Multiple myeloma BM-MSCs increase the tumorigenicity of MM cells via transfer of VLA4-enriched microvesicles.

Multiple myeloma (MM) cells accumulate in the bone marrow (BM) where their interactions impede disease therapy. We have shown that microvesicles (MVs) derived from BM mesenchymal stem cells (MSCs) of MM patients promote the malignant traits via modulation of translation initiation (TI), whereas MVs from normal donors (ND) do not. Here, we observed that this phenomenon is contingent on a MVs' protein constituent, and determined correlations between the MVs from the tumor microenvironment, for example, MM BM-MSCs and patients' clinical characteristics. BM-MSCs' MVs (ND/MM) proteomes were assayed (mass spectrometry) and compared. Elevated integrin CD49d (X80) and CD29 (X2) was determined in MM-MSCs' MVs and correlated with patients' staging and treatment response (free light chain, BM plasma cells count, stage, response to treatment). BM-MSCs' MVs uptake into MM cell lines was assayed (flow cytometry) with/without integrin inhibitors (RGD, natalizumab, and anti-CD29 monoclonal antibody) and recipient cells were analyzed for cell count, migration, MAPKs, TI, and drug response (doxorubicin, Velcade). Their inhibition, particularly together, attenuated the uptake of MM-MSCs MVs (but not ND-MSCs MVs) into MM cells and reduced MM cells' signaling, phenotype, and increased drug response. This study exposed a critical novel role for CD49d/CD29 on MM-MSCs MVs and presented a discriminate method to inhibit cancer promoting action of MM-MSCs MVs while retaining the anticancer function of ND-MSCs-MVs. Moreover, these findings demonstrate yet again the intricacy of the microenvironment involvement in the malignant process and highlight new therapeutic avenues to be explored.

Treatment patterns and clinical outcomes in high-risk newly diagnosed multiple myeloma patients carrying the 17p deletion: An observational multi-center retrospective study.

Del17p is a genomic imbalance occurring in ∼7%-10% of myeloma at diagnosis newly diagnosed myeloma patients (NDMM) and comprises a poor prognostic factor. The goal of this study is to analyze real world data and outcomes among NDMM patients carrying 17p deletion. We report an observational, retrospective, multicenter study. Sixty consecutive patients diagnosed with multiple myeloma in the 8 participating centers diagnosed between 1/2008 and 1/2016 proven to carry 17p deletion by means of fluorescence in situ hybridization (FISH) were identified. Most received a bortezomib-based induction, over half underwent autologous hematopoietic cell transplantation (HCT); 30% of the patients gained early access to new novel agents via clinical trials, access programs or private insurance. Overall response rate (ORR) after induction was 85%; 94% for transplant eligible (TE); and 75% for transplant ineligible (NTE), and declined in subsequent treatment lines, 64% achieved ≥ VGPR. Median overall survival (OS) was 43 months; median progression free survival (PFS) was 11 months, 19 months for TE and 7 for NTE. In multivariate analysis: higher M-Spike, presence of extramedullary disease, and >50% of cells baring del17p were associated with adverse PFS; Autologous HCT and higher hemoglobin were associated with longer PFS; OS was 59 months for patients with early access to newer agents. Older age and higher M-Spike levels were associated with adverse OS, Autologous HCT was associated with favorable OS, 59.7 vs 28.7 months for NTE patients. Despite the improvement achieved with autologous HCT and new novel agents, the prognosis of patients with 17p deletion is still inferior, emphasizing the need for novel approaches.

Ribosomal proteins as distinct "passengers" of microvesicles: new semantics in myeloma and mesenchymal stem cells' communication.

Aberrant mesenchymal stem cells (MSCs) in multiple myeloma (MM) bone marrows (BM) promote disease progression and drug resistance. Here, we assayed the protein cargo transported from MM-MSCs to MM cells via microvesicles (MVs) with focus on ribosomal proteins (RPs) and assessment of their influence on translation initiation and design of MM phenotype. Proteomics analysis (mass spectrometry) demonstrated increased levels and repertoire of RPs in MM-MSCs MVs compared to normal donors (ND) counterparts (n = 3-8; P = 9.96E - 08). We limited the RPs load in MM-MSCs MVs (starvation, RSK and XPO1 inhibitions), reapplied the modified MVs to MM cell lines (U266, MM1S), and demonstrated that the RPs are essential to the proliferative effect of MM-MSCs MVs on MM cells (n = 3; P < 0.05). We also observed that inhibition with KPT-185 (XPO1 inhibitor) displayed the most extensive effect on RPs delivery into the MVs (↓80%; P = 3.12E - 05). Using flow cytometry we assessed the expression of select RPs (n = 10) in BM-MSCs cell populations (ND and MM; n ≥ 6 each). This demonstrated a heterogeneous expression of RPs in MM-MSCs with distinct subgroups, a phenomenon absent from ND-MSCs samples. These findings bring to light a new mechanism in which the tumor microenvironment participates in cancer promotion. MVs-mediated horizontal transfer of RPs between niche MSCs and myeloma cells is a systemic way to bestow pro-cancer advantages. This capacity also differentiates normal MSCs from the MM-modified MSCs and may mark their reprogramming. Future studies will be aimed at assessing the clinical and therapeutic potential of the increased RPs levels in MM-MSCs MVs.

Advanced (>second) line chemotherapy in the treatment of patients with recurrent epithelial ovarian cancer.

OBJECTIVE: To explore the pattern of chemotherapy (beyond the second-line) used to treat patients with recurrent epithelial ovarian cancer (including primary peritoneal carcinoma). STUDY DESIGN: This retrospective study included 156 patients with recurrent epithelial ovarian cancer and primary peritoneal carcinoma who were treated in the Gynecologic Oncologic Department at Meir Medical Center between November 1995 and December 2003. Clinical characteristics and data regarding the surgery, chemotherapy, and response to treatment were abstracted from the patients' medical records to determine patient response to advanced lines of chemotherapy for recurrent epithelial ovarian cancer. RESULTS: Of the 156 patients, 63 (40%) were treated beyond second-line chemotherapy. Clinical response to third-line chemotherapy was 11.9% (6.8% had complete clinical response and 5.1% partial clinical response) and 3.4% had stable disease. A total of 17% did not show immediate progression, with a median progression free-interval of 1.5 months. A drastic decline in clinical response rates was shown beyond third-line chemotherapy. Any response to treatment in more advanced lines was consistently under 5%. CONCLUSION: These results imply that advanced lines of chemotherapy are associated with low response rates, although a small percentage of patients showed some clinical response or remained with stable disease at the end of treatment. Along with patient preferences, the advantages and disadvantages of continued therapy should be considered, for the side effects of each treatment cannot be overlooked.