Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

The treatment of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) has evolved to include several new options. The NCCN Guidelines for WM/LPL provide a framework on which to base decisions regarding diagnosis, treatment, assessment of response to treatment, and follow-up of both newly diagnosed and previously treated WM/LPL.

Gate-controlled Sb2S3 thin film photodetectors for logic switches.

Antimony sulfide (Sb2S3) photodetectors (PDs) have great potential in commercial applications. The performances are affected by photocarrier distribution and recombination. Here, the gate-controlled Sb2S3 thin film PD is fabricated on the TiO2/SiO2/Si substrate by the vacuum method. The p-channel Sb2S3 transistor obtained a threshold voltage of 0.6 V and a switching ratio of 1064, achieving an effective regulation by gate voltages. A negative gate voltage can enhance conductivity and can suppress recombination. The responsivity and detectivity of the PD reach 1.6 A/W and 1.2 × 1011 Jones, respectively. The device realizes logic outputs by the signal inputs of illumination and gate voltage.

Phase I study of opaganib, an oral sphingosine kinase 2-specific inhibitor, in relapsed and/or refractory multiple myeloma.

Multiple myeloma (MM) remains an incurable disease and there is an unmet medical need for novel therapeutic drugs that do not share similar mechanisms of action with currently available agents. Sphingosine kinase 2 (SK2) is an innovative molecular target for anticancer therapy. We previously reported that treatment with SK2 inhibitor opaganib inhibited myeloma tumor growth in vitro and in vivo in a mouse xenograft model. In the current study, we performed a phase I study of opaganib in patients with relapsed/refractory multiple myeloma (RRMM). Thirteen patients with RRMM previously treated with immunomodulatory agents and proteasome inhibitors were enrolled and treated with single-agent opaganib at three oral dosing regimens (250 mg BID, 500 mg BID, or 750 mg BID, 28 days as a cycle). Safety and maximal tolerated dose (MTD) were determined. Pharmacokinetics, pharmacodynamics, and correlative studies were also performed. Opaganib was well tolerated up to a dose of 750 mg BID. The most common possibly related adverse event (AE) was decreased neutrophil counts. There were no serious AEs considered to be related to opaganib. MTD was determined as at least 750 mg BID. On an intent-to-treat basis, one patient (7.7%) in the 500 mg BID dose cohort showed a very good partial response, and one other patient (7.7%) achieved stable disease for 3 months. SK2 is an innovative molecular target for antimyeloma therapy. The first-in-class SK2 inhibitor opaganib is generally safe for administration to RRMM patients, and has potential therapeutic activity in these patients. Clinicaltrials.gov: NCT02757326.

Systemic Light Chain Amyloidosis, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

Primary systemic light chain amyloidosis (SLCA) is characterized by production of light chains that get converted to amyloid fibrils with an affinity for visceral organs and causing organ dysfunction. The therapy for SLCA is directed to recovering the function of the affected organs by targeting the abnormal plasma cell clone and slowing deposition of amyloid fibrils. The NCCN Guidelines for SLCA provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated SLCA.

Multiple Myeloma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

The treatment of relapsed/refractory multiple myeloma (MM) has evolved to include several new options. These include new combinations with second generation proteasome inhibitors (PI); second generation immunomodulators, monoclonal antibodies, CAR T cells, bispecific antibodies, selinexor, venetoclax, and many others. Most patients with MM undergo several cycles of remissions and relapse, and therefore need multiple lines of combination therapies. Selecting treatment options for relapsed/refractory MM requires consideration of resistance status to specific classes, and patient-specific factors such as age and other comorbidities should be considered. The NCCN Guidelines for MM provide a framework on which to base decisions regarding workup, treatment, and follow-up of newly diagnosed and previously treated MM. This manuscript outlines the recommendations from NCCN Guidelines for MM specific to relapsed/refractory disease.

Controlling the morphology and wavelength of self-assembled coaxial GaAs/Ga(As)Sb/GaAs single quantum-well nanowires.

Antimonide-based ternary III-V nanowires (NWs) provide a tunable bandgap over a wide range, and the GaAsSb material system has prospective applications in the 1.3-1.55 µm spectral range of optical communications. In this paper, GaAs/Ga(As)Sb/GaAs single quantum well (SQW) NWs were grown on Si(111) substrates by molecular beam epitaxy (MBE). In addition, the morphologies and tunable wavelengths of the GaAs/Ga(As)Sb/GaAs SQWs were adjusted by interrupting the Ga droplets and changing the growth temperatures and V/III ratios. The four morphologies of the GaAs/Ga(As)Sb/GaAs SQW NWs were observed by scanning electron microscopy (SEM). The microscale lattice structure related to the incorporation of Sb in GaAs/Ga(As)Sb/GaAs SQWs was studied by Raman spectroscopy. The crystal quality of the GaAs/Ga(As)Sb/GaAs SQW NWs was researched by X-ray diffraction (XRD) and transmission electron microscopy (TEM). In addition, the optical properties of the GaAs/Ga(As)Sb/GaAs SQWs were investigated by photoluminescence (PL) spectroscopy. The PL spectra showed the peak emission wavelength range of ∼818 nm (GaAs) to ∼1628 nm (GaSb) at 10 K. This study provides an approach to enhance the effective control of the morphology, structure and wavelength of quantum well or core-shell NWs.

NCCN Guidelines® Insights: Multiple Myeloma, Version 3.2022.

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, initial workup, treatment, follow-up, and supportive care for patients with various plasma cell neoplasms, including multiple myeloma. These NCCN Guidelines Insights highlight some of the important updates/changes specific to the treatment of patients with multiple myeloma in the 2022 version of the guidelines.

Multiple Myeloma, Version 3.2021, NCCN Clinical Practice Guidelines in Oncology.

Multiple myeloma is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. This manuscript discusses the management of patients with solitary plasmacytoma, smoldering multiple myeloma, and newly diagnosed multiple myeloma.

Efficient markerless gene deletions in Pseudomonas protegens Pf-5 using a upp-based counterselective system.

OBJECTIVES: Developing a counterselective system for efficient markerless gene deletions in biocontrol strain P. protegens Pf-5. RESULTS: We successfully implemented a markerless deletion of upp in Pf-5 to obtain the 5-FU resistant strain Pf5139. With this strain, we performed markerless gene deletions for each component of Gac/Rsm system and a 17 kb DNA fragment with the deletion ratio of 20 to 50%, and efficiently constructed a strain with triple deletions based on the suicide plasmid pJQ200UPP. In addition, there is no obvious connection between the deleted fragment length and the deletion ratio. CONCLUSION: The upp-based counterselective system in this study is efficient and valuable for markerless gene deletions in Pf-5, indicating that it has great potential in the study of gene function and in the application of genome reduction for Pseudomonas strains.

The promise of chimeric antigen receptor (CAR) T cell therapy in multiple myeloma.

A cure for multiple myeloma (MM), a malignancy of plasma cells, remains elusive. Nearly all myeloma patients will eventually relapse and develop resistance to currently available treatments. There is an unmet medical need to develop novel and effective therapies that can induce sustained responses. Early phase clinical trials using chimeric antigen receptor (CAR) T cell therapy have shown great promise in the treatment of relapsed and/or refractory MM. In this review article, we provide an overview of the CAR constructs, the gene transfer vector systems, and approaches for T cell activation and expansion. We then summarize the outcomes of several early phase clinical trials of CAR T cell therapy in MM and the novel CAR T targets that are under development. Finally, we explore the potential mechanisms that result in disease relapse after CAR T therapy and propose future directions in CAR T therapy in MM.

NCCN Guidelines Insights: Multiple Myeloma, Version 1.2020.

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, workup, treatment, follow-up, and supportive care for patients with monoclonal gammopathy of renal significance, solitary plasmacytoma, smoldering myeloma, and multiple myeloma. These NCCN Guidelines Insights highlight some of the important updates and changes in the 1.2020 version of the NCCN Guidelines for Multiple Myeloma.

The challenges of checkpoint inhibition in the treatment of multiple myeloma.

Despite significant improvements in the overall survival of patients with multiple myeloma (MM) over the past 15 years, the disease remains incurable. Treatment options are limited for patients who have relapsed or are refractory to immunomodulatory drugs (IMiDs), proteasome inhibitors, and monoclonal antibodies. In these patients, immunotherapies such as checkpoint inhibitors, oncolytic vaccines, and chimeric antigen receptor (CAR) T cells provide a potentially effective alternative treatment. While checkpoint inhibitors are effective in prolonging overall survival in some patients with advanced solid cancers and Hodgkin lymphoma, they have not demonstrated significant activity as a single agent in MM. In fact the combination of checkpoint inhibitors with IMiDs was recently found to increase the risk of death in myeloma patients. These challenges highlight the need for a better understanding of immune dysregulation in myeloma patients, and the mechanisms of action of- and resistance to- checkpoint inhibitors. In this review, we summarize immune dysfunction in patients with MM, and review the preclinical and clinical data regarding checkpoint inhibitors in myeloma. We conclude by proposing strategies to improve the efficacy and safety of checkpoint inhibitors in this population.

NCCN Guidelines Insights: Multiple Myeloma, Version 3.2018.

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, evaluation, treatment, including supportive-care, and follow-up for patients with myeloma. These NCCN Guidelines Insights highlight the important updates/changes specific to the myeloma therapy options in the 2018 version of the NCCN Guidelines.

Outcomes of Maintenance Therapy with Bortezomib after Autologous Stem Cell Transplantation for Patients with Multiple Myeloma.

Comprehensive recommendations for maintenance therapy after autologous stem cell transplantation (ASCT) for patients with multiple myeloma (MM) have yet to be defined. Bortezomib has been utilized as maintenance therapy after ASCT, but data attesting to the safety and efficacy of this agent compared with lenalidomide in the post-ASCT setting are limited. Therefore, we retrospectively analyzed the outcomes of 102 patients with MM who received maintenance therapy with bortezomib after ASCT at Duke University's adult bone marrow transplant clinic between 2005 and 2015. Maintenance with bortezomib was initiated between 60 and 90 days after ASCT as a single agent 1.3 mg/m2 once every 2 weeks (n = 92) or in combination with lenalidomide (10 mg/day) (n = 10). The median age at ASCT was 64 (range, 31 to 78). Of the 99 patients with molecular data available, 42% had high-risk cytogenetics (including d17p, t(4;14), +1q, and t(14;16) by fluorescein in situ hybridization). Overall, 46% of patients experienced side effects from maintenance therapy, with 31% of all patients experiencing peripheral neuropathy. In total, 2% of patients required discontinuation of bortezomib maintenance because of adverse events. No secondary malignancies were reported from the therapy. The median progression-free survival (PFS) for patients receiving maintenance therapy with bortezomib after ASCT was 36.5 months (95% confidence interval [CI], 21.3 to not available) and median overall survival was 72.7 months (95% CI, 63.9 to not available). The PFS of patients with high-risk cytogenetics was not statistically significantly different from those with standard-risk cytogenetics, suggesting that maintenance with bortezomib may help overcome the impact of high-risk cytogenetics on early progression. These results indicate that maintenance therapy with bortezomib represents a safe, well-tolerated, and efficacious option for patients with high-risk cytogenetics, renal insufficiency, an inability to tolerate lenalidomide, or a previous history of another cancer.

Inhibition of sphingosine kinase 2 downregulates the expression of c-Myc and Mcl-1 and induces apoptosis in multiple myeloma.

Sphingolipid metabolism is being increasingly recognized as a key pathway in regulating cancer cell survival and proliferation. However, very little is known about its role in multiple myeloma (MM). We investigated the potential of targeting sphingosine kinase 2 (SK2) for the treatment of MM. We found that SK2 was overexpressed in MM cell lines and in primary human bone marrow (BM) CD1381 myeloma cells. Inhibition of SK2 by SK2- specific short hairpin RNA or ABC294640 (a SK2 specific inhibitor) effectively inhibited myeloma cell proliferation and induced caspase 3­mediated apoptosis. ABC294640 inhibited primary human CD1381 myeloma cells with the same efficacy as with MM cell lines. ABC294640 effectively induced apoptosis of myeloma cells, even in the presence of BM stromal cells. Furthermore, we found that ABC294640 downregulated the expression of pS6 and directed c-Myc and myeloid cell leukemia 1 (Mcl-1) for proteasome degradation. In addition, ABC294640 increased Noxa gene transcription and protein expression. ABC294640, per se, did not affect the expression of B-cell lymphoma 2 (Bcl-2), but acted synergistically with ABT-737 (a Bcl-2 inhibitor) in inducing myeloma cell death. ABC294640 suppressed myeloma tumor growth in vivo in mouse myeloma xenograft models. Our data demonstrated that SK2 provides a novel therapeutic target for the treatment of MM.This trial was registered at www.clinicaltrials.gov as #NCT01410981.

Prediction of poor mobilization of autologous CD34+ cells with growth factor in multiple myeloma patients: implications for risk-stratification.

It is unknown whether clinical characteristics can successfully predict which multiple myeloma (MM) patients would be poor mobilizers with growth factor (GF) alone so they can be assigned to mobilization with chemotherapy + GF or GF + plerixafor. MM patients (N = 477) who underwent autologous mobilization with GF were retrospectively reviewed and assigned into training and validation cohorts. In multiple regression analysis, age, platelet count at time of mobilization, type of GF utilized, and extent of exposure to lenalidomide independently correlated with peripheral blood (PB)-CD34+ and were integrated in a predicting score (PS) for poor mobilizers, defined as PB-CD34+ < 20/mm(3) 4 days after initiation of GF. There was no correlation between institution, gender, time between diagnosis, and mobilization or plasma cells in the bone marrow at time of mobilization and PBCD34+. The PS cut-off found in the training cohort to have 90% sensitivity for prediction of poor mobilizers performed with 89.7% sensitivity but only 34.8% specificity in the validation cohort. Conversely, the PS cut-off developed to have 90% specificity performed with 86.9% specificity but only 37% sensitivity. We conclude that clinical characteristics identifiable before initiation of mobilization should not be used to stratify MM patients for different mobilization strategies.

Pim1 serine/threonine kinase regulates the number and functions of murine hematopoietic stem cells.

The genes and pathways that govern the functions and expansion of hematopoietic stem cells (HSC) are not completely understood. In this study, we investigated the roles of serine/threonine Pim kinases in hematopoiesis in mice. We generated PIM1 transgenic mice (Pim1-Tx) overexpressing human PIM1 driven by vav hematopoietic promoter/regulatory elements. Compared to wild-type littermates, Pim1-Tx mice showed enhanced hematopoiesis as demonstrated by increased numbers of Lin(-) Sca-1 (+) c-Kit (+) (LSK) hematopoietic stem/progenitor cells and cobblestone area forming cells, higher BrdU incorporation in long-term HSC population, and a better ability to reconstitute lethally irradiated mice. We then extended our study using Pim1(-/-), Pim2(-/-), Pim3(-/-) single knockout (KO) mice. HSCs from Pim1(-/-) KO mice showed impaired long-term hematopoietic repopulating capacity in secondary and competitive transplantations. Interestingly, these defects were not observed in HSCs from Pim2(-/-) or Pim3(-/-) KO mice. Limiting dilution competitive transplantation assay estimated that the frequency of LSKCD34(-) HSCs was reduced by approximately 28-fold in Pim1(-/-) KO mice compared to wild-type littermates. Mechanistic studies demonstrated an important role of Pim1 kinase in regulating HSC cell proliferation and survival. Finally, our polymerase chain reaction (PCR) array and confirmatory real-time PCR (RT-PCR) studies identified several genes including Lef-1, Pax5, and Gata1 in HSCs that were affected by Pim1 deletion. Our data provide the first direct evidence for the important role of Pim1 kinase in the regulation of HSCs. Our study also dissects out the relative role of individual Pim kinase in HSC functions and regulation.

Similar dynamics of intraapheresis autologous CD34+ recruitment and collection efficiency in patients undergoing mobilization with or without plerixafor.

BACKGROUND: Compared with growth factor (G) alone, the combination of G with plerixafor (G + P) increases peripheral blood CD34+ count (PB-CD34+) and improves CD34+ collection yield (yCD34+) in multiple myeloma and lymphoma patients undergoing autologous hematopoietic progenitor cell (AHPC) mobilization. It is unknown whether the improved yCD34+ with G + P results entirely from expansion of PB-CD34+ or also from increased intraapheresis CD34+ recruitment and collection efficiency. STUDY DESIGN AND METHODS: We retrospectively studied 192 patients who underwent AHPC mobilization and collection with G (n = 73) or G + P (n = 119) to compare the adjusted relative efficiency (aRE), the proportion of the circulating CD34+ pool that is captured for each blood volume processed. Additionally, in a prospective cohort of nine patients mobilizing with G and 11 with G + P, PB-CD34+ after leukapheresis allowed calculation of the recruitment coefficient (RC), proportion of the initial CD34+ pool recruited from the marrow into peripheral blood for each blood volume processed. RESULTS: There was no difference in aRE between G and G + P (0.50 vs. 0.46; p = 0.37) and no substantial decline in aRE with higher blood volumes processed in either group. RC was also not different between G and G + P (median, 0.39 and 0.38, respectively; p = 0.7). Prediction of yCD34+ was determined essentially by PB-CD34+ and not affected independently by plerixafor. CONCLUSION: Kinetics of intraapheresis CD34+ recruitment and collection is proportional to PB-CD34+ but not influenced further by plerixafor.

Longitudinal intravital imaging of mouse placenta.

Studying placental functions is crucial for understanding pregnancy complications. However, imaging placenta is challenging due to its depth, volume, and motion distortions. In this study, we have developed an implantable placenta window in mice that enables high-resolution photoacoustic and fluorescence imaging of placental development throughout the pregnancy. The placenta window exhibits excellent transparency for light and sound. By combining the placenta window with ultrafast functional photoacoustic microscopy, we were able to investigate the placental development during the entire mouse pregnancy, providing unprecedented spatiotemporal details. Consequently, we examined the acute responses of the placenta to alcohol consumption and cardiac arrest, as well as chronic abnormalities in an inflammation model. We have also observed viral gene delivery at the single-cell level and chemical diffusion through the placenta by using fluorescence imaging. Our results demonstrate that intravital imaging through the placenta window can be a powerful tool for studying placenta functions and understanding the placental origins of adverse pregnancy outcomes.