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Although multiple myeloma (MM) remains an incurable bone marrow cancer, survival rates have dramatically improved over the past decade, most notably in the younger patient population. An understanding of MM biology and improvement in stem-cell transplantation, better supportive care, and novel therapies with higher efficacy and lower toxicity are all responsible for this improvement. Despite these trends, improvements among older patients remain modest, underscoring the need for innovative approaches. The availability of a rich pipeline of novel agents undergoing early-phase clinical trials in MM is an exciting and active area of research. Current novel agents targeting tumor and stromal compartments can be conceptualized as those that target membrane-bound receptors (insulin-like growth factor-1, vascular endothelial growth factor, CD40, etc.), intracellular signaling kinases (Janus kinase/signal transducers and activators of transcription, phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin, mitogen-activated protein kinase pathways), cell cycle molecular machinery (cyclin-dependent kinases inhibitors), epigenetic abnormalities (DNA methyltransferase and histyone deacetylase), protein dynamics (heat-shock protein 90, ubiquitin-proteasome system), and tumor vasculature and microenvironment (angiogenesis, integrins). This review highlights some of these novel agents tested either alone or in combination for the treatment of MM. [ABSTRACT FROM AUTHOR]

OBJECTIVE: An algorithm for the detection of pulmonary arterial hypertension (PAH), based on the presence of dyspnea and the findings of Doppler echocardiographic evaluation of the velocity of tricuspid regurgitation (VTR) and right-sided heart catheterization (RHC), which was applied in a large multicenter systemic sclerosis (SSc) population, estimated the prevalence of PAH to be 7.85%. The aim of this observational study was to investigate the incidence of PAH and pulmonary hypertension (PH) during a 3-year followup of patients from the same cohort (the ItinérAIR-Sclérodermie Study). METHODS: Patients with SSc and without evidence of PAH underwent evaluation for dyspnea and VTR at study entry and during subsequent visits. Patients in whom PAH was suspected because of a VTR of 2.8-3.0 meters/second and unexplained dyspnea or a VTR of >3.0 meters/second underwent RHC to confirm the diagnosis. RESULTS: A total of 384 patients were followed up for a mean +/- SD of 41.03 +/- 5.66 months (median 40.92 months). At baseline, 86.7% of the patients were women, and the mean +/- SD age of the patients was 53.1 +/- 12.0 years. The mean +/- SD duration of SSc at study entry was 8.7 +/- 7.6 years. After RHC, PAH was diagnosed in 8 patients, postcapillary PH in 8 patients, and PH associated with severe pulmonary fibrosis in 2 patients. The incidence of PAH was estimated to be 0.61 cases per 100 patient-years. Two patients who exhibited a mean pulmonary artery pressure of 20-25 mm Hg at baseline subsequently developed PAH. CONCLUSION: The estimated incidence of PAH among patients with SSc was 0.61 cases per 100 patient-years. The high incidence of postcapillary PH highlights the value of RHC in investigating suspected PAH. [ABSTRACT FROM AUTHOR]

Background: Isatuximab is a CD38 monoclonal antibody approved for relapsed or refractory multiple myeloma. We aimed to evaluate the addition of isatuximab to weekly carfilzomib (K), lenalidomide (R), and dexamethasone (d; Isa-KRd) in transplant-eligible patients with newly diagnosed multiple myeloma and stratified maintenance by cytogenetic risk., Methods: This single-arm phase 2 trial was done at three cancer centres (two hospitals and a cancer institute) in Boston (MA, USA). Eligible patients were aged at least 18 years and had transplant-eligible newly diagnosed multiple myeloma and an ECOG performance status of 2 or less. Patients received four 28-day cycles of Isa-KRd, including isatuximab 10 mg/kg intravenously weekly for 8 weeks, then every other week for 16 weeks, and every 4 weeks thereafter; carfilzomib 56 mg/m 2 intravenously on days 1, 8, and 15 (20 mg/m 2 for cycle 1 day 1); lenalidomide 25 mg orally on days 1-21; and dexamethasone 20 mg orally the day of and day after all doses of carfilzomib and isatuximab. Consolidation involved either upfront haematopoietic stem-cell transplantation (HSCT) with two additional cycles or deferred HSCT with four additional cycles of treatment. The primary endpoint was complete response after four cycles of treatment. Analyses were by intention-to-treat. All patients who received one dose of study drug were included in the safety analyses. This study was registered at ClinicalTrials.gov, NCT04430894, and has completed enrolment., Findings: Between July 31, 2020 and Jan 31, 2022, 50 patients were enrolled. Median age was 59 years (range 40-70), 54% (27 of 50 patients) were male, and 44 (88%) were White. 46% (23 of 50) of patients had high-risk cytogenetics. Median follow-up was 26 months (IQR 20·7-30·1). 32% (16 of 50 patients) achieved a complete response after four cycles. The overall response rate (ORR) was 90% (45 patients) and 78% (39 patients) achieved a very good partial response (VGPR) or better. After completion of consolidation, 58% (29 patients) achieved a complete response; the ORR was 90% (45 patients) and 86% (43 patients) achieved a VGPR or better. The most common grade 3 or 4 side-effects (≥two patients) included neutropenia (13 [26%] of 50 patients), elevated alanine aminotransferase (six [12%] patients), fatigue (three [6%] patients), thrombocytopenia (three [6%] patients), acute kidney injury (two [4%] patients), anaemia (two [4%] patients), and febrile neutropenia (two [4%] patients). Grade 1-2 infusion-related reactions were seen in 20% (ten patients), with none grade 3. Grade 1-2 hypertension was seen in 14% (seven patients) with one grade 3 (one [2%] patient). There were two deaths assessed as unrelated to treatment., Interpretation: Although the study did not achieve the prespecified complete response threshold, Isa-KRd induced deep and durable responses in transplant-eligible patients with newly diagnosed multiple myeloma. The treatment proved safe and consistent with similar regimens in this setting., Funding: Amgen, Sanofi, and Adaptive., Competing Interests: Declaration of interests EO’D: consulting, honororia, travels fees, and participation in the advisory board for Sanofi. CM: consulting fees or honoria from Sanofi, Pfizer, Janssen, Karyopharm, Takeda, and GSK. AJY: grants or contracts from Amgen, BMS, and Janssen; consulting fees from AbbVie, Adaptive, Amgen, Bristol Myers Squibb, Celgene, GSK Janssen, Karyopharm, Oncopeptides, Pfizer, Prothena, Regeneron, Sanofi, Sebia, and Takeda. ON: grants or contracts from Janssen; honoraria from Pfizer; and participation on an advisory board for BMS, Janssen, Takeda, Sanofi, and GPCR therapeutics. JR: research funding from BMS and Sanofi; data safety monitoring committee for Karyopharm; and participation in an advisory board for Janssen. NM: consulting fees from Sanofi, Amgen, Bristol Myers Squibb, and Johnson & Johnson. SM: consulting fees and honororia from Pfizer; and stock owned in AbbVie. DC: participation in an advisory board for Sanofi. PR: grants or contracts with Oncopeptides, Celgene and Bristol Myers Squibb, Karyopharm, and Takeda; consulting fees from Oncopeptides, Celgene and Bristol Myers Squibb, Karyopharm, Sanofi, and GSK. NR: consulting fees from Sanofi and Amgen. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Multiple myeloma (MM) is a heterogeneous disease that has an increased incidence in African Americans (AAs). We previously observed that, with equal access to health care, younger AA patients (age < 65 years) have superior overall survival (OS) compared with younger White patients. Because MM prognosis is influenced by 17p deletion (del17p), we investigated racial differences in its occurrence and impact in a large cohort of MM patients from the Veterans Affairs (VA) system. Among 2243 VA patients with MM for whom del17p data were available, del17p was present in 8.83% of all patients, with a significantly lower prevalence in AAs (5.56%) compared with Whites (10.52%; P < .001). The difference was even more pronounced among younger AAs (<65 years) vs younger Whites (4.34% vs 9.8%, respectively; P = .004). However, we did not observe any significant difference in survival between AA and White patients with del17p, regardless of age category, suggesting that del17p carries a poor prognosis across race and age. Interestingly, among patients without del17p, we still noted a significantly superior OS in younger AAs compared with younger Whites (7.75 vs 5.10 years; P = .042). Our study shows a lower incidence of del17p in AAs but suggests that the survival advantage for younger AAs is primarily due to factors other than del17p., (© 2021 by The American Society of Hematology.)

Background: Traditional count-based measures of comorbidity are unlikely to capture the complexity of multiple chronic conditions (multimorbidity) in older adults with cancer. We aimed to define patterns of multimorbidity and their impact in older United States veterans with multiple myeloma (MM)., Methods: We measured 66 chronic conditions in 5076 veterans aged 65 years and older newly treated for MM in the national Veterans Affairs health-care system from 2004 to 2017. Latent class analysis was used to identify patterns of multimorbidity among these conditions. These patterns were then assessed for their association with overall survival, our primary outcome. Secondary outcomes included emergency department visits and hospitalizations., Results: Five patterns of multimorbidity emerged from the latent class analysis, and survival varied across these patterns (log-rank 2-sided P < .001). Older veterans with cardiovascular and metabolic disease (30.9%, hazard ratio [HR] = 1.33, 95% confidence interval [CI] = 1.21 to 1.45), psychiatric and substance use disorders (9.7%, HR = 1.58, 95% CI = 1.39 to 1.79), chronic lung disease (15.9%, HR = 1.69, 95% CI = 1.53 to 1.87), and multisystem impairment (13.8%, HR = 2.25, 95% CI = 2.03 to 2.50) had higher mortality compared with veterans with minimal comorbidity (29.7%, reference). Associations with mortality were maintained after adjustment for sociodemographic variables, measures of disease risk, and the count-based Charlson Comorbidity Index. Multimorbidity patterns were also associated with emergency department visits and hospitalizations., Conclusions: Our findings demonstrate the need to move beyond count-based measures of comorbidity and consider cancer in the context of multiple chronic conditions., (Published by Oxford University Press 2021.)

Electronic frailty indices based on data from administrative claims and electronic health records can be used to estimate frailty in large populations of older adults with cancer where direct frailty measures are lacking. The objective of this study was to use the electronic Veterans Affairs Frailty Index (VA-FI-10)-developed and validated to measure frailty in the national United States (US) VA Healthcare System-to estimate the prevalence and impact of frailty in older US veterans newly treated for multiple myeloma (MM) with contemporary therapies. We designed a retrospective cohort study of 4924 transplant-ineligible veterans aged ≥ 65 years initiating MM therapy within VA from 2004 to 2017. Initial MM therapy was measured using inpatient and outpatient treatment codes from pharmacy data in the VA Corporate Data Warehouse. In total, 3477 veterans (70.6%) were classified as frail (VA-FI-10 > 0.2), with 1510 (30.7%) mildly frail (VA-FI-10 > 0.2-0.3), 1105 (22.4%) moderately frail (VA-FI-10 > 0.3-0.4), and 862 (17.5%) severely frail (VA-FI-10 > 0.4). Survival and time to hospitalization decreased with increasing VA-FI-10 severity (log-rank p -value < 0.001); the VA-FI-10 predicted mortality and hospitalizations independently of age, sociodemographic variables, and measures of disease risk. Varying data sources and assessment periods reclassified frailty severity for a substantial portion of veterans but did not substantially affect VA-FI-10's association with mortality. Our study supports use of the VA-FI-10 in future research involving older veterans with MM and provides insights into its potential use in identifying frailty in clinical practice.

p53-related protein kinase (TP53RK, also known as PRPK) is an upstream kinase that phosphorylates (serine residue Ser15) and mediates p53 activity. Here we show that TP53RK confers poor prognosis in multiple myeloma (MM) patients, and, conversely, that TP53RK knockdown inhibits p53 phosphorylation and triggers MM cell apoptosis, associated with downregulation of c-Myc and E2F-1-mediated upregulation of pro-apoptotic Bim. We further demonstrate that TP53RK downregulation also triggers growth inhibition in p53-deficient and p53-mutant MM cell lines and identify novel downstream targets of TP53RK including ribonucleotide reductase-1, telomerase reverse transcriptase, and cyclin-dependent kinase inhibitor 2C. Our previous studies showed that immunomodulatory drugs (IMiDs) downregulate p21 and trigger apoptosis in wild-type-p53 MM.1S cells, Importantly, we demonstrate by pull-down, nuclear magnetic resonance spectroscopy, differential scanning fluorimetry, and isothermal titration calorimetry that IMiDs bind and inhibit TP53RK, with biologic sequelae similar to TP53RK knockdown. Our studies therefore demonstrate that either genetic or pharmacological inhibition of TP53RK triggers MM cell apoptosis via both p53-Myc axis-dependent and axis-independent pathways, validating TP53RK as a novel therapeutic target in patients with poor-prognosis MM.

Heat shock protein (HSP)90 inhibitors have shown significant anti-tumor activities in preclinical settings in both solid and hematological tumors. We previously reported that the novel, orally available HSP90α/β inhibitor TAS-116 shows significant anti-MM activities. In this study, we further examined the combination effect of TAS-116 with a RAS-RAF-MEK-ERK signaling pathway inhibitor in RAS- or BRAF-mutated MM cell lines. TAS-116 monotherapy significantly inhibited growth of RAS-mutated MM cell lines and was associated with decreased expression of downstream target proteins of the RAS-RAF-MEK-ERK signaling pathway. Moreover, TAS-116 showed synergistic growth inhibitory effects with the farnesyltransferase inhibitor tipifarnib, the BRAF inhibitor dabrafenib, and the MEK inhibitor selumetinib. Importantly, treatment with these inhibitors paradoxically enhanced p-C-Raf, p-MEK, and p-ERK activity, which was abrogated by TAS-116. TAS-116 also enhanced dabrafenib-induced MM cytotoxicity associated with mitochondrial damage-induced apoptosis, even in the BRAF-mutated U266 MM cell line. This enhanced apoptosis in RAS-mutated MM triggered by combination treatment was observed even in the presence of bone marrow stromal cells. Taken together, our results provide the rationale for novel combination treatment with HSP90α/β inhibitor and RAS-RAF-MEK-ERK signaling pathway inhibitors to improve outcomes in patients with in RAS- or BRAF-mutated MM.

Proteasome inhibition induces the accumulation of aggregated misfolded/ubiquitinated proteins in the aggresome; conversely, histone deacetylase 6 (HDAC6) inhibition blocks aggresome formation. Although this rationale has been the basis of proteasome inhibitor (PI) and HDAC6 inhibitor combination studies, the role of disruption of aggresome formation by HDAC6 inhibition has not yet been studied in multiple myeloma (MM). The present study aimed to evaluate the impact of carfilzomib (CFZ) in combination with a selective HDAC6 inhibitor (ricolinostat) in MM cells with respect to the aggresome-proteolysis pathway. We observed that combination treatment of CFZ with ricolinostat triggered synergistic anti-MM effects, even in bortezomib-resistant cells. Immunofluorescent staining showed that CFZ increased the accumulation of ubiquitinated proteins and protein aggregates in the cytoplasm, as well as the engulfment of aggregated ubiquitinated proteins by autophagosomes, which was blocked by ricolinostat. Electron microscopy imaging showed increased autophagy triggered by CFZ, which was inhibited by the addition of ACY-1215. Finally, an in vivo mouse xenograft study confirmed a decrease in tumour volume, associated with apoptosis, following treatment with CFZ in combination with ricolinostat. Our results suggest that ricolinostat inhibits aggresome formation, caused by CFZ-induced inhibition of the proteasome pathway, resulting in enhanced apoptosis in MM cells., (© 2015 John Wiley & Sons Ltd.)

Decorin is a small, leucine-rich proteoglycan found in the extracellular matrix of various connective tissues with potential effective tumor suppressive properties. Recent data suggest low levels of decorin in multiple myeloma (MM) patients compared to healthy volunteers, as well as in patients with osteolytic bone lesions compared to non-osteolytic lesions. In the present report, we investigated the role of decorin in the MM microenvironment or niche. Our data suggests that decorin is produced by osteoblasts (OBs) but not by MM cells. Furthermore, MM cells decrease OB-induced decorin secretion and this effect is mediated by CCL3. Importantly, neutralizing CCL3 from MM cells restores decorin levels in OBs as does proteasome inhibitors such as carfilzomib. These findings indicate that decorin may indirectly act as an antagonist to MM cell survival and that the interplay between MM and decorin may be an important target to explore in manipulating the tumor niche to inhibit tumorigenesis., (© 2014 American Society for Bone and Mineral Research.)

Despite promising preclinical results with mTOR kinase inhibitors in multiple myeloma, resistance to these drugs may arise via feedback activation loops. This concern is especially true for insulin-like growth factor 1 receptor (IGF1R), because IGF1R signaling is downregulated by multiple AKT and mTOR feedback mechanisms. We have tested this hypothesis in multiple myeloma using the novel selective mTOR kinase inhibitor AZD8055. We evaluated p-mTOR S(2481) as the readout for mTORC2/Akt activity in multiple myeloma cells in the context of mTOR inhibition via AZD8055 or rapamycin. We next validated AZD8055 inhibition of mTORC1 and mTORC2 functions in multiple myeloma cells alone or in culture with bone marrow stroma cells and growth factors. Unlike rapamycin, AZD8055 resulted in apoptosis of multiple myeloma cells. AZD8055 treatment, however, induced upregulation of IGF1R phosphorylation in p-Akt S(473)-expressing multiple myeloma cell lines. Furthermore, exposure of AZD8055-treated cells to IGF1 induced p-Akt S(473) and rescued multiple myeloma cells from apoptosis despite mTOR kinase inhibition and TORC2/Akt blockage. The addition of blocking IGF1R antibody resulted in reversing this effect and increased AZD8055-induced apoptosis. Our study suggests that combination treatment with AZD8055 and IGF1R-blocking agents is a promising strategy in multiple myeloma with potential IGF1R/Akt signaling-mediated survival., (©2014 American Association for Cancer Research.)

The PI3K/Akt pathway plays a crucial role in the pathogenesis of multiple myeloma (MM) in the bone marrow (BM) milieu. However, efficacy of selective and potent Akt inhibition has not yet been fully elucidated. In this study, we, therefore, examined the biologic impact of selective and potent Akt inhibition by a novel allosteric inhibitor TAS-117. TAS-117 induced significant growth inhibition, associated with downregulation of phosphorylated Akt (p-Akt), selectively in MM cell lines with high baseline p-Akt. Cytotoxicity of TAS-117 was also observed in patient MM cells, but not in normal peripheral blood mononuclear cells. Importantly, TAS-117 induced significant cytotoxicity in MM cells even in the presence of BM stromal cells, associated with inhibition of IL6 secretion. Oral administration of TAS-117 significantly inhibited human MM cell growth in murine xenograft models. TAS-117 triggered apoptosis and autophagy, as well as induction of endoplasmic reticulum (ER) stress response with minimal expression of C/EBP homologous protein (CHOP), a fatal ER stress marker. Importantly, TAS-117 enhanced bortezomib-induced cytotoxicity, associated with increased CHOP and PARP cleavage and blockade of bortezomib-induced p-Akt, suggesting that TAS-117 augments bortezomib-induced ER stress and apoptotic signaling. Carfilzomib-induced cytotoxicity was similarly enhanced by TAS-117. Importantly, TAS-117 enhanced bortezomib-induced cytotoxicity in vivo, associated with prolonged host survival. Our results show that selective and potent Akt inhibition by TAS-117 triggers anti-MM activities in vitro and in vivo, as well as enhances cytotoxicity of proteasome inhibition, providing the preclinical framework for clinical evaluation of selective Akt inhibitors, alone and in combination with proteasome inhibitors in MM., (©2014 American Association for Cancer Research.)

Objective: To assess the prevalence of systemic sclerosis (SSc) in the Lorraine region, France., Methods: Data from three sources - general practitioners and community and hospital specialists, medical records departments, and regional and national laboratories-and a capture-recapture method with log-linear models were used to estimate SSc prevalence in the region. Double recording was checked, and reported cases were validated after a review of medical records., Results: We identified 560 records of suspected SSc cases corresponding to 327 unique suspected SSc cases existing on June 30, 2006, in Lorraine. On the basis of the 193 validated cases (22 [11.4%] with diffuse disease, 136 [70.5%] with limited disease, 31 [16.1%] with limited involvement and 4 unknown), the observed overall crude prevalence of SSc was 105.4 cases per million adult inhabitants (95% confidence interval [CI]: 91.0; 121.4). With the capture-recapture method, the estimated number of SSc cases was 233 (95% CI: 217.3; 260.0), so an estimated 40 cases were not identified by the three sources. The estimated overall prevalence was 132.2 cases per million adult inhabitants (95% CI: 115.8; 154.0)., Conclusions: Our study provides the first estimate of SSc prevalence in the Lorraine region. The capture-recapture method allowed us to estimate an additional 21% of unobserved cases and is a good alternative to the community-based study design for estimating the prevalence of rare diseases., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Over-expression of the protein Dickkopf-1 (Dkk1) has been associated with multiple myeloma bone disease. Previous reports with the use of anti-Dkk1 neutralizing Ab directed strategies have demonstrated a pro-anabolic effect with associated anti-myeloma activity in 2 in vivo mouse models. However new insights on the role of the wnt pathway in osteoclasts (OC) are emerging and the potential effect of a neutralizing Ab to Dkk1 in osteoclastogenesis remains to be elucidated. In order to better define the effect of an anti-Dkk1 neutralizing Ab on osteoclastogenesis and myeloma, we studied a novel anti-Dkk1 monoclonal Ab in our preclinical models. In vivo data confirmed the pro-anabolic and anti-MM effect. In vitro data in part confirmed the in vivo observation, suggesting an indirect anti-MM effect secondary to inhibition of osteoclastogenesis and thus the interaction between MM and bone microenvironment. However, when studies on osteoclastogenesis were extended to samples derived from MM patients, we observed a variable response to anti-Dkk1 treatment without correlation to expression of surface receptors for Dkk1 in OCs suggesting potential heterogeneity in the efficacy of such a strategy. In conclusion, Dkk1 is a promising target for the treatment of both MM and bone disease, and ongoing clinical studies will help elucidate its efficacy., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: NF-κB transcription factor plays a key role in the pathogenesis of multiple myeloma in the context of the bone marrow microenvironment. Both canonical and noncanonical pathways contribute to total NF-κB activity. Recent studies have shown a critical role for the noncanonical pathway: selective inhibitors of the canonical pathway present a limited activity, mutations of the noncanonical pathway are frequent, and bortezomib-induced cytotoxicity cannot be fully attributed to inhibition of canonical NF-κB activity., Experimental Design: Multiple myeloma cell lines, primary patient cells, and the human multiple myeloma xenograft murine model were used to examine the biologic impact of dual inhibition of both canonical and noncanonical NF-κB pathways., Results: We show that PBS-1086 induces potent cytotoxicity in multiple myeloma cells but not in peripheral blood mononuclear cells. PBS-1086 overcomes the proliferative and antiapoptotic effects of the bone marrow milieu, associated with inhibition of NF-κB activity. Moreover, PBS-1086 strongly enhances the cytotoxicity of bortezomib in bortezomib-resistant multiple myeloma cell lines and patient multiple myeloma cells. PBS-1086 also inhibits osteoclastogenesis through an inhibition of RANK ligand (RANKL)-induced NF-κB activation. Finally, in a xenograft model of human multiple myeloma in the bone marrow milieu, PBS-1086 shows significant in vivo anti-multiple myeloma activity and prolongs host survival, associated with apoptosis and inhibition of both NF-κB pathways in tumor cells., Conclusions: Our data show that PBS-1086 is a promising dual inhibitor of the canonical and noncanonical NF-κB pathways. Our preclinical study therefore provides the framework for clinical evaluation of PBS-1086 in combination with bortezomib for the treatment of multiple myeloma and related bone lesions., (©2012 AACR.)