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Autologous stem cell transplantation (ASCT) is a potentially curative therapy but requires collection of sufficient blood stem cells (PBSC). Up to 40 % of patients with multiple myeloma (MM) fail to collect an optimum number of PBSC using filgrastim only and often require costly plerixafor rescue. The nonsteroidal anti-inflammatory drug meloxicam mobilizes PBSC in mice, nonhuman primates and normal volunteers, and has the potential to attenuate mobilization-induced oxidative stress on stem cells. In a single-center study, we evaluated whether a meloxicam regimen prior to filgrastim increases collection and/or homeostasis of CD34 + cells in MM patients undergoing ASCT. Mobilization was not significantly different with meloxicam in this study; a median of 2.4 × 10 6 CD34 + cells/kg were collected in the first apheresis and 9.2 × 10 6 CD34 + cells/kg were collected overall for patients mobilized with meloxicam-filgrastim, versus 4.1 × 10 6 in first apheresis and 7.2 × 10 6 /kg overall for patients mobilized with filgrastim alone. CXCR4 expression was reduced on CD34 + cells and a higher CD4 + /CD8 + T-cell ratio was observed after mobilization with meloxicam-filgrastim. All patients treated with meloxicam-filgrastim underwent ASCT, with neutrophil and platelet engraftment similar to filgrastim alone. RNA sequencing of purified CD34 + cells from 22 MM patients mobilized with meloxicam-filgrastim and 10 patients mobilized with filgrastim only identified > 4,800 differentially expressed genes (FDR < 0.05). Enrichment analysis indicated significant attenuation of oxidative phosphorylation and translational activity, possibly mediated by SIRT1, suggesting meloxicam may counteract oxidative stress during PBSC collection. Our results indicate that meloxicam was a safe, low-cost supplement to filgrastim mobilization, which appeared to mitigate HSPC oxidative stress, and may represent a simple means to lessen stem cell exhaustion and enhance graft quality., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Multiple myeloma (MM) remains an incurable malignancy indicating a need for continued investigation of novel therapies. Recent studies have highlighted the role of cyclin-dependent kinases (CDK) in the pathogenesis of MM. PD0332991 (Palbociclib) is an orally bioavailable, highly selective inhibitor of the CDK4/6-cyclin complex and downstream retinoblastoma protein (Rb) activation pathway that induces cell cycle arrest in the G1 phase., Areas Covered: In this review, the authors summarize the role of the CDK4/6 signaling pathway in MM. They also summarize the development of PD0332991 as a specific inhibitor of CDK4/6, and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM., Expert Opinion: While PD0332991 is essentially cytostatic, inducing prolonged G1 arrest, it enhances the cytotoxic effect of other agents effective in MM, including bortezomib and lenalidomide, as confirmed in early phase clinical trials. However, with a plethora of other drugs of different classes being tested in MM, further development of PD0332991 will depend on defining the most efficacious combination with least toxicity. An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM. The next few years are likely to better define the place of PD0332991 in the treatment of MM.

Natural killer (NK) cells elicit cytotoxicity against multiple myeloma (MM); however, MM cells express HLA class I molecules as ligands to NK cell inhibitory killer immunoglobulin-like receptors (KIRs) as a means of immunoevasion. KIR-ligand mismatch may improve outcomes in allogeneic transplantation for MM. Extrapolating on this concept, we conducted a phase 1 trial of IPH2101, an anti-KIR antibody, in patients with relapsed/refractory MM. IPH2101 was administered intravenously every 28 days in 7 dose-escalated cohorts (0.0003-3 mg/kg) for up to 4 cycles. Pharmacokinetic, pharmacodynamic, and correlative immunologic studies were completed. A total of 32 patients were enrolled. The biologic endpoint of full KIR2D occupancy across the dosing cycle was achieved without dose-limiting toxicity or maximally tolerated dose. One severe adverse event was noted. Pharmacokinetic and pharmacodynamic findings approximated preclinical predictions, and IPH2101 enhanced ex vivo patient-derived NK cell cytotoxicity against MM. No objective responses were seen. No evidence of autoimmunity was observed. These findings suggest that IPH2101 is safe and tolerable at doses that achieve full inhibitory KIR saturation, and this approach warrants further development in MM. This trial was registered at www.clinicaltrials.gov as #NCT00552396.

Multiple myeloma (MM) patients who receive killer cell Ig-like receptor (KIR) ligand-mismatched, T cell-depleted, allogeneic transplantation may have a reduced risk of relapse compared with patients who receive KIR ligand-matched grafts, suggesting the importance of this signaling axis in the natural killer (NK) cell-versus-MM effect. Expanding on this concept, IPH2101 (1-7F9), an anti-inhibitory KIR mAb, enhances NK-cell function against autologous MM cells by blocking the engagement of inhibitory KIR with cognate ligands, promoting immune complex formation and NK-cell cytotoxicity specifically against MM cell targets but not normal cells. IPH2101 prevents negative regulatory signals by inhibitory KIR, whereas lenalidomide augments NK-cell function and also appears to up-regulate ligands for activating NK-cell receptors on MM cells. Lenalidomide and a murine anti-inhibitory NK-cell receptor Ab mediate in vivo rejection of a lenalidomide-resistant tumor. These mechanistic, preclinical data support the use of a combination of IPH2101 and lenalidomide in a phase 2 trial for MM.

Purpose: Multiple myeloma (MM) is an incurable plasma-cell neoplasm for which most treatments involve a therapeutic agent combined with dexamethasone. The preclinical combination of lenalidomide with the mTOR inhibitor CCI-779 has displayed synergy in vitro and represents a novel combination in MM., Patients and Methods: A phase I clinical trial was initiated for patients with relapsed myeloma with administration of oral lenalidomide on days 1 to 21 and CCI-779 intravenously once per week during a 28-day cycle. Pharmacokinetic data for both agents were obtained, and in vitro transport and uptake studies were conducted to evaluate potential drug-drug interactions., Results: Twenty-one patients were treated with 15 to 25 mg lenalidomide and 15 to 20 mg CCI-779. The maximum-tolerated dose (MTD) was determined to be 25 mg lenalidomide with 15 mg CCI-779. Pharmacokinetic analysis indicated increased doses of CCI-779 resulted in statistically significant changes in clearance, maximum concentrations, and areas under the concentration-time curves, with constant doses of lenalidomide. Similar and significant changes for CCI-779 pharmacokinetics were also observed with increased lenalidomide doses. Detailed mechanistic interrogation of this pharmacokinetic interaction demonstrated that lenalidomide was an ABCB1 (P-glycoprotein [P-gp]) substrate., Conclusion: The MTD of this combination regimen was 25 mg lenalidomide with 15 mg CCI-779, with toxicities of fatigue, neutropenia, and electrolyte wasting. Pharmacokinetic and clinical interactions between lenalidomide and CCI-779 seemed to occur, with in vitro data indicating lenalidomide was an ABCB1 (P-gp) substrate. To our knowledge, this is the first report of a clinically significant P-gp-based drug-drug interaction with lenalidomide.

Introduction: Multiple myeloma (MM) remains incurable, indicating the need for continued investigation of innovative strategies. Recent progress in molecular biology has advanced the discovery of novel drugs for MM. ENMD-2076 is an orally bioavailable, multi-target kinase inhibitor with multiple mechanisms of action, including anti-proliferative and pro-apoptotic activity, and anti-angiogenic effects., Areas Covered: In this review, the authors summarize the preclinical in vitro and in vivo data that have formed the rationale for clinical investigation of ENMD-2076 in MM. In addition, the authors review the early clinical results of ENMD-2076 in MM and other malignancies, and speculate on potential avenues of future clinical research in the development of this drug for MM., Expert Opinion: There is a strong preclinical rationale for investigating ENMD-2076 in MM that is confirmed by early clinical results in an ongoing Phase I trial in patients with relapsed or refractory MM. Optimal strategies for developing ENMD-2076 in MM will require better elucidation of its mechanism of action, investigation of biomarkers for response and development of rationale synergistic combinations with other active agents.

Multiple myeloma (MM) remains incurable with current therapy, indicating the need for continued development of novel therapeutic agents. We evaluated the activity of a novel phenylbutyrate-derived histone deacetylase inhibitor, AR-42, in primary human myeloma cells and cell lines. AR-42 was cytotoxic to MM cells at a mean LC(50) of 0.18 ± 0.06 μmol/l at 48 hr and induced apoptosis with cleavage of caspases 8, 9 and 3, with cell death largely prevented by caspase inhibition. AR-42 downregulated the expression of gp130 and inhibited activation of STAT3, with minimal effects on the PI3K/Akt and MAPK pathways, indicating a predominant effect on the gp130/STAT-3 pathway. AR-42 also inhibited interleukin (IL)-6-induced STAT3 activation, which could not be overcome by exogenous IL-6. AR-42 also downregulated the expression of STAT3-regulated targets, including Bcl-xL and cyclin D1. Overexpression of Bcl-xL by a lentivirus construct partly protected against cell death induced by AR-42. The cyclin dependent kinase inhibitors, p16 and p21, were also significantly induced by AR-42, which together with a decrease in cyclin D1, resulted in G(1) and G(2) cell cycle arrest. In conclusion, AR-42 has potent cytotoxicity against MM cells mainly through gp130/STAT-3 pathway. The results provide rationale for clinical investigation of AR-42 in MM., (Copyright © 2010 UICC.)

ENMD-2076 is a novel, orally-active molecule that has been shown to have significant activity against aurora and multiple receptor tyrosine kinases. We investigated the activity of ENMD-2076 against multiple myeloma (MM) cells in vitro and in vivo. ENMD-2076 showed significant cytotoxicity against MM cell lines and primary cells, with minimal cytotoxicity to haematopoietic progenitors. ENMD-2076 inhibited the phosphoinositide 3-kinase/AKT pathway and downregulated survivin and X-linked inhibitor of apoptosis as early as 6 h after treatment. With longer treatment (24-48 h), ENMD-2076 also inhibited aurora A and B kinases, and induced G(2)/M cell cycle arrest. In non-obese diabetic/severe combined immunodeficient mice implanted with H929 human plasmacytoma xenografts, oral treatment with ENMD-2076 (50, 100, 200 mg/kg per day) resulted in a dose-dependent inhibition of tumour growth. Immunohistochemical staining of excised tumours showed significant reduction in phospho-Histone 3 (pH3), Ki-67, and angiogenesis, and also a significant increase in cleaved caspase-3 at all dose levels compared to tumours from vehicle-treated mice. In addition, a significant reduction in p-FGFR3 was observed on Western blot. ENMD-2076 shows significant activity against MM cells in vitro and in vivo, and acts on several pathways important for myeloma cell growth and survival. These results provide preclinical rationale for clinical investigation of ENMD-2076 in MM.

In a phase II trial, 16 patients with relapsed refractory multiple myeloma received temsirolimus 25mg I.V. weekly until progression. One partial response and 5 minor responses were observed for a total response rate of 38%. The median time to progression was 138 days. Grade 3-4 toxicity included fatigue (n=3), neutropenia (n=2), thrombocytopenia (n=2), interstitial pneumonitis (n=1), stomatitis (n=1) and diarrhea (n=1). Clinical activity was associated with a higher area under the curve (AUC) and maximal reduction in phosphorylated p70(S6)K and 4EBP1 in peripheral blood mononuclear cells. At the dose and schedule used, temsirolimus had low single agent activity. Investigation of alternate dosing schedules and use in combinations is indicated.

Purpose: Nuclear factor-kappaB (NF-kappaB), activated in multiple myeloma (MM) cells by microenvironmental cues, confers resistance to apoptosis. The sesquiterpene lactone parthenolide targets NF-kappaB. However, its therapeutic potential in MM is not known., Experimental Designs: We explored the effects of parthenolide on MM cells in the context of the bone marrow microenvironment., Results: Parthenolide inhibited growth of MM cells lines, including drug-resistant cell lines, and primary cells in a dose-dependent manner. Parthenolide overcame the proliferative effects of cytokines interleukin-6 and insulin-like growth factor I, whereas the adhesion of MM cells to bone marrow stromal cells partially protected MM cells against parthenolide effect. In addition, parthenolide blocked interleukin-6 secretion from bone marrow stromal cells triggered by the adhesion of MM cells. Parthenolide cytotoxicity is both caspase-dependent and caspase-independent. Parthenolide rapidly induced caspase activation and cleavage of PARP, MCL-1, X-linked inhibitor of apoptosis protein, and BID. Parthenolide rapidly down-regulated cellular FADD-like IL-1beta-converting enzyme inhibitory protein, and direct targeting of cellular FADD-like IL-1beta-converting enzyme inhibitory protein using small interfering RNA oligonucleotides inhibited MM cell growth and lowered the parthenolide concentration required for growth inhibition. An additive effect and synergy were observed when parthenolide was combined with dexamethasone and TNF-related apoptosis-inducing ligand, respectively., Conclusion: Collectively, parthenolide has multifaceted antitumor effects toward both MM cells and the bone marrow microenvironment. Our data support the clinical development of parthenolide in MM therapy.

Purpose: OSU-03012 is a novel celecoxib derivative, without cyclooxygenase-2 inhibitory activity, capable of inducing apoptosis in various cancer cells types, and is being developed as an anticancer drug. We investigated the in vitro activity of OSU-03012 in multiple myeloma (MM) cells., Experimental Design: U266, ARH-77, IM-9, and RPMI-8226, and primary myeloma cells were exposed to OSU-03012 for 6, 24, or 72 h. Cytotoxicity, caspase activation, apoptosis, and effects on intracellular signaling pathways were assessed., Results: OSU-03012 was cytotoxic to MM cells with mean LC50 3.69 +/- 0.23 and 6.25 +/- 0.86 micromol/L and at 24 h for primary MM cells and cell lines, respectively. As a known PDK-1 inhibitor, OSU-03012 inhibited the PI3K/Akt pathway with downstream effects on BAD, GSK-3beta, FoxO1a, p70S6K, and MDM-2. However, transfection of MM cells with constitutively active Akt failed to protect against cell death, indicating activity against other pathways is important. Phospho (p)-signal transducers and activators of transcription 3 and p-MAP/ERK kinase 1/2 were down-regulated, suggesting that OSU-03012 also inhibited the Janus-activated kinase 2/signal transducer and activator of transcription 3 and mitogen-activated protein kinase pathways. Although expression of Bcl-2 proteins was unchanged, OSU-03012 also down-regulated survivin and X-linked inhibitor of apoptosis (XIAP), and also induced G2 cell cycle arrest with associated reductions in cyclins A and B. Finally, although OSU-03012 induced cleavage of caspases 3, 8 and 9, caspase inhibition did not prevent cell death., Conclusions: We conclude that OSU-03012 has potent activity against MM cells and acts via different mechanisms in addition to phosphoinositide-3-kinase/Akt pathway inhibition. These studies provide rationale for the clinical investigation of OSU-03012 in MM.

High-dose chemotherapy (HDC) with autologous stem cell transplant (ASCT) has improved response rates and survival for patients with multiple myeloma (MM). We report a single-institution experience using two conditioning regimens, busulfan, cyclophosphamide, and etoposide (BCV) or high-dose melphalan (HDM). Between July 1992 and August 2003, 110 patients with MM (median age=56.1) underwent HDC with ASCT using either BCV (n=62) or HDM (n=48) in sequential cohorts as the preparative regimen. Overall response rates, progression-free survival, and median overall survival were similar. BCV and HDM confer similar long-term outcomes with similar toxicity profiles as conditioning regimens prior to autologous stem cell transplant in patients with MM.

Summary Aurora kinases play an important role in the control of the cell cycle and have been implicated in tumourigenesis in a number of cancers. Among the haematological malignancies, overexpression of Aurora kinases has been reported in acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphoblastic leukaemia, multiple myeloma, aggressive non-Hodgkin lymphoma and Hodgkin lymphoma. A large number of Aurora kinase inhibitors are currently in different stages of clinical development. In addition to varying in their selectivity for the different Aurora kinases, some also have activity directed at other cellular kinases involved in important molecular pathways in cancer cells. This review summarizes the biology of Aurora kinases and discusses why they may be good therapeutic targets in different haematological cancers. We describe preclinical data that has served as the rationale for investigating Aurora kinase inhibitors in different haematological malignancies, and summarize published results from early phase clinical trials. While the anti-tumour effects of Aurora kinase inhibitors appear promising, we highlight important issues for future clinical research and suggest that the optimal use of these inhibitors is likely to be in combination with cytotoxic agents already in use for the treatment of various haematological cancers. [ABSTRACT FROM AUTHOR]

ENMD-2076 is a novel, orally-active molecule that has been shown to have significant activity against aurora and multiple receptor tyrosine kinases. We investigated the activity of ENMD-2076 against multiple myeloma (MM) cells in vitro and in vivo. ENMD-2076 showed significant cytotoxicity against MM cell lines and primary cells, with minimal cytotoxicity to haematopoietic progenitors. ENMD-2076 inhibited the phosphoinositide 3-kinase/AKT pathway and downregulated survivin and X-linked inhibitor of apoptosis as early as 6 h after treatment. With longer treatment (24–48 h), ENMD-2076 also inhibited aurora A and B kinases, and induced G2/M cell cycle arrest. In non-obese diabetic/severe combined immunodeficient mice implanted with H929 human plasmacytoma xenografts, oral treatment with ENMD-2076 (50, 100, 200 mg/kg per day) resulted in a dose-dependent inhibition of tumour growth. Immunohistochemical staining of excised tumours showed significant reduction in phospho-Histone 3 (pH3), Ki-67, and angiogenesis, and also a significant increase in cleaved caspase-3 at all dose levels compared to tumours from vehicle-treated mice. In addition, a significant reduction in p-FGFR3 was observed on Western blot. ENMD-2076 shows significant activity against MM cells in vitro and in vivo, and acts on several pathways important for myeloma cell growth and survival. These results provide preclinical rationale for clinical investigation of ENMD-2076 in MM. [ABSTRACT FROM AUTHOR]

High dose chemotherapy followed by hematopoietic cell transplantation (HCT) is an intensive cancer treatment associated with devastating complications. Persistent physical inactivity after HCT is sufficient to cause muscle mass loss, decreased strength, physical deconditioning, and potential progression to disability. Sustainable physical activity incorporated into activities of daily living may break this negative cycle. This pilot, randomized controlled trial tested the feasibility and preliminary effects of a free-living physical activity intervention (STEPS) compared to usual care on fatigue (primary outcome), functional ability, muscle strength, physical activity, and quality of life (secondary outcomes) in people with multiple myeloma treated with autologous HCT. This study used a two-group, randomized block, repeated measures design (n = 32). The six-week STEPS intervention aimed to increase physical activity by 10% weekly through education, goal-setting, daily step tracking using wearable technology, and guided integration of physical activity into daily routines. Data were collected using self-report questionnaires, physical performance tests, and wrist actigraphy prior to HCT and seven weeks following hospital discharge. Split-plot 2 × 2 ANOVAs were used to analyze the preliminary group (STEPS versus usual care), time (prior to HCT versus seven weeks after hospital discharge), and group x time interactions effects. The STEPS group achieved their daily physical activity goal 53% of the time. Compared to usual care, the STEPS group experienced greater appetite loss (p =.05), more diarrhea (p =.05), and slept more (p =.03). Both groups reported improvements in mental fatigue (p =.02), emotional functioning (p =.01), pain (p =.009), sleep disturbance (p =.001), anger (p =.003), anxiety (p =.001), and depression (p =.02) seven weeks after HCT discharge compared to baseline. Conversely, both groups climbed the stairs slower (p =.003) and had weaker hand-grips (p <.05). The STEPS intervention is feasible for people with multiple myeloma treated with HCT. Although preliminary, differential improvement in the STEPS group's patient outcomes did not occur (no significant group x time interactions). Both groups reported improved symptoms and experienced some declines in physical function seven weeks after HCT hospital discharge. [ABSTRACT FROM AUTHOR]