Association between baseline Controlling Nutritional Status score and clinical outcomes of patients with multiple myeloma.

BACKGROUND: The Controlling Nutritional Status (CONUT) score, a novel immuno-nutritional index, was reported as a predictor of overall survival (OS) in some tumors. OBJECTIVE: We aimed to investigate the association between baseline CONUT Score and clinical outcomes in patients with multiple myeloma (MM). METHODS: We performed a retrospective analysis of 245 patients with MM. The CONUT score was determined prior to therapy. RESULTS: Among the entire cohort, the complete remission rate was markedly higher in the low-CONUT (⩽ 3) group compared to the mid-CONUT (4-9) group or high-CONUT (> 9) group (44.1% vs 25.8%, P= 0.039; 44.1% vs 12.5%, P= 0.002). Patients with CONUT score > 9 had significant poor prognosis, and CONUT score ⩽ 3 group showed better survival outcome than other groups in OS (P< 0.001). Besides, we stratified the patients by combining International Staging System (ISS) stage and CONUT score in a model, and found that CONUT score could improve the prognostic impact of ISS stages on OS. In multivariate analysis, older age (⩾ 70 years) and a high CONUT score (⩾ 4) were independent prognostic risk factors for OS. CONCLUSIONS: The CONUT score was a predictor of OS in MM patients especially in cases with both low ISS staging and CONUT score. The baseline CONUT score may be an early and practical indicator of the efficacy of anti-myeloma treatment.

Development of BET inhibitors as potential treatments for cancer: A search for structural diversity.

We describe our efforts to identify structurally diverse leads in the triazole-containing N1-carboline series of bromodomain and extra-terminal inhibitors. Replacement of the N5 "cap" phenyl moiety with various heteroaryls, coupled with additional modifications to the carboline core, provided analogs with similar potency, improved pharmacokinetic properties, and increased solubility compared to our backup lead, BMS-986225 (2). Rapid SAR exploration was enabled by a convergent, synthetic route. These efforts provided a potent BET inhibitor, 3-fluoropyridyl 12, that demonstrated robust efficacy in a multiple myeloma mouse tumor model at 1 mg/kg.

The anti-mitotic agents PTC-028 and PTC596 display potent activity in pre-clinical models of multiple myeloma but challenge the role of BMI-1 as an essential tumour gene.

Future progress in the treatment of multiple myeloma (MM) requires both the characterisation of key drivers of the disease and novel, innovative approaches to tackle these vulnerabilities. The present study focussed on the pre-clinical evaluation of a novel drug class, BMI-1 modulators, in MM. We demonstrate potent activity of PTC-028 and PTC596 in a comprehensive set of in vitro and in vivo models, including models of drug resistance and stromal support. Treatment of MM cells with PTC-028 and PTC596 downregulated BMI-1 protein levels, which was found to correlate with drug activity. Surprisingly, BMI-1 was dispensable for the activity of BMI-1 modulators and MM cell growth. Our data rather point to mitotic arrest accompanied by myeloid cell leukaemia-1 (MCL-1) loss as key anti-MM mechanisms and reveal impaired MYC and AKT signalling activity due to BMI-1 modulator treatment. Moreover, we observed a complete eradication of MM after PTC596 treatment in the 5TGM.1 in vivo model and define epigenetic compounds and B cell leukaemia/lymphoma 2 homology domain 3 (BH3) mimetics as promising combination partners. These results bring into question the postulated role of BMI-1 as an essential MM gene and confirm BMI-1 modulators as potent anti-mitotic agents with encouraging pre-clinical activity that supports their rapid translation into clinical trials.

Impact of last lenalidomide dose, duration, and IMiD-free interval in patients with myeloma treated with pomalidomide/dexamethasone.

To gain insights into the characteristics of clinical resistance to lenalidomide, we evaluated the outcomes of 147 consecutive patients with multiple myeloma (MM) homogeneously treated with immunomodulatory imide drugs (IMiDs) pomalidomide and dexamethasone (Pd) for relapsed and/or refractory MM (median, 3 prior lines of treatment). We focused our analysis on the effect of the lenalidomide dose at which resistance was developed, the duration of lenalidomide exposure, and lenalidomide-free interval. On intent to treat, 33% of patients achieved ≥partial remission (PR) with Pd. When Pd was given immediately after lenalidomide, ≥PR was 32% (vs 37% after bortezomib). The response rates were similar for patients that received 5 to 15 mg vs 25 mg of lenalidomide (38.5% vs 30.5%, P = .329). Response rates were higher for patients that had received at least 12 months of lenalidomide (44% vs 27%) and for those with ≥18 months from last lenalidomide dose to pomalidomide dose (65% vs 23%). Median progression-free survival (PFS) and overall survival (OS) were 5 and 12.1 months, respectively, which was similar for patients who received lenalidomide, bortezomib or other regimens just before Pd and similar for patients who were receiving different doses of lenalidomide. IMiD-free interval ≥18 months was associated with longer PFS (10.3 vs 3.9 months, P = .003) and OS (27.1 vs 9.3, P = .008) as well as duration of last lenalidomide therapy ≥12 months (PFS: 7.8 vs 3.2, P = .023; OS: 16.5 vs 7.9, P = .005) even after adjustment for the number of prior therapies, duration of disease, and last lenalidomide dose.

Whole-body MRI quantitative biomarkers are associated significantly with treatment response in patients with newly diagnosed symptomatic multiple myeloma following bortezomib induction.

OBJECTIVES: To evaluate whole-body MRI (WB-MRI) parameters significantly associated with treatment response in multiple myeloma (MM). METHODS: Twenty-one MM patients underwent WB-MRI at diagnosis and after two cycles of chemotherapy. Scans acquired at 3.0 T included T2, diffusion-weighted-imaging (DWI) and mDixon pre- and post-contrast. Twenty focal lesions (FLs) matched on DWI and post-contrast mDixon were selected for each time point. Estimated tumour volume (eTV), apparent diffusion coefficient (ADC), enhancement ratio (ER) and signal fat fraction (sFF) were derived. Clinical treatment response to chemotherapy was assessed using conventional criteria. Significance of temporal parameter change was assessed by the paired t test and receiver operating characteristics/area under the curve (AUC) analysis was performed. Parameter repeatability was assessed by interclass correlation (ICC) and Bland-Altman analysis of 10 healthy volunteers scanned at two time points. RESULTS: Fifteen of 21 patients responded to treatment. Of 254 FLs analysed, sFF (p < 0.0001) and ADC (p = 0.001) significantly increased in responders but not non-responders. eTV significantly decreased in 19/21 cases. Focal lesion sFF was the best discriminator of treatment response (AUC 1.0). Bone sFF repeatability was excellent (ICC 0.98) and better than bone ADC (ICC 0.47). CONCLUSION: WB-MRI derived focal lesion sFF shows promise as an imaging biomarker of treatment response in newly diagnosed MM. KEY POINTS: • Bone signal fat fraction using mDixon is a robust quantifiable parameter • Fat fraction and ADC significantly increase in myeloma lesions responding to treatment • Bone lesion fat fraction is the best discriminator of myeloma treatment response.

Targeting autophagy in multiple myeloma.

Autophagy plays an important role in plasma cell ontogeny and in the pathophysiology of multiple myeloma. Autophagy is usually considered a pro-survival mechanism, and cooperates with the ubiquitin proteasome system in maintaining the homeostasis of myeloma cells by degrading excessive and misfolded proteins for energy recycling. Therefore, the inhibition of autophagy could effectively induce death in myeloma cells, and could synergize with proteasome inhibitors. However, the excessive activation of autophagy could also lead to the extreme degradation of the organelles that induce autophagic cell death. Hence, the activation of autophagic cell death might also represent a promising approach for treating myeloma. Recent studies have demonstrated that autophagy also mediates drug resistance in myeloma cells and the complications of myeloma, while the inhibition of autophagy may reverse the response to drugs. In this study, we have mainly reviewed recent research on autophagy in relationship to the therapeutic effect, the reversal of drug resistance, and the mediation of complications.

Antitumoral Effect of Hibiscus sabdariffa on Human Squamous Cell Carcinoma and Multiple Myeloma Cells.

Cancer is a leading cause of death worldwide. Despite therapeutic improvements, some cancers are still untreatable. Recently there has been an increasing interest in the use of natural substances for cancer prevention and treatment. Hibiscus sabdariffa (HS) is a plant, belonging to Malvaceae family, widespread in South Asia and Central Africa. HS extract (HSE) used in folk medicine, gained researchers' interest thanks to its antioxidant, anti-inflammatory, and chemopreventive properties. In the present study, we initially assessed HSE effect on a panel of human tumor cell lines. Then we focused our study on the following that are most sensitive to HSE action cell lines: Multiple Myeloma (MM) cells (RPMI 8226) and Oral Squamous Cell Carcinoma (OSCC) cells (SCC-25). In both RPMI 8226 and SCC-25 cells, HSE impaired cell growth, exerted a reversible cytostatic effect, and reduced cell motility and invasiveness. We evaluated the involvement of MAPKs ERK1/2 and p38 in HSE effects by using specific inhibitors, U0126 and SB203580, respectively. For both SCC-25 and RPMI 8226, HSE cytostatic effect depends on p38 activation, whereas ERK1/2 modulation is crucial for cell motility and invasiveness. Our results suggest that HSE may be a potential therapeutic agent against MM and OSCC.

Role of micro-RNAs in drug resistance of multiple myeloma.

While novel therapeutic approaches have profoundly improved survival of multiple myeloma (MM) patients, drug resistance and treatment refractoriness still persists. This obstacle highly demands thorough investigation into the root and underlying molecular mechanisms to develop more effective strategies. The advent of micro-RNAs (miRNAs) in the study of cancer biology and pathogenesis in recent years has revolutionized therapy in this field and particularly opened new windows to further understanding of tumor drug resistance. However; in spite of the fact that miRNAs involvement in MM pathogenesis and progression has been substantially evidenced, miRNA investigation in MM drug resistance is still in its infancy. Our knowledge of the potential role of miRNAs in MM drug resistance comes from few recent reports confirming that some miRNAs including miR-137/197, miR-21 and miR-221/222 could negatively modulate drug sensitivity of MM cells. Further continuous researches are required to exploit miRNAs to elucidate the critical mechanisms controlling drug resistance in MM. In this review, we will highlight the most recent observations on the role of miRNAs in MM drug resistance. Moreover, approaches and insights into clinical application of miRNAs to overcome MM drug resistance will be discussed.

Comparative cost-effectiveness models for the treatment of multiple myeloma.

OBJECTIVES: To compare cost effectiveness models for the first-line treatment of multiple myeloma, and explore the differences between the models' structure, parameters, assumptions and results. METHODS: Three cost effectiveness models for the treatment of multiple myeloma, were compared that had been developed to inform resource allocation in the UK for the chemotherapy regimens bortezomib, melphalan and prednisolone (BMP); and melphalan, prednisolone and thalidomide (MPT) versus melphalan and prednisolone (MP). The models used alternative approaches and assumptions to estimate the overall survival and progression-free survival for each of the interventions. Through the use of sensitivity analyses, the most influential parameters and assumptions of each of the models were identified. RESULTS: The models developed by the manufacturers gave conflicting results, with each manufacturer favouring their drug. The differences between the model results were determined by two parameters: the hazard ratio for overall survival for MPT vs. MP and the cost of bortezomib. CONCLUSIONS: Using models developed for assessing treatments for multiple myeloma we demonstrated that it was feasible to compare models, which then aided decision makers in making reimbursement decisions.

Incident hyperglycemia, parenteral nutrition administration and adverse outcomes in patients with myeloma admitted for initial auto-SCT.

Parenteral nutrition (PN) exacerbates hyperglycemia, which is associated with increased morbidity and mortality in various cancer populations. By using a retrospective design, we examined incident hyperglycemia in PN and non-PN recipients and the associations with clinical events and 5-year survival in a cohort treated for myeloma with melphalan and auto-SCT (n=112). Clinical comparisons were made at admission, and 'before' and 'after' initiating PN to discern differences and temporality. Actual infusion times were used for PN patients; time frames based on mean PN infusion days were created for the non-PN recipients. Oral intake was lower 'before' in PN vs non-PN patients (P<0.001); however, no differences in mucositis, emesis, infections or transfusions were detected 'before.' Incident hyperglycemia (≥7.0 mmol/L) was significant 'after' PN initiation, and PN recipients experienced delays in WBC (P<0.05) and platelet engraftment (P=0.009), and required significantly greater RBC (P=0.0014) and platelet (P=0.001) support 'after' than non-PN patients. Neutropenic fever and longer hospital stay were more frequent among PN vs non-PN recipients (P<0.001). Differences in 5-year mortality were not apparent. The findings fail to support clinical benefits of PN administration during auto-SCT for myeloma. Further study is needed to discern if hyperglycemia or feeding per se was deleterious in this patient population.

Questioning the role of a neutropenic diet following hematopoetic stem cell transplantation.

The use of a neutropenic diet (ND) after hematopoietic stem cell transplantation (HSCT) was instituted more than 30 years ago as a means of preventing infection from organisms colonizing the gastrointestinal tract. Evidence supporting this practice is lacking, however, and the actual efficacy of the ND remains unknown. Institutional policy at Northwestern Memorial Hospital discontinued the use of ND in 2006. We conducted a retrospective study of 726 consecutive HSCT recipients, 363 who received an ND and 363 who received a general hospital diet, to determine the incidence of microbiologically confirmed infections during and after transplantation. Our findings indicate a higher rate of infections in the HSCT recipients who received an ND.

Natural polyphenols antagonize the antimyeloma activity of proteasome inhibitor bortezomib by direct chemical interaction.

Bortezomib is a therapeutic proteasome inhibitor with antimyeloma activity and polyphenols are well known compounds that exert antiproliferative effects against tumuors. We attempted to co-treat myeloma cells with bortezomib and polyphenols, anticipating a synergistic effect. However, the anticancer activity of bortezomib was blocked by the polyphenols. The structural features of the polyphenols correlated strikingly with their antagonistic effect; in particular, the presence or absence of a vicinal diol moiety was the key element for effective blockage of the anticancer function of bortezomib. We speculated that the vicinal diols in the polyphenols interact with the boronic acid of bortezomib and convert the active triangular boronic acid of bortezomib to an inactive tetrahedral boronate, thus abolishing the antimyeloma activity of bortezomib. We confirmed this hypothesis by (11)B nuclear magnetic resonance spectroscopy and an in vitro assay on multiple myeloma (MM) cell lines and primary myeloma cells from patients. Based on these findings, restriction of the intake of natural polyphenols in foods or vitamin supplements during bortezomib treatment in MM patients should be considered.

Dietary flavonoids inhibit the anticancer effects of the proteasome inhibitor bortezomib.

Dietary flavonoids have many health-promoting actions, including anticancer activity via proteasome inhibition. Bor-tezomib is a dipeptide boronate proteasome inhibitor that has activity in the treatment of multiple myeloma but is not effective in chronic lymphocytic leukemia (CLL). Although CLL cells are sensitive in vitro to bortezomib-induced apoptosis when cultured in medium, the killing activity was blocked when cultured in 50% fresh autologous plasma. Dietary flavonoids, quercetin and myricetin, which are abundant in plasma, inhibited bortezomib-induced apoptosis of primary CLL and malignant B-cell lines in a dose-dependent manner. This inhibitory effect was associated with chemical reactions between quercetin and the boronic acid group, -RB(OH)2, in bortezomib. The addition of boric acid diminished the inhibitory effect of both quercetin and plasma on bortezomib-induced apoptosis. The protective effect was also reduced when myeloma cell lines, but not B-cell lines, were preincubated with quercetin, indicating a direct effect of quercetin on myeloma cells. At high doses, quercetin itself induced tumor cell death. These data indicate that dietary flavonoids limit the efficacy of bortezomib, whereas supplemental inorganic boric acid is able to reverse this. The complex interactions between quercetin, tumor cells, and bortezomib mean caution is required when giving dietary advice to patients.

Dangerous nutrition? Calcium, vitamin D, and shark cartilage nutritional supplements and cancer-related hypercalcemia.

The use of nutritional supplements in the general population and in cancer patients has become very popular. These supplements are not perceived as medications and are presumed to be safe by cancer patients, who may however be at risk for hypercalcemia. We note that many of our patients who have developed symptomatic hypercalcemia were taking vitamin D, calcium, or shark cartilage supplements. We report eight cases of hypercalcemia in cancer patients seen at the Cleveland Clinic Foundation in whom these nutritional supplements may have contributed to the prevalence or severity of hypercalcemia.