Impact of acquired del(17p) in multiple myeloma.

The high-risk abnormality del(17p) can be detected by fluorescence in situ hybridization on malignant plasma cells (PCs) and has an adverse prognostic impact in patients with multiple myeloma (MM). Patients with del(17p) have reduced overall survival (OS). Patients who acquire del(17p) later during the disease course are not well described. The disease characteristics at diagnosis predicting for acquired del(17p) and its overall impact on patient survival is not known. We compared 76 patients with MM who were negative for del(17p) at diagnosis and acquired it later with 152 control MM patients who did not acquire del(17p) at a comparable time point. Patients acquired del(17p) at a median of 35.6 months (range, 4.6-116.1 months) from diagnosis of MM after a median of 2 lines of therapy (range, 1-10 lines of therapy). When compared with controls, patients with acquired del(17p) had shorter median progression-free survival (PFS) (30.1 vs 23.0 months; P = .032) and OS (106.1 vs 68.2 months; P < .001) from diagnosis. After the detection of del(17p), the median PFS was 5.4 months and the median OS was 18.1 months. High lactate dehydrogenase level (odds ratio [OR], 3.69; 95% confidence interval [CI], 1.11-12.24) and presence of t(4;14) (OR, 2.66; 95% CI, 1.09-6.48) or any high-risk translocation (OR, 2.23; 95% CI, 1.00-4.95) at diagnosis predicted acquisition of del(17p). High PC proliferative rate predicted shorter OS from detection of del(17p) (hazard ratio, 2.28; 95% CI, 1.31-3.96; P = .004). Our study shows that acquisition of del(17p) is an important molecular event associated with reduction in OS in MM. Certain baseline factors may predict acquisition of del(17p). This needs validation in prospective data sets.

Natural history of multiple myeloma with de novo del(17p).

We compared the outcomes of 310 patients with newly diagnosed multiple myeloma with del(17p) detected by FISH to patients with high-risk translocations (HRT) (n = 79) and standard-risk (SR) cytogenetics (n = 541). The median progression-free survival (PFS) following initial therapy for the three groups was 21.1, 22, and 30.1 months, respectively (P = 0.437- del(17p) vs. HRT); the median overall survival (OS) was 47.3, 79.1, and 109.8 months, respectively, (P = 0.007- del(17p) vs. HRT). PFS and OS for patients with relative loss of 17p (n = 21) were comparable to other patients with del(17p). The PFS was similar between the del(17p) and HRT groups when stratified for age, ISS stage or treatment. The OS of del(17p) and HRT groups were similar in presence of advanced age, ISS III stage or if patients did not receive a proteasome-inhibitor containing induction. ISS III stage, high LDH and HRT, but not the percentage of cells with del(17p) predicted shorter OS in patients with del(17p). The median OS for low (ISS I, normal LDH and no HRT), intermediate (neither low nor high-risk) and high-risk (ISS III and either elevated LDH or coexistent HRT) groups among del(17p) patients were 96.2, 45.4, and 22.8 months, respectively, allowing further risk stratification.

Aurora kinase and FGFR3 inhibition results in significant apoptosis in molecular subgroups of multiple myeloma.

Aberrant expression of proteins involved in cell division is a constant feature in multiple myeloma (MM), especially in high-risk disease. Increasingly, therapy of myeloma is moving towards individualization based on underlying genetic abnormalities. Aurora kinases are important mediators of cell cycle and are up regulated in MM. Functional loss of Aurora kinases results in genetic instability and dysregulated division leading to cellular aneuploidy and growth arrest. We investigated the role of Aurora kinase inhibition in MM, using a small molecule inhibitor A1014907. Low nanomolar A1014907 concentrations induced aneuploidy in MM cell lines independent of underlying cytogenetic abnormalities by inhibiting Aurora Kinases. However, A1014907 induced more pronounced and dose dependent apoptosis in cell lines with t(4;14) translocation. Translocation t(4;14) is observed in about 15% of patients with MM leading to constitutive activation of FGFR3 in two-thirds of these patients. Further investigation of the mechanism of action of A1014907 revealed potent FGFR3 pathway inhibition only in the sensitive cell lines. Thus, our results show that aurora kinase inhibition causes cell cycle arrest and aneuploidy with minimal apoptosis whereas inhibiting both aurora kinase and FGFR3 activity induced potent apoptosis in MM cells. These results support clinical evaluation of A1014907 in MM patients with t(4;14) translocation and/or FGFR3 expression.

Myelomatous Involvement of the Central Nervous System.

INTRODUCTION: Limited data exist with respect to the outcome and optimal treatment of patients with myelomatous involvement of the central nervous system (CNS). MATERIALS AND METHODS: Of 4060 patients with multiple myeloma (MM), evaluated at Mayo Clinic from 1998 to 2014, 29 (0.7%) had identifiable CNS involvement, established by the presence of atypical plasma cells in the cerebrospinal fluid (CSF) and/or identification of intraparenchymal or meningeal involvement on magnetic resonance imaging (MRI). A cohort of 87 MM patients without CNS disease served as the control group (1:3), matched by diagnosis date and gender. RESULTS: Plasma cells were detected in the CSF in 87% and MRI findings consistent with CNS involvement were noted in 82% of the patients. A bone marrow plasma cell labeling index of ≥ 3%, the presence of disease at other extramedullary sites, or peripheral blood plasma cells of > 800 per 150,000 events were associated with an odds ratio of 7.1, 10.3, and 14, respectively, for the risk of CNS involvement. Overall survival (OS) from the diagnosis of MM was significantly shorter in the CNS-MM group (median 40 months; 95% confidence interval [CI], 24-56 months) than in the control group (median, 93 months; 95% CI, 67-129 months). OS was 3.4 months from the detection of CNS disease. Patients who underwent autologous stem cell transplantation after CNS involvement (n = 7) had a median OS of 19 months (95% CI, 10-67 months) from the detection of CNS involvement. CONCLUSION: Myelomatous involvement of the CNS is a rare complication that portends a poor survival. Current therapeutic approaches appear to be largely ineffective for this subset of patients with MM.

Smac mimetic LCL161 overcomes protective ER stress induced by obatoclax, synergistically causing cell death in multiple myeloma.

Bcl2 and IAP families are anti-apoptotic proteins deregulated in multiple myeloma (MM) cells. Pharmacological inhibition of each of these families has shown significant activity only in subgroups of MM patients. Here, we have examined a broad-spectrum Bcl2 family inhibitor Obatoclax (OBX) in combination with a Smac mimetic LCL161 in MM cell lines and patient cells. LCL161/OBX combination induced synergistic cytotoxicity and anti-proliferative effects on a broad range of human MM cell lines. The cytotoxicity was mediated through inhibition of the IAPs, activation of caspases and up regulation of the pro-apoptotic proteins Bid, Bim, Puma and Noxa by the drug combination. In addition, we observed that OBX caused ER stress and activated the Unfolded Protein Response (UPR) leading to drug resistance. LCL161, however inhibited spliced Xbp-1, a pro-survival factor. In addition, we observed that OBX increased GRP78 localization to the cell surface, which then induced PI3K dependent Akt activation and resistance to cell death. LCL161 was able to block OBX induced Akt activation contributing to synergistic cell death. Our results support clinical evaluation of this combination strategy in relapsed refractory MM patients.

Efficacy of bortezomib as first-line treatment for patients with multiple myeloma.

Recent years have seen a dramatic change in the approach towards diagnosing and treating Multiple Myeloma. Newer and more target specific approach to treatment has prolonged the survival for patients with multiple myeloma. The proteasome inhibitors make an important class of anti-myeloma drugs that disrupts the proteolytic machinery of the tumor cells preferentially, enhancing their susceptibility to apoptosis. Bortezomib, in particular has shown significant clinical efficacy in myeloma treatment. It is the most commonly used proteasome inhibitor and has been tested to be effective in prolonging the overall survival in several trials. Its combinations with cyclophosphamide and dexamethasone are the treatment of choice for standard risk patients following the mSMART guidelines. The success with its lower dosage in elderly and its proven efficacious subcutaneous usage makes Bortezomib a useful agent for maximizing patient compliance and minimizing therapy related toxicity and costs. This review discusses several trials where Bortezomib has been used as a single/combination agent for front-line treatment of multiple myeloma.

Anti-myeloma activity of Akt inhibition is linked to the activation status of PI3K/Akt and MEK/ERK pathway.

The PI3K/Akt/mTOR signal transduction pathway plays a central role in multiple myeloma (MM) disease progression and development of therapeutic resistance. mTORC1 inhibitors have shown limited efficacy in the clinic, largely attributed to the reactivation of Akt due to rapamycin induced mTORC2 activity. Here, we present promising anti-myeloma activity of MK-2206, a novel allosteric pan-Akt inhibitor, in MM cell lines and patient cells. MK-2206 was able to induce cytotoxicity and inhibit proliferation in all MM cell lines tested, albeit with significant heterogeneity that was highly dependent on basal pAkt levels. MK-2206 was able to inhibit proliferation of MM cells even when cultured with marrow stromal cells or tumor promoting cytokines. The induction of cytotoxicity was due to apoptosis, which at least partially was mediated by caspases. MK-2206 inhibited pAkt and its down-stream targets and up-regulated pErk in MM cells. Using MK-2206 in combination with rapamycin (mTORC1 inhibitor), LY294002 (PI3K inhibitor), or U0126 (MEK1/2 inhibitor), we show that Erk- mediated downstream activation of PI3K/Akt pathway results in resistance to Akt inhibition. These provide the basis for clinical evaluation of MK-2206 alone or in combination in MM and potential use of baseline pAkt and pErk as biomarkers for patient selection.