|Harrison, S. J., Mainwaring, P., Price, T., Millward, M. J., Padrik, P., Underhill, C. R., Cannell, P. K., Reich, S. D., Trikha, M., Spencer, A.|Clinical Cancer Research current issue|Labels: proteasome, MM, clinical trial

Purpose: Marizomib (NPI-0052) is an irreversible proteasome inhibitor, derived from a marine actinomycete, with activity and specificity that is distinct from other proteasome inhibitors.

Experimental Design: Phase I study (NPI-0052-102) evaluated the MTD, pharmacokinetics, and pharmacodynamics of marizomib intravenously on two dosing schedules.

Results: Forty-two patients with advanced malignancies received Schedule A (0.1–0.9 mg/m2 over 1–10 minutes on days 1, 8, 15 in 4-week cycles); 44 patients with relapsed and/or refractory multiple myeloma (RRMM) and other hematologic malignancies received Schedule B (0.075–0.6 mg/m2 over 1 minute to 2 hours on days 1, 4, 8, 11, in 3-week cycles). The Schedule A recommended phase II dose was 0.7 mg/m2 over 10 minutes; Schedule B was 0.5 mg/m2 over 2 hours. The most common (>25% of patients) related adverse events were fatigue, nausea, diarrhea, and infusion site pain (Schedule A); and fatigue (Schedule B). Overall response rate of 11% was seen in 27 efficacy-evaluable RRMM Schedule B patients (1 very good partial response, 3 partial responses, 4 minimal responses, and 12 stable disease). One Schedule A patient with transformed marginal zone lymphoma had complete response. Marizomib has a short half-life (<30 minutes), with high volume of distribution (~15–416 L) and clearance (~0.9–22 L/minutes).

Conclusions: Marizomib does not exhibit the severe peripheral neuropathy or hematologic toxicity observed with other proteasome inhibitors. Marizomib was generally well tolerated with low-dose dexamethasone, demonstrated activity in heavily pretreated RRMM patients, and warrants further evaluation. Clin Cancer Res; 22(18); 4559–66. ©2016 AACR.

Thursday, September 15, 2016 7:42 AM|A.|JournalTOCs API - Clinical Cancer Research (27 articles)|Labels: proteasome, MM, clinical trial

Marizomib in Advanced Malignancies Including Multiple Myeloma
Harrison, S. J Mainwaring, P, Price, T, Millward, M. J, Padrik, P, Underhill, C. R, Cannell, P. K, Reich, S. D, Trikha, M, Spencer, A.
Clinical Cancer Research, Vol. 22, No. 18 (2016) pp. 4559 - 4566
Purpose: Marizomib (NPI-0052) is an irreversible proteasome inhibitor, derived from a marine actinomycete, with activity and specificity that is distinct from other proteasome inhibitors. Experimental Design: Phase I study (NPI-0052-102) evaluated the MTD, pharmacokinetics, and pharmacodynamics of marizomib intravenously on two dosing schedules. Results: Forty-two patients with advanced malignancies received Schedule A (0.1&ndash;0.9 mg/m2 over 1&ndash;10 minutes on days 1, 8, 15 in 4-week cycles); 44 patients with relapsed and/or refractory multiple myeloma (RRMM) and other hematologic malignancies received Schedule B (0.075&ndash;0.6 mg/m2 over 1 minute to 2 hours on days 1, 4, 8, 11, in 3-week cycles). The Schedule A recommended phase II dose was 0.7 mg/m2 over 10 minutes; Schedule B was 0.5 mg/m2 over 2 hours. The most common (>25% of patients) related adverse events were fatigue, nausea, diarrhea, and infusion site pain (Schedule A); and fatigue (Schedule B). Overall response rate of 11% was seen in 27 efficacy-evaluable RRMM Schedule B patients (1 very good partial response, 3 partial responses, 4 minimal responses, and 12 stable disease). One Schedule A patient with transformed marginal zone lymphoma had complete response. Marizomib has a short half-life (<30 minutes), with high volume of distribution (~15&ndash;416 L) and clearance (~0.9&ndash;22 L/minutes). Conclusions: Marizomib does not exhibit the severe peripheral neuropathy or hematologic toxicity observed with other proteasome inhibitors. Marizomib was generally well tolerated with low-dose dexamethasone, demonstrated activity in heavily pretreated RRMM patients, and warrants further evaluation. Clin Cancer Res; 22(18); 4559&ndash;66. &copy;2016 AACR.

Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: MM, clinical trial
This phase I trial studies the side effects and best dose of yttrium Y 90 anti-CD45 monoclonal antibody BC8 when given together with fludarabine phosphate and total-body irradiation followed by donor peripheral blood stem cell transplant in treating patients with multiple myeloma. Radiolabeled monoclonal antibodies, such as yttrium Y 90 anti-CD45 monoclonal antibody BC8, can find cancer cells and carry cancer-killing substances to them without harming normal cells. Giving chemotherapy drugs, such as fludarabine phosphate, and total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells and helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving yttrium Y 90 anti-CD45 monoclonal antibody BC8, fludarabine phosphate, and total-body irradiation before the transplant together with cyclosporine and mycophenolate mofetil after the transplant may stop this from happening and may be an effective treatment for multiple myeloma.
The drugs, lenalidomide, bortezomib, and dexamethasone, are approved by the FDA. They have not been approved in the combination for multiple myeloma or any other type of cancer. Bortezomib is currently approved by the FDA for the treatment of multiple myeloma. Lenalidomide is approved for use with dexamethasone for patients with multiple myeloma who have received at least one prior therapy and for the treatment of certain types of myelodysplastic syndrome (another type of cancer affecting the blood). Dexamethasone is commonly used, either alone, or in combination with other drugs, to treat multiple myeloma. Melphalan and cyclophosphamide, the drugs used during stem cell collection and transplant, are also approved by the FDA. Melphalan is an FDA-approved chemotherapy for multiple myeloma and is used as a high-dose conditioning treatment prior to stem cell transplantation. Cyclophosphamide is used, either alone, or in combination with other drugs, to treat multiple myeloma. These drugs have been used in other multiple myeloma studies and information from those studies suggests that this combination of therapy may help to treat newly diagnosed multiple myeloma. In this research study, we are looking to explore the drug combination, lenalidomide, bortezomib and dexamethasone alone or when combined with autologous stem cell transplantation to see what side effects it may have and how well it works for treatment of newly diagnosed multiple myeloma. Specifically, the objective of this trial is to determine if, in the era of novel drugs, high dose therapy (HDT) is still necessary in the initial management of multiple myeloma in younger patients. In this study, HDT as compared to conventional dose treatment would be considered superior if it significantly prolongs progression-free survival by at least 9 months or more, recognizing that particular subgroups may benefit more compared to others.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: MM, clinical trial
This phase II trial studies the safety of alternating ixazomib citrate and lenalidomide as treatment to help keep cancer from coming back after stem cell transplant (maintenance therapy) in treating patients with multiple myeloma. Ixazomib citrate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Lenalidomide may stimulate the immune system to attack cancer cells. Giving ixazomib citrate and lenalidomide as maintenance therapy after transplant may prolong the length of time until the cancer returns.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: MM, clinical trial
This study is designed to compare long-term outcomes among patients randomized on the BMT CTN 0702 protocol (NCT01109004), "A Trial of Single Autologous Transplant with or without Consolidation Therapy versus Tandem Autologous Transplant with Lenalidomide Maintenance for Patients with Multiple Myeloma". It is hypothesized that use of novel anti-myeloma agents will improve long-term progression-free survival (PFS) after high-dose melphalan followed by autologous hematopoietic cell transplantation (HCT) as compared to a second autologous transplantation.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: CLL, MM, clinical trial, NHL
This phase II trial studies autologous peripheral blood stem cell transplant followed by donor bone marrow transplant in treating patients with high-risk hodgkin lymphoma, non-hodgkin lymphoma, multiple myeloma, or chronic lymphocytic leukemia. Autologous stem cell transplantation uses the patient's stem cells and does not cause graft-versus-host disease (GVHD) and has a very low risk of death, while minimizing the number of cancer cells. Peripheral blood stem cell (PBSC) transplant uses stem cells from the patient or a donor and may be able to replace immune cells that were destroyed by chemotherapy. These donated stem cells may help destroy cancer cells. Bone marrow transplant known as a nonmyeloablative transplant uses steam cells from a haploidentical family donor. Autologous peripheral blood stem cell transplant followed by donor bone marrow transplant may work better in treating patients with high-risk hodgkin lymphoma, non-hodgkin lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
This study will assess the safety, pharmacokinetic (PK), pharmacodynamic (PD) and the therapeutic potential of GSK2857916 in subjects with multiple myeloma (MM) and other hematologic malignancies that express B cell maturation antigen (BCMA). The hypothesis is that GSK2857916 can be safely administered to subjects with BCMA positive malignancies at doses where target engagement can be demonstrated. This study will determine if adequate target engagement of BCMA receptors translates into clinical benefit for subjects with MM and other BCMA positive hematologic malignancies. The study will consists of two parts: a Part 1 dose escalation phase and a Part 2 expansion phase for safety, and clinical activity testing. The study will enroll a total of approximately 80 subjects with relapsed/refractory MM or other BCMA-expressing hematologic malignancies.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: MM, clinical trial
The purpose of this study is to compare the efficacy of daratumumab in combination with lenalidomide and dexamethasone to that of lenalidomide and dexamethasone in terms of progression-free survival (PFS) in participants with newly diagnosed multiple myeloma (a blood cancer of plasma cells) who are not candidates for high dose chemotherapy (treatment of disease, usually cancer, by chemical agents) and autologous stem cell transplant (ASCT).
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: MM, clinical trial
The purpose of this study is to evaluate three daratumumab dose schedules in participants with Smoldering Multiple Myeloma.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: MM, clinical trial
The purpose of this study is to determine if adding elotuzumab to pomalidomide and low-dose dexamethasone is a more effective treatment of relapsed and refractory multiple myeloma compared to pomalidomide and low-dose dexamethasone alone.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: MM, clinical trial
This is a dose finding pilot study to evaluate the safety and determine the maximum tolerated dose of the combination of carfilzomib and pomalidomide with dexamethasone (CPD) in patients with relapsed or refractory multiple myeloma followed by a phase II expansion at the MTD to evaluate efficacy. The study will explore the efficacy of CPD including overall response, time to progression, progression free survival, and time to next therapy.
Wednesday, September 14, 2016 2:47 PM|Onclive Articles|Labels: MM
Despite multiple therapeutic advances in recent years, proteasome inhibitors remain a cornerstone of therapy for multiple myeloma, both newly diagnosed and relapsed and refractory disease.
Wednesday, September 14, 2016 11:10 AM|Mayo Clinic Cancer Center - Research news|Labels: proteasome, MM, clinical trial
ROCHESTER, Minn. — The investigational drug ixazomib taken orally in combination with lenalidomide and dexamethasone shows promise in patients with newly diagnosed multiple myeloma, according to the results of a phase 1/2 study published in the journal Lancet Oncology. "Ixazomib is an investigational, oral proteasome inhibitor with promising anti-myeloma effects and low rates of peripheral [...]
Tuesday, September 13, 2016 8:19 PM|Artur Jurczyszyn, Anna Zebzda, Jacek Czepiel, Joanna Gdula-Argasińska, William Perucki, Aleksander B. Skotnicki, Marcin Majka|Journal of Cancer (RSS 2.0)|Labels: WNT, MM

The bone marrow microenvironment plays a key role in the stimulation of growth and survival of multiple myeloma (MM) cells. We investigated whether membrane microfragments (MFBs) exert a stimulatory effect on mesenchymal stem cell (MSC) gene expression or differentiation. MSCs from patients with multiple myeloma (MMBM-MSCs) proliferated at a slower rate than MSCs from healthy volunteers (BM-MSCs), and fewer MMBM-MSCs adhered to the substrate as compared to BM-MSCs. Phenotypic analysis revealed that MMBM-MSCs and BM-MSCs differed significantly in terms of their CD166 and CXCR4 expressions. In conclusion, our comparative analysis of mesenchymal cells from MM patients and healthy volunteers revealed differences in the genetic and phenotypic profiles of these two populations, their potential for osteodifferentiation, and expression of surface antigens. Moreover, we showed that membrane MFBs may alter the genetic profile of MSCs, leading to disorders of their osteodifferentiation, and interact with the WNT pathway via presentation of the DKK-1 protein.

Tuesday, September 13, 2016 2:05 PM|Deanna J. Fall, Holly Stessman, Sagar S. Patel, Zohar Sachs, Brian G. Van Ness, Linda B. Baughn, Michael A. Linden|Journal of Cancer|Labels: MM, biomarker diagnostic

Multiple myeloma (MM) is an incurable malignant neoplasm hallmarked by a clonal expansion of plasma cells, the presence of a monoclonal protein in the serum and/or urine (M-spike), lytic bone lesions, and end organ damage. Clinical outcomes for patients with MM have improved greatly over the last decade as a result of the re-purposing of compounds such as thalidomide derivatives, as well as the development of novel chemotherapeutic agents including first and second generation proteasome inhibitors, bortezomib (Bz) and carfilzomib. Unfortunately, despite these improvements, the majority of patients relapse following treatment. While Bz, one of the most commonly used proteasome inhibitors, has been successfully incorporated into clinical practice, some MM patients have de novo resistance to Bz, and the majority of the remainder subsequently develop drug resistance following treatment. A significant gap in clinical care is the lack of a reliable clinical test that would predict which MM patients have or will subsequently develop Bz resistance. Thus, as Bz resistance remains a significant challenge, research efforts are needed to identify novel biomarkers of early Bz resistance, particularly when an early therapeutic intervention can be initiated. Recent advances in MM research indicate that genomic data can be extracted to identify novel biomarkers that can be utilized to select more effective, personalized treatment protocols for individual patients. Computationally integrating large patient databases with data from whole transcriptome profiling and laboratory-based models can potentially revolutionize our understanding of MM disease mechanisms. This systems-wide approach can provide rational therapeutic targets and novel biomarkers of risk and treatment response. In this review, we discuss the use of high-content datasets (predominantly gene expression profiling) to identify novel biomarkers of treatment response and resistance to Bz in MM.

Tuesday, September 13, 2016 2:05 PM|Guillemette Fouquet, Benjamin Hebraud, Sylvain Garciaz, Anne Marie Stoppa, Murielle Roussel, Denis Caillot, Marie Lorraine Chrétien, Bertrand Arnulf, Raphael Szalat, Laurent Garderet, Lina Benajiba, Brigitte Pegourie, Caroline Regny, Bruno Royer, Alexis Caulier, Cyrille Touzeau, Benoit Tessoulin, Jean Paul Fermand, Thierry Facon, Michel Attal, Hervé Avet Loiseau, Philippe Moreau, Xavier Leleu|Journal of Cancer|Labels: MM

The impact of consolidation on response rates and PFS has recently been demonstrated after induction and autotransplantation upfront in Multiple Myeloma (MM). We further showed that patients in ≥VGPR following the intensification procedure benefited most from consolidation. Question remains as to the benefit of consolidation for patients in PR at completion of induction - feature of partial resistance to the induction regimen.

We collected data from 54 newly diagnosed MM treated with VTd-auto-VTd regimen that reached only PR at completion of the induction procedure.

Overall, 37 patients (68%) improved depth of response (≥VGPR) at completion of consolidation, including 35% that reached CR and 38% solely related to consolidation. Of patients that remained on PR or improved depth of response after ASCT, 26% and 38% further responded to consolidation, respectively. With a median follow-up of 36 months, improved depth of response translated into lower relapse rate compared with patients remaining in PR, 19% vs. 36%. This difference was more striking in patients that reached CR vs. others, 8% and 38%, respectively (p=0.039). The median TTP was prolonged in patients that improved depth of response after consolidation (p=0.012), with a 3-year TTP of 87% vs. 18% otherwise. In multivariate analysis, lack of improved depth of response to consolidation independently predicted shorten median TTP [OR=4.4, 95%CI=1-21; p=0.039], with elevated LDH and beta2m, and adverse FISH.

This study shows that VTd consolidation should be recommended to patients solely on PR at completion of induction with VTd, feature of lower sensitivity to VTd.

Tuesday, September 13, 2016 1:02 PM|Gutierrez-Gonzalez, A., Martinez-Moreno, M., Samaniego, R., Arellano-Sanchez, N., Salinas-Munoz, L., Relloso, M., Valeri, A., Martinez-Lopez, J., Corbi, A. L., Hidalgo, A., Garcia-Pardo, A., Teixido, J., Sanchez-Mateos, P.|BLOOD First Edition Papers|Labels: MM

Tumor associated macrophages (TAM) are important components of the multiple myeloma (MM) microenvironment that support malignant plasma cell survival and resistance to therapy. It has been proposed that macrophages (MØ) retain the capacity to change in response to stimuli that can restore their antitumor functions. Here we investigated several approaches to reprogram MØ as a novel therapeutic strategy in MM. First, we found tumor-limiting and tumor-supporting capabilities for monocyte-derived M1-like MØ and M2-like MØ, respectively, when mixed with MM cells, both in vitro and in vivo. Multicolor confocal microscopy revealed that MM associated MØ displayed a predominant M2-like phenotype in the bone marrow of MM patient samples, and a high expression of the pro-M2 cytokine macrophage migration inhibitory factor (MIF). To reprogram the pro-tumoral M2-like MØ present in MM towards anti-tumoral M1-like MØ we tested the pro-M1 cytokine GM-CSF plus blockade of the M2 cytokines M-CSF or MIF. The combination of GM-CSF plus the MIF inhibitor 4-IPP achieved the best reprogramming responses towards an M1 profile, both at gene and protein expression levels, as well as remarkable tumoricidal effects. Furthermore, this combined treatment elicited macrophage-dependent therapeutic responses in MM xenograft mouse models, which were linked to up-regulation of M1 and reciprocal down-regulation of M2 macrophage markers. Our results reveal the therapeutic potential of reprogramming macrophages in the context of MM.

Contributors : Irene Riz ; Teresa S Hawley ; Robert G Hawley
Series Type : Expression profiling by array
Organism :

LP-1 cells were exposed to stepwise increasing concentrations of carfilzomib over a period of 18 weeks: cells adapted to growth in 4 nM carfilzomib by 4 weeks, in 6 nM in another 6 weeks and in 12 nM after a further 8 weeks. The resulting cell culture, denoted LP-1/Cfz, retained resistance to carfilzomib even when tested after removal of selective pressure for approximately 8 weeks.

Wednesday, September 7, 2016 6:00 PM|Jeffrey Medin|International Journal of Molecular Sciences|Labels: MM
Multiple myeloma (MM) is a disorder of terminally differentiated plasma cells characterized by clonal expansion in the bone marrow (BM). It is the second-most common hematologic malignancy. Despite significant advances in therapeutic strategies, MM remains a predominantly incurable disease emphasizing the need for the development of new treatment regimens. Immunotherapy is a promising treatment modality to circumvent challenges in the management of MM. Many novel immunotherapy strategies, such as adoptive cell therapy and monoclonal antibodies, are currently under investigation in clinical trials, with some already demonstrating a positive impact on patient survival. In this review, we will summarize the current standards of care and discuss major new approaches in immunotherapy for MM.
Thursday, September 1, 2016 10:05 PM|Jiang, D., Tam, A. B., Alagappan, M., Hay, M. P., Gupta, A., Kozak, M. M., Solow-Cordero, D. E., Lum, P. Y., Denko, N. C., Giaccia, A. J., Le, Q.-T., Niwa, M., Koong, A. C.|Molecular Cancer Therapeutics current issue|Labels: MM

Using a luciferase reporter–based high-throughput chemical library screen and topological data analysis, we identified N-acridine-9-yl-N',N'-dimethylpropane-1,3-diamine (DAPA) as an inhibitor of the inositol requiring kinase 1α (IRE1α)–X-box binding protein-1 (XBP1) pathway of the unfolded protein response. We designed a collection of analogues based on the structure of DAPA to explore structure–activity relationships and identified N9-(3-(dimethylamino)propyl)-N3,N3,N6,N6-tetramethylacridine-3,6,9-triamine (3,6-DMAD), with 3,6-dimethylamino substitution on the chromophore, as a potent inhibitor. 3,6-DMAD inhibited both IRE1α oligomerization and in vitro endoribonuclease (RNase) activity, whereas the other analogues only blocked IRE1α oligomerization. Consistent with the inhibition of IRE1α-mediated XBP1 splicing, which is critical for multiple myeloma cell survival, these analogues were cytotoxic to multiple myeloma cell lines. Furthermore, 3,6-DMAD inhibited XBP1 splicing in vivo and the growth of multiple myeloma tumor xenografts. Our study not only confirmed the utilization of topological data analysis in drug discovery but also identified a class of compounds with a unique mechanism of action as potent IRE1α–XBP1 inhibitors in the treatment of multiple myeloma. Mol Cancer Ther; 15(9); 2055–65. ©2016 AACR.

Thursday, September 1, 2016 10:05 PM|Ishibashi, M., Tamura, H., Sunakawa, M., Kondo-Onodera, A., Okuyama, N., Hamada, Y., Moriya, K., Choi, I., Tamada, K., Inokuchi, K.|Cancer Immunology Research recent issues|Labels: PD-1/PD-L1, proteasome, MM

B7 homolog 1 (B7-H1)–expressing myeloma cells not only inhibit myeloma-specific cytotoxic T lymphocytes (CTL), but also confer a proliferative advantage: resistance to antimyeloma chemotherapy. However, it remains unknown whether B7-H1 expressed on myeloma cells induces cellular responses associated with aggressive myeloma behaviors. To address this question, we analyzed the proliferation and drug sensitivity of B7-H1–expressing myeloma cells transfected with B7-H1–specific short-hairpin RNA or treated with programmed cell death (PD)-1-Fc–coupled beads. Knockdown of B7-H1 expression in myeloma cells significantly inhibited cell proliferation and increased apoptosis induced by the chemotherapeutic alkylating agent melphalan, with downregulation of the expression of cell cycle–related genes (CCND3 and CDK6) and antiapoptotic genes (BCL2 and MCL1). B7-H1 molecules thus contributed to myeloma cell-cycle progression and suppression of drug-induced apoptosis. B7-H1–expressing myeloma cells had a higher affinity for PD-1 than for CD80. PD-1-Fc bead–treated myeloma cells also became resistant to apoptosis that was induced by melphalan and the proteasome inhibitor bortezomib. Apoptosis resistance was associated with the PI3K/AKT pathway. Both myeloma cell drug resistance and antiapoptotic responses occurred through the PI3K/AKT signaling pathway, initiated from "reverse" stimulation of B7-H1 by PD-1. Therefore, B7-H1 itself may function as an oncogenic protein in myeloma cells. The interaction between B7-H1 on myeloma cells and PD-1 molecules not only inhibits tumor-specific CTLs but also induces drug resistance in myeloma cells through the PI3K/AKT signaling pathway. These observations provide mechanistic insights into potential immunotherapeutic benefits of blocking the B7-H1–PD-1 pathway. Cancer Immunol Res; 4(9); 779–88. ©2016 AACR.

Thursday, September 1, 2016 10:01 AM|Gkotzamanidou, M., Terpos, E., Bamia, C., Munshi, N. C., Dimopoulos, M. A., Souliotis, V. L.|Blood LYMPHOID NEOPLASIA|Labels: MM

DNA repair activity of malignant cells seems to influence therapeutic outcome and patients’ survival. Herein, we investigated the mechanistic basis for the link between DNA repair efficiency and response to antimyeloma therapy. Nucleotide excision repair (NER), interstrand cross-links repair (ICL/R), double-strand breaks repair (DSB/R), and chromatin structure were evaluated in multiple myeloma (MM) cell lines (melphalan-sensitive RPMI8226; melphalan-resistant LR5) and bone marrow plasma cells (BMPCs) from MM patients who responded (n = 17) or did not respond (n = 9) to subsequent melphalan therapy. The effect of DSB/R inhibition was also evaluated. Responders’ BMPCs showed slower rates of NER and DSB/R (P < .0022), similar rates of ICL/R, and more condensed chromatin structure compared with nonresponders. Moreover, apoptosis rates of BMPCs were inversely correlated with individual DNA repair efficiency and were higher in responders’ cells compared with those of nonresponders (P = .0011). Similarly, RPMI8226 cells showed slower rates of NER and DSB/R, comparable rates of ICL/R, more condensed chromatin structure, and higher sensitivity than LR5 cells. Interestingly, cotreatment of BMPCs or cell lines with DSB/R inhibitors significantly reduced the rates of DSB/R and increased melphalan sensitivity of the cells, with the nonhomologous end-joining inhibitor SCR7 showing the strongest effect. Together, responders’ BMPCs are characterized by lower efficiencies of NER and DSB/R mechanisms, resulting in higher accumulation of the extremely cytotoxic ICLs and DSBs lesions, which in turn triggers the induction of the apoptotic pathway. Moreover, the enhancement of melphalan cytotoxicity by DSB/R inhibition offers a promising strategy toward improvement of existing antimyeloma regimens.

Thursday, September 1, 2016 10:01 AM|Avet-Loiseau, H., Fonseca, R., Siegel, D., Dimopoulos, M. A., Špička, I., Masszi, T., Hajek, R., Rosinol, L., Goranova-Marinova, V., Mihaylov, G., Maisnar, V., Mateos, M.-V., Wang, M., Niesvizky, R., Oriol, A., Jakubowiak, A., Minarik, J., Palumbo, A., Bensinger, W., Kukreti, V., Ben-Yehuda, D., Stewart, A. K., Obreja, M., Moreau, P.|Blood CLINICAL TRIALS AND OBSERVATIONS|Labels: MM, clinical trial

The presence of certain high-risk cytogenetic abnormalities, such as translocations (4;14) and (14;16) and deletion (17p), are known to have a negative impact on survival in multiple myeloma (MM). The phase 3 study ASPIRE (N = 792) demonstrated that progression-free survival (PFS) was significantly improved with carfilzomib, lenalidomide, and dexamethasone (KRd), compared with lenalidomide and dexamethasone (Rd) in relapsed MM. This preplanned subgroup analysis of ASPIRE was conducted to evaluate KRd vs Rd by baseline cytogenetics according to fluorescence in situ hybridization. Of 417 patients with known cytogenetic risk status, 100 patients (24%) were categorized with high-risk cytogenetics (KRd, n = 48; Rd, n = 52) and 317 (76%) were categorized with standard-risk cytogenetics (KRd, n = 147; Rd, n = 170). For patients with high-risk cytogenetics, treatment with KRd resulted in a median PFS of 23.1 months, a 9-month improvement relative to treatment with Rd. For patients with standard-risk cytogenetics, treatment with KRd led to a 10-month improvement in median PFS vs Rd. The overall response rates for KRd vs Rd were 79.2% vs 59.6% (high-risk cytogenetics) and 91.2% vs 73.5% (standard-risk cytogenetics); approximately fivefold as many patients with high- or standard-risk cytogenetics achieved a complete response or better with KRd vs Rd (29.2% vs 5.8% and 38.1% vs 6.5%, respectively). KRd improved but did not abrogate the poor prognosis associated with high-risk cytogenetics. This regimen had a favorable benefit-risk profile in patients with relapsed MM, irrespective of cytogenetic risk status, and should be considered a standard of care in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01080391.

Wednesday, August 31, 2016 10:05 PM|S.|JournalTOCs API - Clinical Cancer Research (27 articles)|Labels: MM

GWAS in Multiple Myeloma Pharmacogenomics
Magrangeas, F Kuiper, R, Avet-Loiseau, H, Gouraud, W, Guerin-Charbonnel, C, Ferrer, L, Aussem, A, Elghazel, H, Suhard, J, Der Sakissian, H, Attal, M, Munshi, N. C, Sonneveld, P, Dumontet, C, Moreau, P, van Duin, M, Campion, L, Minvielle, S.
Clinical Cancer Research, Vol. 22, No. 17 (2016) pp. 4350 - 4355
Purpose: Painful peripheral neuropathy is a frequent toxicity associated with bortezomib therapy. This study aimed to identify loci that affect susceptibility to this toxicity. Experimental Design: A genome-wide association study (GWAS) of 370,605 SNPs was performed to identify risk variants for developing severe bortezomib-induced peripheral neuropathy (BiPN) in 469 patients with multiple myeloma who received bortezomib&ndash;dexamethasone therapy prior to autologous stem cell in randomized clinical trials of the Intergroupe Francophone du Myelome (IFM) and findings were replicated in 114 patients with multiple myeloma of the HOVON-65/GMMG-HD4 clinical trial. Results: An SNP in the PKNOX1 gene was associated with BiPN in the exploratory cohort [rs2839629; OR, 1.89, 95% confidence interval (CI), 1.45&ndash;2.44; P = 7.6 x 10&ndash;6] and in the replication cohort (OR, 2.04; 95% CI, = 1.11&ndash;3.33; P = 8.3 x 10&ndash;3). In addition, rs2839629 is in strong linkage disequilibrium (r 2 = 0.87) with rs915854, located in the intergenic region between PKNOX1 and cystathionine-&szlig;-synthetase (CBS). Expression quantitative trait loci mapping showed that both rs2839629 and rs915854 genotypes have an impact on PKNOX1 expression in nerve tissue, whereas rs2839629 affects CBS expression in skin and blood. Conclusions: The use of GWAS in multiple myeloma pharmacogenomics has identified a novel candidate genetic locus mapping to PKNOX1 and in the immediate vicinity of CBS at 21q22.3 associated with the severe bortezomib-induced toxicity. The proximity of these two genes involved in neurologic pain whose tissue-specific expression is modified by the two variants provides new targets for neuroprotective strategies. Clin Cancer Res; 22(17); 4350&ndash;5. &copy;2016 AACR.

Wednesday, August 31, 2016 10:05 PM|Menoret, E, Dubljevic, V, Menu, E, Vanderkerken, K, Lapa, C, Steinbrunn, T, Chatterjee, M, Knop, S, Düll, J, Greenwood, D. L, Hensel, F, Rosenwald, A, Einsele, H, Brändlein, S.|JournalTOCs API - Clinical Cancer Research (27 articles)|Labels: MM

Targeting GRP78 in Drug-Resistant Myeloma
Rasche, L Menoret, E, Dubljevic, V, Menu, E, Vanderkerken, K, Lapa, C, Steinbrunn, T, Chatterjee, M, Knop, S, Düll, J, Greenwood, D. L, Hensel, F, Rosenwald, A, Einsele, H, Brändlein, S.
Clinical Cancer Research, Vol. 22, No. 17 (2016) pp. 4341 - 4349
Purpose: Glucose-regulated protein (GRP) 78 is overexpressed in multiple myeloma, and both its surface expression and its biologic significance as key sensor of the unfolded protein response make GRP78 an ideal candidate for immunotherapeutic intervention. The monoclonal antibody PAT-SM6 targets surface GRP78 and leads to disease stabilization when used as single agent in a clinical trial. In this article, we evaluated expression of GRP78 in relapsed-refractory disease and explored PAT-SM6 therapy in combination regimens. Experimental Design: GRP78 expression was immunohistochemically analyzed during disease progression and development of drug resistance throughout different stages of multiple myeloma. Activity of PAT-SM6 was evaluated in combination with anti&ndash;multiple myeloma agents lenalidomide, bortezomib, and dexamethasone in vitro. Finally, we report on a multiple myeloma patient with relapsed-refractory disease treated with PAT-SM6 in combination with bortezomib and lenalidomide. Results: Although sGRP78 expression was present at all stages, it increased with disease progression and was even strongly elevated in patients with drug-resistant and extramedullary disease. Pretreatment with dexamethasone as well as dual combination of PAT-SM6/lenalidomide further increased sGRP78 expression and consecutively showed synergistic anti&ndash;multiple myeloma effects with PAT-SM6 in proliferation assays. As proof of concept, a 62-year-old male with triple resistant multiple myeloma treated with PAT-SM6, bortezomib, and lenalidomide experienced partial remission of both intra- and extramedullary lesions. Conclusions: PAT-SM6 therapy in combination regimens showed efficacy in relapsed-refractory multiple myeloma. Clin Cancer Res; 22(17); 4341&ndash;9. &copy;2016 AACR.

Wednesday, August 31, 2016 10:05 PM|Beauvais, D. M., Jung, O., Yang, Y., Sanderson, R. D., Rapraeger, A. C.|Cancer Research recent issues|Labels: IGFR, MM
Syndecan-1 (Sdc1/CD138) expression is linked to disease severity in multiple myeloma, although the causal basis for this link remains unclear. Here we report that capture of the IGF1 receptor (IGF1R) by Sdc1 suppresses ASK1-dependent apoptosis in multiple myeloma cells. Sdc1 binds two different fractions of IGF1R, one that is constitutively active and a second that is activated by IGF1 ligand. Notably, IGF1R kinase activity in both fractions is blocked by synstatinIGF1R (SSTNIGF1R), a peptide that inhibits IGF1R capture by Sdc1, as well as by a truncated peptide (SSTNIGF1R-T) that appears to be specific for multiple myeloma cells. Mechanistically, we show that ASK1 is bound to active IGF1R and inhibited by Tyr and Ser83/Ser966 phosphorylation. When IGF1R engagement with Sdc1 is blocked by SSTNIGF1R, ASK1 becomes activated, and initiates JNK- and caspase-3–mediated apoptosis. In pharmacologic tests, we find SSTNIGF1R is highly stable in human plasma and displays a half-life of 27 hours in mice, wherein it significantly reduces both the size and neovascularization of CAG myeloma tumor xenografts. Taken together, our results offer a preclinical proof of concept and mechanistic rationale for the exploration of SSTNIGF1R as an experimental therapeutic to dually attack multiple myeloma tumor cell survival and tumor angiogenesis. Cancer Res; 76(17); 4981–93. ©2016 AACR.
Wednesday, August 31, 2016 7:55 PM|Shinsuke Iida, Daisuke Ogiya, Yasunobu Abe, Masafumi Taniwaki, Hiroya Asou, Kaijiro Maeda, Kazunori Uenaka, Soshi Nagaoka, Tsuyoshi Ishiki, Ilaria Conti, Kensei Tobinai|Cancer Science|Labels: MM, clinical trial
B-cell activating factor (BAFF) promotes the survival and adhesion of multiple myeloma (MM) cells. Tabalumab (LY2127399) is an anti-BAFF monoclonal antibody. This phase 1, multicenter, open-label, nonrandomized, dose-escalation study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of tabalumab in combination with bortezomib and dexamethasone in Japanese patients with relapsed or refractory MM (RRMM). Sixteen patients received intravenous i.v. tabalumab 100 mg (Cohort 1, n = 4) or i.v. tabalumab 300 mg (Cohort 2, n = 12) in combination with oral dexamethasone 20 mg/day and i.v. or s.c. bortezomib 1.3 mg/m2. All patients had treatment-emergent adverse events (TEAE) possibly related to study treatment; the most common TEAE were thrombocytopenia (81.3%), lymphopenia (43.8%) and increased alanine aminotransferase (43.8%). Two (20.0%) dose-limiting toxicities were observed, both in Cohort 2 (tabalumab 300 mg), which was below the predefined cutoff for tolerability (<33%). The pharmacokinetics of tabalumab were similar when bortezomib was coadministered i.v. versus s.c. The overall response rate was 56.3%, suggesting that the combined treatment was effective. In conclusion, combined treatment with these three agents was well tolerated in this population of Japanese patients with RRMM. The study was registered at www.clinicaltrials.gov (NCT01556438). Tabalumab (LY2127399) is a potent, selective, fully human, immunoglobulin G subclass 4 (IgG4) monoclonal antibody that neutralizes soluble and membrane-bound BAFF. Tabalumab prevents free BAFF from binding its receptor but does not interfere with bound BAFF and thus does not directly interact with B-cells. This phase 1, multicenter, open-label, nonrandomized, dose-escalation study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of tabalumab in combination with bortezomib and dexamethasone in Japanese patients with relapsed or refractory multiple myeloma.
Sunday, August 28, 2016 11:38 PM|News-Medical.Net Apoptosis News Feed|Comments|Labels: MM, regulatory
Janssen-Cilag International NV has announced the submission of a Type II variation application to the European Medicines Agency (EMA), seeking to broaden the existing marketing authorisation for the immunotherapy DARZALEX® (daratumumab) to include treatment of adult patients with relapsed multiple myeloma who have received at least one prior therapy. The expanded indication is based on daratumumab in combination with lenalidomide (an immmunomodulatory agent) and dexamethasone, or bortezomib (a PI) and dexamethasone.
Thursday, August 18, 2016 10:00 AM|Nijhof, I. S., Casneuf, T., van Velzen, J., van Kessel, B., Axel, A. E., Syed, K., Groen, R. W. J., van Duin, M., Sonneveld, P., Minnema, M. C., Zweegman, S., Chiu, C., Bloem, A. C., Mutis, T., Lokhorst, H. M., Sasser, A. K., van de Donk, N. W. C. J.|Blood LYMPHOID NEOPLASIA|Labels: MM

The anti-CD38 monoclonal antibody daratumumab is well tolerated and has high single agent activity in heavily pretreated relapsed and refractory multiple myeloma (MM). However, not all patients respond, and many patients eventually develop progressive disease to daratumumab monotherapy. We therefore examined whether pretreatment expression levels of CD38 and complement-inhibitory proteins (CIPs) are associated with response and whether changes in expression of these proteins contribute to development of resistance. In a cohort of 102 patients treated with daratumumab monotherapy (16 mg/kg), we found that pretreatment levels of CD38 expression on MM cells were significantly higher in patients who achieved at least partial response (PR) compared with patients who achieved less than PR. However, cell surface expression of the CIPs, CD46, CD55, and CD59, was not associated with clinical response. In addition, CD38 expression was reduced in both bone marrow–localized and circulating MM cells, following the first daratumumab infusion. CD38 expression levels on MM cells increased again following daratumumab discontinuation. In contrast, CD55 and CD59 levels were significantly increased on MM cells only at the time of progression. All-trans retinoic acid increased CD38 levels and decreased CD55 and CD59 expression on MM cells from patients who developed daratumumab resistance, to approximately pretreatment values. This resulted in significant enhancement of daratumumab-mediated complement-dependent cytotoxicity. Together, these data demonstrate an important role for CD38 and CIP expression levels in daratumumab sensitivity and suggest that therapeutic combinations that alter CD38 and CIP expression levels should be investigated in the treatment of MM. These trials were registered at www.clinicaltrials.gov as #NCT00574288 (GEN501) and #NCT01985126 (SIRIUS).

Tuesday, August 16, 2016 1:45 PM|Plesner, T., Arkenau, H.-T., Gimsing, P., Krejcik, J., Lemech, C., Minnema, M. C., Lassen, U., Laubach, J. P., Palumbo, A., Lisby, S., Basse, L., Wang, J., Sasser, A. K., Guckert, M. E., de Boer, C., Khokhar, N. Z., Yeh, H., Clemens, P. L., Ahmadi, T., Lokhorst, H. M., Richardson, P. G.|BLOOD First Edition Papers|Labels: MM, clinical trial

Daratumumab, a human CD38 IgG1 monoclonal antibody, has activity as monotherapy in multiple myeloma (MM). This phase 1/2 study investigated daratumumab plus lenalidomide/dexamethasone in refractory and relapsed/refractory MM. Part 1 (dose-escalation) evaluated 4 daratumumab doses plus lenalidomide (25 mg/day p.o. on Days 1 21 of each cycle) and dexamethasone (40 mg/week). Part 2 (dose-expansion) evaluated daratumumab at the recommended phase 2 dose (RP2D) plus lenalidomide/dexamethasone. Safety, efficacy, pharmacokinetics, immunogenicity and accelerated daratumumab infusions were studied. In Part 1 (13 patients), no dose-limiting toxicities were observed; 16 mg/kg was selected as the R2PD. In Part 2 (32 patients), median time since diagnosis was 3.2 years, with a median (range) of two (one-three) prior therapies, including proteasome inhibitors (91%), alkylating agents (91%), autologous stem cell transplant (78%), thalidomide (44%), and lenalidomide (34%); 22% were refractory to last line of therapy. Grade 3/4 adverse events (≥5%) included neutropenia, thrombocytopenia, and anemia. In Part 2, infusion-related reactions (IRRs) occurred in 18 patients (56%); most were grade ≤2 (grade 3, 6.3%). IRRs predominantly occurred during first infusions and were more common during accelerated infusions. In Part 2 (median follow-up of 15.6 months), overall response rate was 81% with 8 (25%) stringent complete responses, 3 (9%) complete responses, and 9 (28%) very good partial responses. Eighteen-month progression-free and overall survival rates were 72% (95% CI, 51.7-85.0) and 90% (95% CI, 73.1-96.8), respectively. Daratumumab plus lenalidomide/dexamethasone resulted in rapid, deep, durable responses. The combination was well-tolerated and consistent with the safety profiles observed with lenalidomide/dexamethasone or daratumumab monotherapy.

Tuesday, August 16, 2016 1:45 PM|Xiang, M., Kim, H., Ho, V. T., Walker, S. R., Bar-Natan, M., Anahtar, M., Liu, S., Toniolo, P. A., Kroll, Y., Jones, N., Giaccone, Z. T., Heppler, L. N., Ye, D. Q., Marineau, J. J., Shaw, D., Bradner, J. E., Blonquist, T., Neuberg, D., Hetz, C., Stone, R. M., Soiffer, R. J., Frank, D. A.|BLOOD First Edition Papers|Labels: STAT, MM

The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is frequently activated inappropriately in a wide range of hematological and solid cancers, but clinically-available therapies targeting STAT3 are lacking. Using a computational strategy to identify compounds opposing the gene expression signature of STAT3, we discovered atovaquone (Mepron™), an FDA-approved anti-microbial, to be a potent STAT3 inhibitor. We show that, at drug concentrations routinely achieved clinically in human plasma, atovaquone inhibits STAT3 phosphorylation, the expression of STAT3 target genes, and the viability of STAT3-dependent hematological cancer cells. These effects were also observed with atovaquone treatment of primary blasts isolated from patients with acute myelogenous leukemia or acute lymphocytic leukemia. Atovaquone is not a kinase inhibitor, but instead rapidly and specifically downregulates cell-surface expression of glycoprotein 130 (gp130), which is required for STAT3 activation in multiple contexts. The administration of oral atovaquone to mice inhibited tumor growth and prolonged survival in a murine model of multiple myeloma. Finally, in patients with acute myelogenous leukemia treated with hematopoietic stem cell transplantation, extended use of atovaquone for Pneumocystis prophylaxis was associated with improved relapse-free survival. These findings establish atovaquone as a novel, clinically-accessible STAT3 inhibitor with evidence of anti-cancer efficacy in both animal models and humans.

Sunday, August 14, 2016 10:05 PM|Tang, M., Zhao, R., van de Velde, H., Tross, J. G., Mitsiades, C., Viselli, S., Neuwirth, R., Esseltine, D.-L., Anderson, K., Ghobrial, I. M., San Miguel, J. F., Richardson, P. G., Tomasson, M. H., Michor, F.|Clinical Cancer Research recent issues|Labels: MM

Purpose: Since the pioneering work of Salmon and Durie, quantitative measures of tumor burden in multiple myeloma have been used to make clinical predictions and model tumor growth. However, such quantitative analyses have not yet been performed on large datasets from trials using modern chemotherapy regimens.

Experimental Design: We analyzed a large set of tumor response data from three randomized controlled trials of bortezomib-based chemotherapy regimens (total sample size n = 1,469 patients) to establish and validate a novel mathematical model of multiple myeloma cell dynamics.

Results: Treatment dynamics in newly diagnosed patients were most consistent with a model postulating two tumor cell subpopulations, "progenitor cells" and "differentiated cells." Differential treatment responses were observed with significant tumoricidal effects on differentiated cells and less clear effects on progenitor cells. We validated this model using a second trial of newly diagnosed patients and a third trial of refractory patients. When applying our model to data of relapsed patients, we found that a hybrid model incorporating both a differentiation hierarchy and clonal evolution best explains the response patterns.

Conclusions: The clinical data, together with mathematical modeling, suggest that bortezomib-based therapy exerts a selection pressure on myeloma cells that can shape the disease phenotype, thereby generating further inter-patient variability. This model may be a useful tool for improving our understanding of disease biology and the response to chemotherapy regimens. Clin Cancer Res; 22(16); 4206–14. ©2016 AACR.

Tuesday, August 9, 2016 1:45 PM|Hoyos, V., Borrello, I.|BLOOD First Edition Papers|Labels: MM

The treatment of multiple myeloma (MM) has evolved significantly over the past decades from primarily alkylator-based chemotherapeutic agents with minimal efficacy to the introduction of more effective agents including IMIDs and proteasome inhibitors, which have changed the landscape of therapy for this disease. We are now entering a new era that will increasingly integrate immunotherapy into standard treatment. This review discusses the current immune-based strategies currently approved as well as various immune approaches being actively investigated including monoclonal antibodies, checkpoint inhibitors, vaccines and adoptive T cell therapies.

Sunday, July 31, 2016 10:05 PM|Shukla, N., Somwar, R., Smith, R. S., Ambati, S., Munoz, S., Merchant, M., D'Arcy, P., Wang, X., Kobos, R., Antczak, C., Bhinder, B., Shum, D., Radu, C., Yang, G., Taylor, B. S., Ng, C. K. Y., Weigelt, B., Khodos, I., de Stanchina, E., Reis-Filho, J. S., Ouerfelli, O., Linder, S., Djaballah, H., Ladanyi, M.|Cancer Research recent issues|Labels: proteasome, childhood cancer, MM, sarcoma
Ewing sarcoma is a primitive round cell sarcoma with a peak incidence in adolescence that is driven by a chimeric oncogene created from the fusion of the EWSR1 gene with a member of the ETS family of genes. Patients with metastatic and recurrent disease have dismal outcomes and need better therapeutic options. We screened a library of 309,989 chemical compounds for growth inhibition of Ewing sarcoma cells to provide the basis for the development of novel therapies and to discover vulnerable pathways that might broaden our understanding of the pathobiology of this aggressive sarcoma. This screening campaign identified a class of benzyl-4-piperidone compounds that selectively inhibit the growth of Ewing sarcoma cell lines by inducing apoptosis. These agents disrupt 19S proteasome function through inhibition of the deubiquitinating enzymes USP14 and UCHL5. Functional genomic data from a genome-wide shRNA screen in Ewing sarcoma cells also identified the proteasome as a node of vulnerability in Ewing sarcoma cells, providing orthologous confirmation of the chemical screen findings. Furthermore, shRNA-mediated silencing of USP14 or UCHL5 in Ewing sarcoma cells produced significant growth inhibition. Finally, treatment of a xenograft mouse model of Ewing sarcoma with VLX1570, a benzyl-4-piperidone compound derivative currently in clinical trials for relapsed multiple myeloma, significantly inhibited in vivo tumor growth. Overall, our results offer a preclinical proof of concept for the use of 19S proteasome inhibitors as a novel therapeutic strategy for Ewing sarcoma. Cancer Res; 76(15); 4525–34. ©2016 AACR.
Thursday, July 28, 2016 4:07 PM|Press Releases | AbbVie Newsroom|Labels: proteasome, MM, clinical trial

NORTH CHICAGO, Ill., July 28, 2016 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global biopharmaceutical company, today announced the initiation of a Phase 3 clinical trial to study the safety and efficacy of venetoclax in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma who are considered sensitive or naïve to proteasome inhibitors and have received one to three prior lines of therapy. The combination of venetoclax, bortezomib and dexamethasone will be compared to treatment with bortezomib, dexamethasone and placebo.1 Bortezomib, a proteasome inhibitor, and dexamethasone, a corticosteroid, are both common therapies used to treat symptomatic multiple myeloma.3  

Wednesday, July 27, 2016 12:43 PM|Gong, J.-N., Khong, T., Segal, D., Yao, Y., Riffkin, C. D., Garnier, J.-M., Khaw, S. L., Lessene, G., Spencer, A., Herold, M. J., Roberts, A. W., Huang, D. C. S.|BLOOD First Edition Papers|Labels: Bcl-2, MM

New therapeutic targets are needed to address the poor prognosis of patients with high-risk multiple myeloma. Myeloma cells usually express a range of the pro-survival BCL2 proteins. To define the hierarchy of their relative importance for maintaining the survival of myeloma cells, we targeted each of them in a large panel of cell lines using pharmacological inhibitors, gene editing or by peptide-based approaches, alone or in combination. The majority of well-established immortalized cell lines (17/25) or low-passage myeloma cell lines (5/7) are readily killed when MCL1 is targeted, even including those cell lines sensitive to BCL2 inhibition. Targeting MCL1 also constrained the growth of myeloma in vivo. We also identified a previously unrecognized sub-set of myeloma that is highly BCLXL-dependent, and the potential for co-targeting MCL1 and BCLXL. As MCL1 is pivotal for maintaining survival of most myelomas, it should be prioritized for targeting in the clinic once high quality, validated inhibitors become available.

Monday, July 25, 2016 8:16 AM|Friedel, M., Andre, S., Goldschmidt, H., Gabius, H.-J., Schwartz-Albiez, R.|Glycobiology - Advance Access|Labels: GAL, MM

Multiple myeloma is characterized by abnormal infiltration of malignant plasma cells into bone marrow. Testing the hypothesis that bivalent galectin-8 (Gal-8) may influence homing of myeloma cells to vascular endothelium as a key prerequisite for infiltration, we analyzed the two Gal-8 splice variants (Gal-8S, Gal-8L). They differ in the length of their linker peptide connecting the two lectin domains. Both Gal-8 isoforms bind to cells of the myeloma lines Gal-8+ MOLP-8 and Gal-8 LP-1 in a glycan-inhibitable manner. Both Gal-8 isoforms led to enhanced adhesion of myeloma cells to vascular endothelium under dynamic shear stress conditions, Gal-8L (by more than 40-fold) even stronger than Gal-8S. Additional treatment of endothelial cells with tumour necrosis factor prior to the dynamic shear stress assay entailed an almost 100-fold enhanced adhesion of myeloma cells without addition of Gal-8 variants and a further 1.5–1.7-fold enhancement by addition of Gal-8 variants. We also found that elevated expression of Gal-8 in native multiple myeloma cells is an adverse prognostic factor for overall and event-free survival using patients’ gene expression profile data of the total therapy 2 and 3 myeloma studies. Also, elevated concentrations of Gal-8 were detected (45%, 19/42 patients) in sera of multiple myeloma patients compared to those of healthy, age-matched donors. Both experimental and clinical data strongly point to the significance of Gal-8 for multiple myeloma development.

Wednesday, July 20, 2016 9:31 AM|Paino, T., Garcia-Gomez, A., Gonzalez-Mendez, L., San Segundo, L., Hernandez-Garcia, S., Lopez-Iglesias, A.-A., Algarin, E. M., Martin-Sanchez, M., Corbacho-Gonzalez, D., Ortiz-de-Solorzano, C., Corchete, L., Gutierrez, N. C., Mateos, M. V., Garayoa, M., Ocio, E. M.|Clinical Cancer Research Online First Articles|Labels: MM

Purpose: PIM kinases are a family of serine/threonine kinases recently proposed as therapeutic targets in oncology. In the present work, we have investigated the effects of the novel pan-PIM kinase inhibitor, PIM447, on myeloma cells and myeloma-associated bone disease using different preclinical models. Experimental Design: In vitro/ex vivo cytotoxicity of PIM447 was evaluated on myeloma cell lines and patient samples. Synergistic combinations with standard treatments were analyzed with Calcusyn Software. PIM447 effects on bone cells were assessed on osteogenic and osteoclastogenic cultures. The mechanisms of PIM447 were explored by immunoblotting, qPCR and immunofluorescence. A murine model of disseminated multiple myeloma was employed for in vivo studies. Results: PIM447 is cytotoxic for myeloma cells due to cell cycle disruption and induction of apoptosis mediated by a decrease in phospho-Bad (Ser112) and c-Myc levels and the inhibition of mTORC1 pathway. Importantly, PIM447 demonstrates a very strong synergy with different standard treatments such as bortezomib + dexamethasone (combination index, CI=0.002), lenalidomide + dexamethasone (CI=0.065) and pomalidomide + dexamethasone (CI=0.077). PIM447 also inhibits in vitro osteoclast formation and resorption, downregulates key molecules involved in these processes and partially disrupts the F-actin ring, while increasing osteoblast activity and mineralization. Finally, PIM447 significantly reduced the tumor burden and prevented tumor-associated bone loss in a disseminated murine model of human myeloma. Conclusions: Our results demonstrate dual anti-tumoral and bone protective effects of PIM447. This fact, together with the very strong synergy exhibited with standard-of-care treatments, supports the future clinical development of this drug in multiple myeloma.

Tuesday, July 19, 2016 9:21 AM|Rasche, L., Menoret, E., Dubljevic, V., Menu, E., Vanderkerken, K., Lapa, C., Steinbrunn, T., Chatterjee, M., Knop, S., Düll, J., Greenwood, D. L., Hensel, F., Rosenwald, A., Einsele, H., Brändlein, S.|Clinical Cancer Research Online First Articles|Labels: MM

Purpose: Glucose-regulated protein (GRP) 78 is overexpressed in multiple myeloma, and both its surface expression and its biologic significance as key sensor of the unfolded protein response make GRP78 an ideal candidate for immunotherapeutic intervention. The monoclonal antibody PAT-SM6 targets surface GRP78 and leads to disease stabilization when used as single agent in a clinical trial. In this article, we evaluated expression of GRP78 in relapsed-refractory disease and explored PAT-SM6 therapy in combination regimens.

Experimental Design: GRP78 expression was immunohistochemically analyzed during disease progression and development of drug resistance throughout different stages of multiple myeloma. Activity of PAT-SM6 was evaluated in combination with anti–multiple myeloma agents lenalidomide, bortezomib, and dexamethasone in vitro. Finally, we report on a multiple myeloma patient with relapsed-refractory disease treated with PAT-SM6 in combination with bortezomib and lenalidomide.

Results: Although sGRP78 expression was present at all stages, it increased with disease progression and was even strongly elevated in patients with drug-resistant and extramedullary disease. Pretreatment with dexamethasone as well as dual combination of PAT-SM6/lenalidomide further increased sGRP78 expression and consecutively showed synergistic anti–multiple myeloma effects with PAT-SM6 in proliferation assays. As proof of concept, a 62-year-old male with triple resistant multiple myeloma treated with PAT-SM6, bortezomib, and lenalidomide experienced partial remission of both intra- and extramedullary lesions.

Conclusions: PAT-SM6 therapy in combination regimens showed efficacy in relapsed-refractory multiple myeloma. Clin Cancer Res; 1–9. ©2016 AACR.

Monday, July 18, 2016 3:00 PM|Cancer|Cancer via MedWorm.com|Comments|Labels: MM, clinical trial
CONCLUSIONSThe current phase 1 study established a dosing schedule for the combination of these agents that demonstrated a favorable safety profile with a low incidence of nonhematologic toxicity and manageable hematologic toxicity. The combination of filanesib, bortezomib, and dexamethasone appears to have durable activity in patients with recurrent/refractory multiple myeloma. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Monday, July 18, 2016 12:46 PM|Felices, M., Miller, J. S.|Clinical Cancer Research Online First Articles|Labels: MM

Findings within the current issue indicate that treatment with IPH2101 when used as monotherapy in smoldering multiple myeloma, meant to enhance natural killer cell function through inhibitory KIR blockade, results in a surprising reduction of NK cell function mediated through monocyte trogocytosis. The significance of these findings is discussed.

Wednesday, July 13, 2016 12:33 PM|Ali, S. A., Shi, V., Maric, I., Wang, M., Stroncek, D. F., Rose, J. J., Brudno, J. N., Stetler-Stevenson, M., Feldman, S. A., Hansen, B. G., Fellowes, V. S., Hakim, F. T., Gress, R. E., Kochenderfer, J. N.|BLOOD First Edition Papers|Labels: MM

Therapies with novel mechanisms of action are needed for multiple myeloma (MM). B-cell maturation antigen (BCMA) is expressed by most cases of MM. We conducted the first-in-humans clinical trial of chimeric antigen receptor (CAR) T cells targeting BCMA. T cells expressing the CAR used in this work (CAR-BCMA) specifically recognized BCMA-expressing cells. Twelve patients received CAR-BCMA T cells on this dose-escalation trial. Among the 6 patients treated on the lowest two dose levels, limited anti-myeloma activity and mild toxicity occurred. On the third dose level, one patient obtained a very good partial remission. Two patients were treated on the fourth dose level of 9x106 CAR+ T cells/kg bodyweight. Before treatment, the first patient on the fourth dose level had chemotherapy-resistant MM making up 90% of bone marrow cells. After treatment, bone marrow plasma cells became undetectable by flow cytometry, and the patient's MM entered a stringent complete remission that lasted for 17 weeks before relapse. The second patient on the fourth dose level had chemotherapy-resistant MM making up 80% of bone marrow cells before treatment. Twenty-eight weeks after this patient received CAR-BCMA T-cells, bone marrow plasma cells were undetectable by flow cytometry, and the serum monoclonal protein had decreased by >95%. This patient is in an ongoing very good partial remission. Both patients treated on the fourth dose level had toxicity consistent with cytokine-release syndrome including fever, hypotension, and dyspnea. Both patients also had prolonged cytopenias. Our findings demonstrate powerful anti-myeloma activity of CAR-BCMA T cells. The trial is registered to www.clinicaltrials.gov as NCT02215967.

Thursday, June 30, 2016 10:05 PM|Sanchez, E., Gillespie, A., Tang, G., Ferros, M., Harutyunyan, N. M., Vardanyan, S., Gottlieb, J., Li, M., Wang, C. S., Chen, H., Berenson, J. R.|Clinical Cancer Research recent issues|Labels: MM

Purpose: Reduced uninvolved immunoglobulin (Ig) levels are a hallmark of multiple myeloma. We previously showed that B-cell maturation antigen (BCMA) is solubilized and at high levels in multiple myeloma patient serum. We hypothesize that soluble BCMA binds B-cell–activating factor (BAFF) preventing its function to stimulate late B cells, and would result in lower polyclonal antibody levels in these patients.

Experimental Design: Mice were dosed with recombinant human BCMA (rhBCMA) and BCMA–BAFF complexes were analyzed in plasma, and its effects on antibody and Ig heavy chain mRNA levels determined. Using flow cytometry, BAFF binding to B cells was examined in the presence of rhBCMA and sera from multiple myeloma patients. In multiple myeloma sera, BCMA–BAFF complex formation and BCMA, IgA, IgG levels, and heavy–light chain isoform pair levels were determined.

Results: rhBCMA–BAFF complexes formed in immune-competent and deficient mice. Mice with human multiple myeloma xenografts, which contain plasma hBCMA and hBCMA–BAFF complexes, showed reduced plasma-free BAFF levels. rhBCMA administered to immune competent mice markedly reduced plasma IgA, IgG, and IgM levels and splenic Ig heavy chain mRNA levels. In serum from multiple myeloma patients, BCMA–BAFF complexes were detected and BAFF levels were reduced. Multiple myeloma patient sera containing BCMA prevented binding of BAFF to B cells. There is an inverse correlation between serum BCMA and uninvolved polyclonal Ig level in multiple myeloma patients.

Conclusions: Our results show that soluble BCMA sequesters circulating BAFF, thereby preventing it from performing its signaling to stimulate normal B-cell and plasma cell development, resulting in reduced polyclonal antibody levels in multiple myeloma patients. Clin Cancer Res; 22(13); 3383–97. ©2016 AACR.

Thursday, June 30, 2016 10:05 PM|Unknown Author|Cancer Discovery recent issues|Labels: MM

Updates to the National Comprehensive Cancer Network's guidelines for treating multiple myeloma include new criteria for initiating treatment and an expanded menu of therapies based on recent FDA approvals. The changes extend the population of patients eligible for treatment and provide oncologists with better prognostic tools.

Monday, June 27, 2016 10:52 AM|SCHMEEL, L. C., SCHMEEL, F. C., SCHMIDT-WOLF, I. G. H.|Anticancer Research recent issues|Labels: lymphoma, MM

Background/Aim: Multiple myeloma (MM), a hematological malignancy of monoclonal B-lymphocytes, remains largely incurable and novel treatments are urgently required. Aberrant activation of wingless-related integration site (WNT)/β-catenin signaling has been demonstrated in both lymphoma and MM, rendering its signaling molecules attractive for the development of new targeted-therapies. Clofibrate has proven anticarcinogenic effects attributed to peroxisome proliferator-activated receptor alpha (PPARα) agonism, also affecting WNT-associated signaling molecules. Materials and Methods: The antitumor apoptotic effect of clofibrate at doses ranging from 0.1-600 μM was investigated on four human and one murine myeloma cell lines, as well as in two human lymphoma cell lines, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide assay. Results: Clofibrate significantly reduced cell viability in all tested myeloma and lymphoma cell lines in a dose-dependent manner, while healthy cells were hardly affected. Conclusion: Given the known safety profile and induction of apoptosis at low effective doses, our data warrant further investigation of clofibrate as a novel therapy agent in MM.

Wednesday, June 15, 2016 10:56 AM|Carlsten, M., Korde, N., Kotecha, R., Reger, R., Bor, S., Kazandjian, D., Landgren, O., Childs, R. W.|Clinical Cancer Research Online First Articles|Labels: MM, clinical trial

Purpose: Immune checkpoint inhibitors have recently revolutionized cancer immunotherapy. Based on data showing KIR-ligand mismatched NK-cells reduce the risk of leukemia and multiple myeloma (MM) relapse following allogeneic hematopoietic stem cell transplantation, investigators have developed a checkpoint inhibition antibody that blocks KIR on NK-cells. Although in vitro studies suggest the KIR2D-specific antibody IPH2101 induces KIR-ligand mismatched tumor killing by NK-cells, our single-arm phase II clinical trial in patients with smoldering MM was prematurely terminated due to lack of clinical efficacy. This study aimed at unveiling the underlying mechanisms behind lack of clinical efficacy. Experimental Design: Treatment-naïve patients received an intravenous infusion of 1 mg/kg IPH2101 every other month for up to a year. Peripheral blood was collected at baseline and twenty-four hours after first infusion, followed by weekly samples for the first month and monthly samples thereafter. NK-cell phenotype and function was analyzed using high-resolution flow cytometry. Results: Unexpectedly, infusion of IPH2101 resulted in rapid reduction in both NK-cell responsiveness and KIR2D expression on the NK-cell surface. In vitro assays revealed KIR2D molecules are removed from the surface of IPH2101-treated NK-cells by trogocytosis, with reductions in NK-cell function directly correlating with loss of free KIR2D surface molecules. Although IPH2101 marginally augmented the anti-myeloma cytotoxicity of remaining KIR2Ddull patient NK-cells, the overall response was diminished by significant contraction and reduced function of KIR2D-expressing NK-cells. Conclusions: These data raise concerns that the unexpected biological events reported in this study could compromise antibody-based strategies designed at augmenting NK-cell tumor killing via checkpoint inhibition.

Friday, June 10, 2016 10:57 AM|Raje, N., Faber, E., Richardson, P. G., Schiller, G., Hohl, R. J., Cohen, A. D., Forero, A., Carpenter, S., Nguyen, T. S., Conti, I., Kaiser, C., Cronier, D. M., Wooldridge, J. E., Anderson, K. C.|Clinical Cancer Research Online First Articles|Labels: MM, clinical trial

Purpose: Tabalumab, a human monoclonal antibody that neutralizes B-cell activating factor (BAFF), demonstrated anti-tumor activity in xenograft models of multiple myeloma. Here we report on a phase 1 study of relapsed/refractory multiple myeloma patients in which the primary objective was to identify a tolerable and potentially efficacious dose of tabalumab when combined with bortezomib. Experimental Design: Forty-eight patients were enrolled; 20 to the dose-escalation cohort, and 28 to cohort expansion in which a dose of 100 mg of tabalumab was evaluated. All patients had received either prior bortezomib or an immunomodulatory drug; the median number of prior therapies was 3. Bortezomib was administered intravenously on days 1, 4, 8, and 11 of a 21-day schedule. Tabalumab was given every 21 days for 3 cycles, then every 42 days thereafter. Results: The most common grade 3/4 toxicities included thrombocytopenia, neutropenia, pneumonia and peripheral sensory neuropathy. There were no dose-limiting toxicities, the maximum tolerated dose was not reached. Pharmacokinetic data suggested serum exposure increased in a greater than dose-proportional manner up to a dose of 100 mg. Out of 46 evaluable patients, 20 had confirmed responses. The median time to progression (9 patients censored) was 4.8 months; the median response duration (4 patients censored) was 7.2 months. Conclusions: A dose of 100 mg tabalumab in combination with bortezomib was well tolerated and active and is currently under further investigation.

Friday, June 10, 2016 7:44 AM|Leukemia News -- ScienceDaily|Labels: MM
A group of researchers is the first to identify a protein, AF1q, associated with multiple myeloma and a condition that occurs in approximately one-fourth of very aggressive multiple myeloma, extramedullary disease or EMD.
Saturday, June 4, 2016 7:58 PM|Leukemia News -- ScienceDaily|Labels: MM
Lenalidomide maintenance following stem cell transplant now a standard of care for people with multiple myeloma
Friday, May 27, 2016 9:18 AM|Pawlyn, C., Kaiser, M., Heuck, C., Melchor, L., Wardell, C., Murison, A., Chavan, S., Johnson, D. C., Begum, D. B., Dahir, N., Proszek, P., Cairns, D. A., Boyle, E., Jones, J., Cook, G., Drayson, M. T., Owen, R., Gregory, W. M., Jackson, G., Barlogie, B., Davies, F. E., Walker, B. A., Morgan, G.|Clinical Cancer Research Online First Articles|Labels: MM

Purpose: Epigenetic dysregulation is known to be an important contributor to myeloma pathogenesis but, unlike in other B cell malignancies, the full spectrum of somatic mutations in epigenetic modifiers has not been previously reported. We sought to address this using results from whole-exome sequencing in the context of a large prospective clinical trial of newly diagnosed patients and targeted sequencing in a cohort of previously treated patients for comparison. Experimental Design: Whole-exome sequencing analysis of 463 presenting myeloma cases entered in the UK NCRI Myeloma XI study and targeted sequencing analysis of 156 previously treated cases from the University of Arkansas for Medical Sciences. We correlated the presence of mutations with clinical outcome from diagnosis and compared the mutations found at diagnosis with later stages of disease. Results: In diagnostic myeloma patient samples we identify significant mutations in genes encoding the histone 1 linker protein, previously identified in other B-cell malignancies. Our data suggest an adverse prognostic impact from the presence of lesions in genes encoding DNA methylation modifiers and the histone demethylase KDM6A/UTX. The frequency of mutations in epigenetic modifiers appears to increase following treatment most notably in genes encoding histone methyltransferases and DNA methylation modifiers. Conclusions: Numerous mutations identified raise the possibility of targeted treatment strategies for patients either at diagnosis or relapse supporting the use of sequencing-based diagnostics in myeloma to help guide therapy as more epigenetic targeted agents become available.

CONCLUSIONSDespite inducing a superior time to progression, long‐term follow‐up revealed that PLD‐bortezomib did not improve OS compared with bortezomib alone in patients with relapsed/refractory multiple myeloma. The inability to sustain the early observed survival advantage may have been caused by the effects of subsequent lines of therapy, and underscores the need for long‐term follow‐up of phase 3 trials while recognizing the challenge of having adequate power to detect long‐term differences in OS. Cancer 2016;000:000–000. © 2016 American Cancer Society. (Source: Cancer)
Friday, April 29, 2016 1:48 PM|News-Medical.Net Erlotinib News Feed|Comments|Labels: proteasome, MM
A gene known as TJP1 (tight junction protein 1) could help determine which multiple myeloma patients would best benefit from proteasome inhibitors such as bortezomib, as well as combination approaches to enhance proteasome inhibitor sensitivity, according to a study led by The University of Texas MD Anderson Cancer Center.
Wednesday, January 13, 2016 8:49 PM|Postepy higieny i medycyny doswiadczalnej|MedWorm: Cancer Therapy|Comments|Labels: proteasome, MM, clinical trial
Proteasomes are multisubunit enzyme complexes. They contain three enzymatic active sites which are termed chymotrypsin-like, trypsin-like, and caspase-like. The elementary function of the proteasomes is degradation of damaged proteins. Proteasome inhibition leads to accumulation of damaged protein, which leads to caspase activation and cell death. This relationship is used in cancer therapy. Bortezomib is the first proteasome inhibitor approved by the US Food and Drug Administration for the treatment of relapsed/refractory multiple myeloma. Carfilzomib belongs to the second generation of drugs, which was approved by the US FDA in 2012. Currently in the study phase there are four new inhibitors: ixazomib (MLN9780/MLN2238), delanzomib (CEP-18770), oprozomib (ONX0912/PR-047) and marizomib (NP...