Outcomes of primary refractory multiple myeloma and the impact of novel therapies

Majithia, Neil; Rajkumar, S. Vincent; Lacy, Martha Q.; Buadi, Francis K.; Dispenzieri, Angela; Gertz, Morie A.; Hayman, Suzanne R.; Dingli, David; Kapoor, Prashant; Hwa, Lisa; Lust, John A.; Russell, Stephen J.; Go, Ronald S.; Kyle, Robert A.; Kumar, Shaji

doi:10.1002/ajh.24131

Cited by 42 publications

(37 citation statements)

References 49 publications

(48 reference statements)

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“…20 In that study, patients with primary refractory disease were found to have worse outcomes compared with those who achieved at least a PR to initial treatment. Further, patients who achieved a depth of response that was at least VGPR experienced longer median OS compared with those who only attained PR.…”

Section: Discussionmentioning

confidence: 94%

Early relapse following initial therapy for multiple myeloma predicts poor outcomes in the era of novel agents

et al. 2016

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Outcomes for patients with multiple myeloma (MM) have improved in recent years owing to use of novel agents and high-dose therapy followed by autologous stem cell transplant (ASCT). We analyzed the outcomes of 511 consecutive patients treated with novel therapies at our institution between 2006 and 2014 to determine the impact of relapse within 12 months of initiating treatment. A total of 82 patients (16.0%) experienced early relapse, with median time to relapse of 8.0 months (95% confidence interval (CI); 6.3, 8.9). Median overall survival (OS) was significantly worse for this group at 21.0 months (95% CI; 16.3, 27.2) vs not reached (NR) (95% CI; 96.3, NR) for those with late relapse (P<0.001). Survival outcomes remained poor among early relapse patients irrespective of depth of response to initial therapy. In multivariate analysis, low albumin and high-risk cytogenetics predicted early relapse. Outcomes of early relapse from early ASCT were also considered; median OS from ASCT for those relapsing within 12 months was 23.1 months (95% CI; 15.7, 32.4) vs 122.2 months (95% CI; 111.5, 122.2) for the remaining patients (P<0.001). Early relapse remains a marker of poor prognosis in the current era, and such patients should be targeted for clinical trials.

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Section: Discussionmentioning

confidence: 94%

Early relapse following initial therapy for multiple myeloma predicts poor outcomes in the era of novel agents

et al. 2016

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“…Clinical course of MM is fraught with emergence of refractory disease and high mortality [2, 3]. A growing body of evidence suggests that a minor, therapy-resistant, clonogenic sub-population of tumor cells is most likely the principal roadblock to curing MM [4, 8].…”

Section: Discussionmentioning

confidence: 99%

“…New pharmacological drugs (i.e. lenalidomide, pomalidomide, bortezomib, carfilzomib, ixazomib, panobinostat) show anti-MM activity and in combination with conventional therapies offer deep clinical remissions [2]. However, most patients eventually relapse with aggressive drug-resistant MM disease [3].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial-Targeted Decyl-Triphenylphosphonium Enhances 2-Deoxy-D-Glucose Mediated Oxidative Stress and Clonogenic Killing of Multiple Myeloma Cells

et al. 2016

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Therapeutic advances have markedly prolonged overall survival in multiple myeloma (MM) but the disease currently remains incurable. In a panel of MM cell lines (MM.1S, OPM-2, H929, and U266), using CD138 immunophenotyping, side population staining, and stem cell-related gene expression, we demonstrate the presence of stem-like tumor cells. Hypoxic culture conditions further increased CD138low stem-like cells with upregulated expression of OCT4 and NANOG. Compared to MM cells, these stem-like cells maintained lower steady-state pro-oxidant levels with increased uptake of the fluorescent deoxyglucose analog. In primary human MM samples, increased glycolytic gene expression correlated with poorer overall and event-free survival outcomes. Notably, stem-like cells showed increased mitochondrial mass, rhodamine 123 accumulation, and orthodox mitochondrial configuration while more condensed mitochondria were noted in the CD138high cells. Glycolytic inhibitor 2-deoxyglucose (2-DG) induced ER stress as detected by qPCR (BiP, ATF4) and immunoblotting (BiP, CHOP) and increased dihydroethidium probe oxidation both CD138low and CD138high cells. Treatment with a mitochondrial-targeting agent decyl-triphenylphosphonium (10-TPP) increased intracellular steady-state pro-oxidant levels in stem-like and mature MM cells. Furthermore, 10-TPP mediated increases in mitochondrial oxidant production were suppressed by ectopic expression of manganese superoxide dismutase. Relative to 2-DG or 10-TPP alone, 2-DG plus 10-TPP combination showed increased caspase 3 activation in MM cells with minimal toxicity to the normal hematopoietic progenitor cells. Notably, treatment with polyethylene glycol conjugated catalase significantly reduced 2-DG and/or 10-TPP-induced apoptosis of MM cells. Also, the combination of 2-DG with 10-TPP decreased clonogenic survival of MM cells. Taken together, this study provides a novel strategy of metabolic oxidative stress-induced cytotoxicity of MM cells via 2-DG and 10-TPP combination therapy.

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“…Refractory MM refers to patients with MM that, following initial treatment and 2-3 courses of VAD or MP chemotherapy, show no signs of improvement or only partial remission (<2 months) that is susceptible to relapse. Patients with refractory MM are challenging to cure and have a poor prognosis (37). Previous studies have demonstrated that survivin has an important role in anti-apoptosis signaling by inhibiting the activity of caspase-3 and caspase-7 (38,39).…”

Section: Survivin ----------------------------------------------mentioning

confidence: 99%

Effects of survivin on FVADT chemotherapy for refractory multiple myeloma

Yang

2016

Experimental and Therapeutic Medicine

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Abstract. The present study aimed to investigate the effects of survivin, an apoptosis inhibitor protein, on the efficacy of the fludarabine, vincristine, epirubicin, dexamethasone and thalidomide (FVADT) chemotherapy regime for the treatment of refractory multiple myeloma (MM). A total of 82 patients with MM were selected from the Hematology Inpatient Department at The Second Affiliated Hospital of Zhengzhou University (Zhengzhou, China). The initial treatment group consisted of 40 patients with MM, who received the vincristine, epirubicin and dexamethasone (VAD) chemotherapy regime. The refractory group consisted of 42 patients with refractory MM, who received the FVADT chemotherapy regime. Bone marrow biopsies were collected via marrow aspirations, and the protein expression of survivin was analyzed by immunohistochemistry. In addition, the Kaplan-Meier method was used for survival analyses. Intergroup differences in the protein expression levels of survivin were compared, and the association between survivin expression and the short-and long-term effects of FVADT chemotherapy were analyzed. The positive expression rate of survivin was significantly higher in the refractory group, as compared with the initial treatment group (P<0.05). Furthermore, the complete remission rate and the effective rate were significantly lower in the survivin-positive group, as compared with the survivin-negative group (P<0.05). The overall survival, progression free survival and 1 and 3 year survival rates of the survivin-positive group were significantly higher, as compared with the survivin-negative group (P<0.05). The results of the present study suggested that the protein expression of survivin was upregulated in refractory MM tissues, which was indicative of a poor short-and long-term efficacy for FVADT chemotherapy.

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Outcomes of primary refractory multiple myeloma and the impact of novel therapies

Cited by 42 publications

References 49 publications

Early relapse following initial therapy for multiple myeloma predicts poor outcomes in the era of novel agents

Early relapse following initial therapy for multiple myeloma predicts poor outcomes in the era of novel agents

Mitochondrial-Targeted Decyl-Triphenylphosphonium Enhances 2-Deoxy-D-Glucose Mediated Oxidative Stress and Clonogenic Killing of Multiple Myeloma Cells

Effects of survivin on FVADT chemotherapy for refractory multiple myeloma

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