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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.

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.

Antimony sulfide (Sb 2 S 3 ) photodetectors (PDs) have great potential in commercial applications. The performances are affected by photocarrier distribution and recombination. Here, the gate-controlled Sb 2 S 3 thin film PD is fabricated on the TiO 2 /SiO 2 /Si substrate by the vacuum method. The p-channel Sb 2 S 3 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 × 10 11  Jones, respectively. The device realizes logic outputs by the signal inputs of illumination and gate voltage.

Multiple myeloma (MM) is a common hematological malignancy that has fostered several new therapeutic approaches to combat newly diagnosed or relapsed MM. While the field has advanced over the past 2 decades, the majority of patients will develop resistance to these treatments, causing the need for new therapeutic targets. SLAMF7 is an attractive therapeutic target in multiple myeloma, and a monoclonal antibody that targets SLAMF7 has shown consistent beneficial outcomes in clinical trials to date. In this review, we will focus on the structure and regulation of SLAMF7 and its mechanism of action. The most recent clinical trials will be reviewed to further understand the clinical implications and improve the prognosis of MM. Furthermore, the efficacy of anti-SLAMF7 monoclonal antibodies combined with standard therapies and possible resistance mechanisms will be discussed. This review aimed to provide a detailed summary of the role of SLAMF7 in the pathogenesis of patients with MM and the rationale for further investigation into SLAMF7-mediated molecular pathways associated with MM development.

Retinoid X receptor ( RXR ) heterodimerizes with the PPAR nuclear hormone receptor and regulates its downstream events. We investigated the effects of RXR agonists (LG100754, bexarotene, AGN194204, and LG101506) on lenalidomide's anti-myeloma activity, T cell functions, and the level of glucose and lipids in vivo. Genetic overexpression and CRISPR/Cas9 knockout experiments were conducted in multiple myeloma (MM) cell lines and Jurkat T cell lines to determine the roles of CRBN in RXR -agonist mediated effects. A xenograft mouse model of MM was established to determine the combination effect of LG100754 and lenalidomide. The combination of RXR agonists and lenalidomide demonstrated synergistic activity in increasing CRBN expression and killing myeloma cells. Mechanistically, the RXR agonists reduced the binding of PPARs to the CRBN promoter, thereby relieving the repressor effect of PPARs on CRBN transcription. RXR agonists downregulated the exhaustion markers and increased the activation markers of Jurkat T cells and primary human T cells. Co-administration of LG100754 and lenalidomide showed enhanced anti-tumor activity in vivo. LG100754 retained its glucose- and lipid-lowering effects. RXR agonists demonstrate potential utility in enhancing drug sensitivity and T-cell function in the treatment of myeloma.

Mitophagy plays an important role in maintaining mitochondrial homeostasis by clearing damaged mitochondria. Sphingosine kinase 2 (SK2), a type of sphingosine kinase, is an important metabolic enzyme involved in generating sphingosine-1-phosphate. Its expression level is elevated in many cancers and is associated with poor clinical outcomes. However, the relationship between SK2 and mitochondrial dysfunction remains unclear. We found that the genetic downregulation of SK2 or treatment with ABC294640, a specific inhibitor of SK2, induced mitophagy and apoptosis in multiple myeloma cell lines. We showed that mitophagy correlates with apoptosis induction and likely occurs through the SET/PP2AC/PARK2 pathway, where inhibiting PP2AC activity may rescue this process. Furthermore, we found that PP2AC and PARK2 form a complex, suggesting that they might regulate mitophagy through protein-protein interactions. Our study demonstrates the important role of SK2 in regulating mitophagy and provides new insights into the mechanism of mitophagy in multiple myeloma.

Despite the exciting advancement of novel therapies, chronic graft-versus-host disease (cGVHD) remains the most common cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (HCT). Frontline treatment of cGVHD involves systemic steroids, which are associated with significant morbidities. We previously found that inhibition of spleen tyrosine kinase (SYK) with fostamatinib preferentially eradicated aberrantly activated B cells in both ex vivo studies of cGVHD patient B cells, as well as in vivo mouse studies. These and other preclinical studies implicated hyper-reactive B-cell receptor signaling and increased SYK expression in the pathogenesis of cGVHD and compelled this first in-human allogeneic HCT clinical trial. We investigated the safety and efficacy of the oral SYK inhibitor, fostamatinib, for both the prevention and treatment of cGVHD. The primary objective was to evaluate the safety of fostamatinib and determine its maximum tolerated dose in the post-HCT setting. Secondary objectives included assessing the efficacy of fostamatinib in preventing and treating cGVHD, as well as examining alterations in B-cell compartments with treatment. This was a single-institution phase I clinical trial that evaluated the use of fostamatinib in allogeneic HCT patients before the development of cGVHD or at the time of steroid-refractory cGVHD (SR-cGVHD). Patients received fostamatinib at one of three dose levels using a continual reassessment algorithm to determine the maximum tolerated dose. Multiparameter flow cytometry was used to evaluate changes in B cell subpopulations over the first year of treatment with fostamatinib. Nineteen patients were enrolled in this phase I trial, with 5 in the prophylaxis arm and 14 in the therapeutic arm. One patient (5%) required discontinuation of therapy for a dose-limiting toxicity. At a median follow-up of over 3 years, no patients had cancer relapse while on fostamatinib treatment, and recurrent malignancy was observed in 1 patient 2 years after the end of therapy. In the prophylaxis arm, 1 of 5 patients (20%) developed cGVHD while on fostamatinib. In the therapeutic arm, the overall response rate was 77%, with a complete response rate of 31%. The median duration of response was 19.3 months and the 12-month failure-free survival was 69% (95% confidence interval, 48-100). Patients were able to reduce their steroid dose by a median of 80%, with 73% remaining on a lower dose at 1 year compared to baseline. There was an early reduction in the proportion of IgD - CD38 hi plasmablast-like cells with fostamatinib treatment, particularly in those SR-cGVHD patients who had an eventual response. B-cell reconstitution was not significantly impacted by fostamatinib therapy after allogeneic HCT. Fostamatinib featured a favorable safety profile in the post-HCT setting. Our data suggests an early efficacy signal that was associated with effects on expected cell targets in both the prophylaxis and treatment of cGVHD, providing rationale for a phase II investigation., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

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., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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.

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.

Background: Thioredoxin-1 (TXN1) is one of the major cellular antioxidants in mammals and is involved in a wide range of physiological cellular responses. However, little is known about the roles and the underlying molecular mechanisms of TXN1 in the regulation of hematopoietic stem/progenitor cells (HSPCs)., Methods: TXN1 conditional knockout mice (ROSA-CreER-TXN1 fl/fl ) and TXN1 fl/fl control mice were used. The mice were treated with tamoxifen and the number and biological functions of HSPCs were measured by flow cytometry, PCR and western blot. Limiting dilution competitive transplantation with sorted HSCs and serial transplantations were performed to assess the effects of TXN1 knockout on HSC self-renewal and long-term reconstitutional capacity. RNA sequencing (RNA-seq) was performed to investigate the downstream molecular pathways of TXN1 deletion in murine HSPCs. CRISPR/Cas9 knockout experiments were performed in vitro in EML murine hematopoietic stem/progenitor cell line to investigate the effects of TXN1 and/or TP53 deletion on cell survival, senescence and colony forming units. TP53 protein degradation assay, CHiP PCR and PGL3 firefly/renilla reporter assay were performed. The effects of TXN1 on various molecular pathways relevant to HSC radiation protection were examined in vitro and in vivo., Results: TXN1-TP53 tumor suppressor axis regulates HSPC biological fitness. Deletion of TXN1 in HSPCs using in vivo and in vitro models activates TP53 signaling pathway, and attenuates HSPC capacity to reconstitute hematopoiesis. Furthermore, we found that knocking out of TXN1 renders HSPCs more sensitive to radiation and treatment with recombinant TXN1 promotes the proliferation and expansion of HSPCs., Conclusions: Our findings suggest that TXN1-TP53 axis acts as a regulatory mechanism in HSPC biological functions. Additionally, our study demonstrates the clinical potential of TXN1 for enhancing hematopoietic recovery in hematopoietic stem cell transplant and protecting HSPCs from radiation injury., (© 2022. The Author(s).)

Our previous study demonstrated that peroxisome proliferator-activated receptor (PPAR) agonists downregulated cereblon (CRBN) expression and reduced the anti-myeloma activity of lenalidomide in vitro and in vivo. We aimed to determine whether DNA methylation and protein degradation contribute to the effects of PPAR agonists. CRBN promoter methylation status was detected using methylation-specific polymerase chain reaction. The CRBN protein degradation rate was measured using a cycloheximide chase assay. Metabolomic analysis was performed in multiple myeloma (MM) cells treated with PPAR agonists and/or lenalidomide. Our retrospective study determined the effect of co-administration of PPAR agonists with immunomodulatory drugs on the outcomes of patients with MM. CpG islands of the CRBN promoter region became highly methylated upon treatment with PPAR agonists, whereas treatment with PPAR antagonists resulted in unmethylation. The CRBN protein was rapidly degraded after treatment with PPAR agonists. Lenalidomide and fenofibrate showed opposite effects on acylcarnitines and amino acids. Co-administration of immunomodulatory drugs and PPAR agonists was associated with inferior treatment responses and poor survival. Our study provides the first evidence that PPAR agonists reduce CRBN expression through various mechanisms including inducing methylation of CRBN promoter CpG island, enhancing CRBN protein degradation, and affecting metabolomics of MM cells.

The United States is undergoing a demographic shift towards an older population with profound economic, social, and healthcare implications. The number of Americans aged 65 and older will reach 80 million by 2040. The shift will be even more dramatic in the extremes of age, with a projected 400% increase in the population over 85 years old in the next two decades. Understanding the molecular and cellular mechanisms of ageing is crucial to reduce ageing-associated disease and to improve the quality of life for the elderly. In this review, we summarized the changes associated with the ageing of hematopoietic stem cells (HSCs) and what is known about some of the key underlying cellular and molecular pathways. We focus here on the effects of reactive oxygen species and the thioredoxin redox homeostasis system on ageing biology in HSCs and the HSC microenvironment. We present additional data from our lab demonstrating the key role of thioredoxin-1 in regulating HSC ageing.

Objective To investigate the effect of the injectable hydrogel generated from a decellularized amniotic membrane (dAM)-gel on preventing the development of an intrauterine adhesion (IUA) on a rat model. Methods The dAM-gel was developed from an amniotic membrane (AM) by a process of decellularization, lyophilization, and enzyme digestion. Histological analysis, residual component determination, electronic microscopy and turbidimetric gelation kinetics analysis were performed to characterize the dAM-gel. The proliferation and migration of endometrial cells on the dAM-gel coated surface was examined. IUA was surgically created in rats and received dAM-gel injection immediately after wound creation. Gene profiles of epithelial cells cultured on the dAM-gel coated surface were evaluated by RNA-sequencing. Results The collagen content was retained in the dAM-gel, while the GAG content decreased significantly compared with fresh AM (fAM). Gelation of the gel was temperature-sensitive and showed a matrix concentration-dependent manner. Transplantation of the dAM-gel significantly reduced fibrosis of IUA with a recovered uterine cavity, regenerated endometrium and increased microvascular density, along with elevated pregnancy rate compared with endometrium damage groups. Migration of epithelial cells was greatly promoted by the dAM-gel in a surgically created uterine wound model. By comparing the RNA-sequence data of epithelial cells that were cultured on dAM-gel coated and non-coated surfaces, respectively, distinct gene profiles relative to the cellular migration, adhesion and angiogenesis and involved signaling pathway were identified. Conclusions The injectable dAM-gel developed from AM offers a promising option for preventing endometrial fibrosis by promotion of the re-epithelialization of the damaged endometrium.

Damaged hyaline cartilage has no capacity for self-healing, making osteoarthritis (OA) "difficult-to-treat". Cartilage destruction is central to OA patho-etiology and is mediated by matrix degrading enzymes. Here we report decreased expression of miR-17 in osteoarthritic chondrocytes and its deficiency contributes to OA progression. Supplementation of exogenous miR-17 or its endogenous induction by growth differentiation factor 5, effectively prevented OA by simultaneously targeting pathological catabolic factors including matrix metallopeptidase-3/13 (MMP3/13), aggrecanase-2 (ADAMTS5), and nitric oxide synthase-2 (NOS2). Single-cell RNA sequencing of hyaline cartilage revealed two distinct superficial chondrocyte populations (C1/C2). C1 expressed physiological catabolic factors including MMP2, and C2 carries synovial features, together with C3 in the middle zone. MiR-17 is highly expressed in both superficial and middle chondrocytes under physiological conditions, and maintains the physiological catabolic and anabolic balance potentially by restricting HIF-1α signaling. Together, this study identified dual functions of miR-17 in maintaining cartilage homeostasis and prevention of OA., (© 2022. The Author(s).)

Background: In the single-arm, phase 1b/2 CARTITUDE-1 study, ciltacabtagene autoleucel (cilta-cel), an anti-B-cell maturation antigen chimeric antigen receptor T-cell (CAR-T) therapy, showed encouraging efficacy in US patients with multiple myeloma (MM) who previously received an immunomodulatory drug, proteasome inhibitor, and anti-CD38 monoclonal antibody (triple-class exposed)., Patients and Methods: A dataset of US patients refractory to an anti-CD38 monoclonal antibody (MAMMOTH) was used to identify patients who would meet eligibility for CARTITUDE-1 and received subsequent non-CAR-T therapy. The intent-to-treat (ITT) population in CARTITUDE-1 included patients who underwent apheresis (N = 113); the modified ITT (mITT) population was the subset who received cilta-cel (n = 97). Corresponding populations were identified from the MAMMOTH dataset: ITT population (n = 190) and mITT population of patients without progression/death within 47 days (median apheresis-to-cilta-cel infusion time) from onset of therapy (n = 122). Using 1:1 nearest neighbor propensity score matching to control for selected baseline covariates, 95 and 69 patients in CARTITUDE-1 ITT and mITT populations, respectively, were matched to MAMMOTH patients., Results: In ITT cohorts of CARTITUDE-1 vs. MAMMOTH, improved overall response rate (ORR; 84% vs. 28% [P < .001]) and longer progression-free survival (PFS; hazard ratio [HR], 0.11 [95% confidence interval (CI), 0.05-0.22]) and overall survival (OS; HR, 0.20 [95% CI, 0.10-0.39]) were observed. Similar results were seen in mITT cohorts of CARTITUDE-1 vs. MAMMOTH (ORR: 96% vs. 30% [P < .001]; PFS: HR, 0.02 [95% CI, 0.01-0.14]; OS: HR, 0.05 [95% CI, 0.01-0.22]) and with alternative matching methods., Conclusion: Cilta-cel yielded significantly improved outcomes versus real-world therapies in triple-class exposed patients with relapsed/refractory MM., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Although treatment outcomes of multiple myeloma patients have improved significantly during the last two decades, myeloma is still an incurable disease. There are newly emerging immunotherapies to treat multiple myeloma including monoclonal antibodies, antibody-drug conjugate, bispecific antibodies, and chimeric antigen receptor (CAR) T cell therapy. Impressive response rate and clinical efficacy in heavily pretreated myeloma patients led to the FDA approval of the first myeloma CAR-T therapy in March 2021. Among many different targets for myeloma CAR-T therapies, B Cell Maturation Antigen (BCMA) has been the most successful target so far, but other targets which can be used either for single-target or dual-target CAR-T's are actively being explored. Clinical efficacy and safety of current myeloma CAR-T therapies will be presented here. Potential mechanisms leading to resistance include clearance of CAR-T cells, antigenic escape, and immunosuppressive tumor microenvironment. Novel strategies to enhance myeloma CAR-T will also be described. In this article, we provide a comprehensive review of the current data and the future directions of myeloma CAR-T therapies., Competing Interests: Declaration of Competing Interest Taewoong Choi has served for the Janssen Biotech speaker bureau. Yubin Kang has served at the Sanofi-Genzyme Advisory panel and PSI advisory board., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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.

Background: Anaplastic multiple myeloma (AMM) is a very rare but distinct subtype of multiple myeloma (MM) with an extremely poor prognosis. Due to its rarity, AMM lacks detailed descriptions and clear definitions. Moreover, there is no consensus on the treatment and evidence suggests that AMM responds poorly to several novel therapies. We conducted a literature review and retrospective case series to determine clinical characteristics, pathological features, and outcomes of AMM., Case Presentation: Published case reports and case series of AMM since 1983 were systematically extracted and reviewed. A total of 52 patients with AMM were reported in the PUBMED since 1983, including 26 males (50%) and 26 females (50%). The age ranged from 29 years old to 85 years old, with a mean age of 57.02 years old. Most of the patients presented with bone pain (23, 44.2%), fatigue (18, 34.6%), plasmacytoma (18, 34.6%) and weight loss (7, 13.5%). The median survival of the patients was 4 months. To investigate the outcomes of patients with AMM in the current era of treatment, a series of 14 patients with AMM diagnosed at our institute between December 2012 and July 2021was retrospectively analyzed. Our retrospective case series consisted of 12 males (85.7%) and 2 females (14.3%), with a mean age of 59 years old. Most of our AMM patients displayed bone lytic lesions as a common manifestation. The common cytogenetic abnormality was 1q amplification. All patients received standard combination chemotherapy consisting of proteasome inhibitors and/or immunomodulatory agents, and half of the patients underwent autologous hematopoietic stem cell transplantation. The median progression-free survival (PFS) and overall survival (OS) for our 14 AMM patients were 0.84 years and 1.52 years, respectively, which was significantly worse than the regular MM patients treated at our institute from 2003-2013 who had a PFS of 2.28 years and OS of 4.92 years., Conclusions: AMM is a very rare, morphologically distinct variant of MM. It has adverse cytogenetics and an aggressive course. It is often resistant to standard chemotherapy and presents with an extremely low survival rate.

Myeloid-derived suppressor cells (MDSCs) are a hetero geneous group of cells, which can suppress the immune response, promote tumor progression and impair the efficacy of immunotherapies. Consequently, the pharmacological targeting of MDSC is emerging as a new immunotherapeutic strategy to stimulate the natural anti-tumor immune response and potentiate the efficacy of immunotherapies. Herein, we leveraged genetically modified models and a small molecule inhibitor to validate Calcium-Calmodulin Kinase Kinase 2 (CaMKK2) as a druggable target to control MDSC accumulation in tumor-bearing mice. The results indicated that deletion of CaMKK2 in the host attenuated the growth of engrafted tumor cells, and this phenomenon was associated with increased antitumor T cell response and decreased accumulation of MDSC. The adoptive transfer of MDSC was sufficient to restore the ability of the tumor to grow in Camkk2 -/- mice, confirming the key role of MDSC in the mechanism of tumor rejection. In vitro studies indicated that blocking of CaMKK2 is sufficient to impair the yield of MDSC. Surprisingly, MDSC generated from Camkk2 -/- bone marrow cells also showed a higher ability to terminally differentiate toward more immunogenic cell types (e.g inflammatory macrophages and dendritic cells) compared to wild type (WT). Higher intracellular levels of reactive oxygen species (ROS) accumulated in Camkk2 -/- MDSC, increasing their susceptibility to apoptosis and promoting their terminal differentiation toward more mature myeloid cells. Mechanistic studies indicated that AMP-activated protein kinase (AMPK), which is a known CaMKK2 proximal target controlling the oxidative stress response, fine-tunes ROS accumulation in MDSC. Accordingly, failure to activate the CaMKK2-AMPK axis can account for the elevated ROS levels in Camkk2 -/- MDSC. These results highlight CaMKK2 as an important regulator of the MDSC lifecycle, identifying this kinase as a new druggable target to restrain MDSC expansion and enhance the efficacy of anti-tumor immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Huang, Liu, Luz, Berrong, Meyer, Zou, Swann, Sundaramoorthy, Kang, Jauhari, Lento, Chao and Racioppi.)

Prophylactic donor lymphocyte infusions (DLI) are used to augment post-transplant immune recovery to reduce both infectious complications and disease recurrence. Preclinical studies implicate the naive T-cell subset as the primary driver of graft-versus-host disease (GvHD). In this phase I dose escalation study, we assessed the safety of a DLI that was depleted of CD45RA+ naive T cells. Sixteen adult patients received a prophylactic DLI at a median of 113 days (range 76-280 days) following an HLA-identical, non-myeloablative allogeneic hematopoietic stem cell transplantation. Three patients each received the naive T-cell depleted DLI with a CD3+ dose of 1 × 10 5 /kg, 1 × 10 6 /kg, and 5 × 10 6 /kg. The maximum dose of 1 × 10 7 /kg was expanded to 7 patients. No dose-limiting grade III/IV acute GvHD or adverse events attributable to the DLI were observed at any dose level. One patient developed grade 2 acute GvHD of skin and upper intestines, and another developed moderate chronic GvHD of the lungs following the DLI. With a median follow-up of 2.8 years, 2-year progression-free and overall survival is 50.0% and 68.8%, respectively. In conclusion, these data suggest that a DLI that has been depleted of CD45RA+ naive T cells is feasible and carries a low risk of acute or chronic GvHD.

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.

The introduction of CD38-targeting monoclonal antibodies (CD38 MoABs), daratumumab and isatuximab, has significantly impacted the management of patients with multiple myeloma (MM). Outcomes of patients with MM refractory to CD38 MoABs have not been described. We analyzed outcomes of 275 MM patients at 14 academic centers with disease refractory to CD38 MoABs. Median interval between MM diagnosis and refractoriness to CD38 MoAB (T 0 ) was 50.1 months. The median overall survival (OS) from T 0 for the entire cohort was 8.6 [95% C.I. 7.5-9.9] months, ranging from 11.2 months for patients not simultaneously refractory to an immunomodulatory (IMiD) agent and a proteasome inhibitor (PI) to 5.6 months for "penta-refractory" patients (refractory to CD38 MoAB, 2 PIs and 2 IMiDs). At least one subsequent treatment regimen was employed after T 0 in 249 (90%) patients. Overall response rate to first regimen after T 0 was 31% with median progression-free survival (PFS) and OS of 3.4 and 9.3 months, respectively. PFS was best achieved with combinations of carfilzomib and alkylator (median 5.7 months), and daratumumab and IMiD (median 4.5 months). Patients with MM refractory to CD38 MoAB have poor prognosis and this study provides benchmark for new therapies to be tested in this population.

Objectives: Multiple myeloma (MM) primarily strikes older adults, but full-dose chemotherapy such as bortezomib (Velcade), cyclophosphamide and dexamethasone (VCD) is often excessively toxic to very old or frail adults and those with substantial comorbidities. We piloted dose-attenuated VCD ("VCD-Lite") in such vulnerable adults with newly diagnosed MM (NDMM)., Materials and Methods: Subjects with NDMM and a high risk of therapy-related toxicity due to factors above received bortezomib 1.3mg/m 2 subcutaneously, cyclophosphamide 300mg/m 2 and dexamethasone 40mg orally, all on days 1, 8, and 15 of a 28day cycle for eight cycles, followed by indefinite, alternating bortezomib and lenalidomide maintenance. Toxicity, overall response rate (ORR), progression-free and overall survival (PFS and OS) were determined. The Cancer and Aging Research Group geriatric assessment (CARG GA) was administered at baseline in an exploratory manner as a predictor of severe toxicity., Results: 14 patients went on the study, which was closed early due to slow accrual. Intention-to-treat ORR was 64%. 64% of patients experienced grade ≥3 adverse events, the majority of which were unlikely therapy-related. Median PFS was 24.2months and OS 29.7months, with 14%, 36% and 29% of patients discontinuing study drugs due to toxicity, MM progression and other reasons respectively. Baseline CARG GA was successfully completed by all subjects but one., Conclusion: VCD-Lite is a viable option for vulnerable adults with NDMM. CARG GA is feasible. Further studies to optimize therapy and to explore CARG GA as a toxicity predictor are vital., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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 3–mediated 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.

Amyloidosis refers to a group of widely diverse conditions characterized by the deposition of insoluble protein within the extracellular space, leading to disruption of normal organ function. AL primary amyloidosis is associated with plasma cell dyscrasias and is caused by the deposition of insoluble kappa or lambda light chains. Cardiac involvement by AL primary amyloidosis has a very poor prognosis, and patients are treated with systemic chemotherapy. Clinically, the presence of cardiac amyloidosis in patients with plasma cell disorders is usually presumed to represent AL primary amyloidosis, and they are often managed as such. We reported four cases of elderly patients with plasma cell disorders who were found to have biopsy-proven cardiac senile transthyretin amyloidosis. Our cases demonstrated that cardiac amyloidosis in patients with plasma cell disorders does not necessarily represent AL primary amyloidosis. Cardiac biopsy is important in making the correct diagnosis. Accurate subtyping of the amyloid has significant implications in the management of patients and discussion of prognosis.

Thioredoxin (Trx) is an inflammation-inducible small oxidoreductase protein ubiquitously expressed in all organisms. Trx acts both intracellularly and extracellularly and is involved in a wide range of physiological cellular responses. Inside the cell, Trx alleviates oxidative stress by scavenging reactive oxygen species (ROS), regulates a variety of redox-sensitive signaling pathways as well as ROS-independent genes, and exerts cytoprotective effects. Outside the cell, Trx acts as growth factors or cytokines and promotes cell growth and many other cellular responses. Trx is also implicated in tumorigenesis. Trx is a proto-oncogene and is overexpressed in many cancers and correlates with poor prognosis. Trx stimulates cancer cell survival, promotes tumor angiogenesis, and inhibits both spontaneous apoptosis and drug-induced apoptosis. Inhibitors targeting Trx pathway provide a promising therapeutic strategy for cancer prevention and intervention. More recently, data from our laboratory demonstrate an important role of Trx in expanding long-term repopulating hematopoietic stem cells. In this chapter, we first provide an overview of Trx including its isoforms, compartmentation, and functions. We then discuss the roles of Trx in hematologic malignancies. Finally, we summarize the most recent findings from our lab on the use of Trx to enhance hematopoietic reconstitution following hematopoietic stem cell transplantation., (© 2014 Elsevier Inc. All rights reserved.)