The effect of novel therapies in high-molecular-risk multiple myeloma.

Multiple myeloma is a heterogeneous disease with a prognosis that varies with patient factors, disease burden, tumor biology, and treatments. Certain molecular abnormalities confer a worse prognosis and thus are considered high-risk. These include t(4;14), del(17p), t(14;16), t(14;20), hypodiploidy, and gain(1q)/del(1p). In our previous review in 2013, we discussed the effect of available therapies on prognosis in these high-risk patients. Since then, seven phase 3 clinical trials in relapsed myeloma with 1 to 3 lines of therapy have been conducted, resulting in the approval of panobinostat, ixazomib, daratumumab, and elotuzumab, as well as additional data on carfilzomib. In our current review of these studies, all the novel therapies resulted in an improvement in progression-free survival for high-risk patients, but none of the trials provided clear statistical evidence that they overcame high-risk status. Moreover, there are several limitations in the currently available data. For example, the patient's Revised International Staging System score is generally not reported, and even when it is reported, it is usually at the time of initial diagnosis rather than at the time of study entry. Furthermore, the methodology used to determine risk suffers from technologic issues. Finally, the clonal and allele burden and concurrent molecular abnormalities can affect risk status and prognosis. To determine the optimal therapy for high-risk patients, future clinical trials should provide standardized risk assessments for all patients in addition to hazard ratios for Kaplan-Meier survival curves of high-risk patients vs those of standard-risk patients to determine if high-risk status has truly been overcome by a novel agent.

Immunomodulatory drug- and proteasome inhibitor-backbone regimens in the treatment of relapsed multiple myeloma: an evidence-based review.

INTRODUCTION: Recent advances and drug approvals in the last decade have substantially changed the landscape of relapsed and refractory multiple myeloma (RRMM), which not only improved outcomes for patients but also increased complexity of treatment decisions. The approvals are based on randomized studies of novel agents added to an immunomodulatory drug- (IMiD) or proteasome inhibitor (PI)-backbone showing an improvement in outcomes. However, differences in enrolled patient populations/study designs limit comparisons of results, making the choice and sequencing of agents challenging. AREAS COVERED: This review summarizes the latest updates of key clinical trials of IMiD- and PI-backbone regimens in RRMM. Additionally, it highlights carfilzomib dosing strategies and toxicity profiles of varying carfilzomib combination regimens and provides a clinical guideline for the use of carfilzomib therapy. PubMed and relevant meeting (ASH, ASCO, EHA, IMW) databases from 2010 to 2020, as well as clinicaltrials.gov, were queried for this review. EXPERT OPINION: The choice of therapy for RRMM requires careful consideration of patient factors (age/frailty and comorbidities), disease factors (symptom burden/biology), and treatment-related factors (toxicities/responses to prior therapies). Importantly, a critical factor in selecting an agent based on the published data is a patient's sensitivity to lenalidomide and bortezomib at the time of relapse.

Diagnostic Advances in Multiple Myeloma.

There have been several advances in the diagnosis of multiple myeloma (MM) in recent years. Serum free light chains have improved the ability to diagnose light chain MM; however, there are still difficulties in the serologic diagnosis of MM in some cases, particularly IgA MM. A novel heavy/light chain assay is able to improve the accuracy of diagnosis in these cases. Free light chains may also improve the diagnosis of extramedullary disease in difficult cases such as disease involving the central nervous system, pleura, or ascites. Advances in imaging such as whole body low-dose computed tomography (CT) whole body magnetic resonance imaging (MRI), and positron emission tomography/computed tomography (PET/CT) have improved sensitivity in identifying lytic bone lesions, which would enable earlier treatment, and monitoring of osseous disease particularly in non- or oligosecretory disease. New techniques such as fused PET/MRI may further enhance the diagnosis of both bone lesions and extramedullary disease.

Outcomes and management of lenalidomide-associated rash in patients with multiple myeloma.

The immunomodulatory drugs thalidomide, lenalidomide, and pomalidomide (IMiDs) are an important component of myeloma treatment; one of six available drug classes for this incurable disease. Rash is a frequent side effect of IMiDs, particularly lenalidomide, often leading to treatment discontinuation. We retrospectively reviewed 52 patients (7.2% of patients seen during that time) with IMiD associated at a median of 3 weeks after exposure. Nearly all rashes were morbilliform, and 45% of evaluable rashes were grade 3-4 by NCI-CTCAE criteria. IMiDs were initially held in 33 patients (62%), and 25% received a short course of higher dose steroids. Seventy-nine percent of patients were reexposed to the same IMiD, often with dose reduction, and 57% were switched from weekly dexamethasone to thrice-weekly prednisone. Ninety-three percent of patients reexposed to the same IMiD with these interventions were able to tolerate and continue treatment, and only 14% had rash with reexposure, predominantly grade 1-2.

Serum Free Light Chain Assessment Early After Stem Cell Transplantation as a Prognostic Factor in Multiple Myeloma.

BACKGROUND: Multiple myeloma is an incurable cancer commonly treated with stem cell transplantation (SCT). Response is traditionally evaluated 100 days after SCT, both to allow for hematopoietic reconstitution and due to immunoglobulins' long half-lives. Free light chains (FLC) have significantly shorter half-lives and may provide evidence of response or treatment failure earlier after SCT. PATIENTS AND METHODS: We retrospectively studied 83 consecutive patients with multiple myeloma who underwent SCT and found 69 who had FLC measured 30 or 60 days after SCT. Using conventional FLC response criteria, we considered a patient to be at high risk for early relapse if he or she failed to experience a partial response by day 30 or 60. RESULTS: After a median overall follow-up of only 335 days, these high-risk patients had significantly shorter progression-free survival (median, 98 vs. 335 days, P = .001) and overall survival (366 days vs. median not reached, P = .016). CONCLUSION: Early FLC assessment either 1 or 2 months after SCT using standard FLC response criteria was able to identify a subset of patients at high risk of early relapse, and these patients may benefit from earlier interventions.

Safety and efficacy of triplet regimens in newly diagnosed light chain amyloidosis.

BACKGROUND: The prognosis of patients with systemic light chain (AL) amyloidosis, particularly cardiac, is poor. Treatments have been derived from multiple myeloma, but there are few studies that use triplet regimens in AL amyloidosis because of concern of greater toxicity than seen in myeloma. PATIENTS AND METHODS: We conducted a retrospective review of patients with newly diagnosed AL amyloidosis who were initially treated with a triplet regimen. RESULTS: For the 9 patients included, the median age was 64 years, and 8 were ineligible for stem cell transplantation. At least 2 organs were involved in 4 patients, including 7 with kidney and 4 with heart involvement, 2 of whom had New York Heart Association class 3 heart failure. All the patients received bortezomib, cyclophosphamide or lenalidomide/thalidomide, and dexamethasone. With a median follow-up of 13 months, 8 of 9 patients had a hematologic response, including 2 who achieved complete response, with a median time to response of 2.7 months. An organ response was seen in 7 of 9 patients, including all 4 patients with cardiac involvement. There were no deaths, and only 1 patient had progressive disease. The major toxicity observed was fluid overload and syncope, seen only in patients with heart failure, who eventually achieved a partial or complete response. CONCLUSIONS: Dose-attenuated triplet regimens achieved rapid hematologic responses with manageable and reversible toxicity in patients with newly diagnosed AL amyloidosis.

Gene expression abnormalities and oligodendrocyte deficits in the internal capsule in schizophrenia.

Deficits in the expression of oligodendrocyte (Ol) and myelin genes have been described in numerous brain regions in schizophrenia (SZ) in association with abnormalities of cell cycle markers. We have previously reported a SZ-associated decrease in the expression of genes expressed after, but not prior to, the terminal differentiation of Ols in the posterior limb of the internal capsule (ICp). This pattern of deficits could reflect a failure of Ol precursors to exit the cell cycle and differentiate to meet the demands imposed by the high rate of apoptosis among myelinating Ols. Here we explore this hypothesis using quantitative real time PCR to examine the mRNA expression of additional genes in the ICp of the previously examined sample of 14 subjects with SZ and 15 normal controls (NCs). The genes examined in the present study were chosen because they are associated with particular phases of the cell cycle (CCND1, CCND2, p21(Cip1), p27(Kip1), and p57(Kip2)), with DNA replication and repair (PCNA), apoptosis (CASP3), or the Notch signaling pathway (JAG1, HES1, HES5, andDTX1). The Notch pathway influences whether Ol precursors continue to proliferate or exit the cell cycle. We also determined the densities of Ols in the ICp. Genes associated with maintenance of the cell cycle tended to exhibit increased expression levels in SZ relative to NCs and to be negatively correlated with the expression levels of the previously assessed mature Ol genes. In contrast, genes associated with cell cycle arrest tended to show the opposite pattern (decreased expression in SZ and positive correlations with mature Ol genes). CASP3 and PCNA expression levels were significantly decreased in SZ and positively correlated with mature Ol genes, suggesting that myelinating Ols may turnover more rapidly in normal controls than in subjects with SZ. JAG1 expression was significantly increased in SZ and exhibited positive correlations with mediators of the canonical Notch pathway but negative correlations with mature Ol genes. Ol densities were significantly decreased in SZ. These data are consistent with the hypothesis that Ol and myelin deficits in SZ involve a failure of Ol precursors to appropriately exit the cell cycle in order to differentiate and mature into myelinating Ols.

HIV-1 viral protein r induces ERK and caspase-8-dependent apoptosis in renal tubular epithelial cells.

OBJECTIVE: HIV-associated nephropathy (HIVAN) is the most common cause of end-stage renal disease in persons with HIV/AIDS and is characterized by focal glomerulosclerosis and dysregulated renal tubular epithelial cell (RTEC) proliferation and apoptosis. HIV-1 viral protein r (Vpr) has been implicated in HIV-induced RTEC apoptosis but the mechanisms of Vpr-induced RTEC apoptosis are unknown. The aim of this study was therefore to determine the mechanisms of Vpr-induced apoptosis in RTEC. METHODS: Apoptosis and caspase activation were analyzed in human RTEC (HK2) after transduction with Vpr-expressing and control lentiviral vectors. Bax and BID were inhibited with lentiviral shRNA, and ERK activation was blocked with the MEK1,2 inhibitor, U0126. RESULTS: Vpr induced apoptosis as indicated by caspase 3/7 activation, PARP-1 cleavage and mitochondrial injury. Vpr activated both caspases-8 and 9. Inhibition of Bax reduced Vpr-induced apoptosis, as reported in other cell types. Additionally, Vpr-induced cleavage of BID to tBID and suppression of BID expression prevented Vpr-induced apoptosis. Since sustained ERK activation can activate caspase-8 in some cell types, we studied the role of ERK in Vpr-induced caspase-8 activation. Vpr induced sustained ERK activation in HK2 cells and incubation with U0126 reduced Vpr-induced caspase-8 activation, BID cleavage and apoptosis. We detected phosphorylated ERK in RTEC in HIVAN biopsy specimens by immunohistochemistry. CONCLUSIONS: These studies delineate a novel pathway of Vpr-induced apoptosis in RTEC, which is mediated by sustained ERK activation, resulting in caspase 8-mediated cleavage of BID to tBID, thereby facilitating Bax-mediated mitochondrial injury and apoptosis.

Subcortical oligodendrocyte- and astrocyte-associated gene expression in subjects with schizophrenia, major depression and bipolar disorder.

Deficits in the expression of oligodendrocyte and myelin genes have been described in numerous cortical regions in schizophrenia and affective disorders; however, relatively little attention has been paid to subcortical structures. Here we employed quantitative real time PCR to examine the mRNA expression of 17 genes that are expressed by oligodendrocyte precursors (OLPs) and their derivatives, including astrocytes. Four subcortical regions were examined (the anteroventral (AV) and mediodorsal thalamic nuclei (MDN), internal capsule (IC) and putamen (Put)) in postmortem material from subjects (age 25-68 at time of death) with no known psychiatric history (NCs) as well as in subjects with schizophrenia (SZ), major depressive disorder (MDD), and bipolar disorder (BPD). In all regions examined, genes expressed after the terminal differentiation of oligodendrocytes tended to have lower levels of mRNA expression in subjects with SZ compared to NCs. These differences were statistically significant across regions for four genes (CNP, GALC, MAG and MOG) and approached significance for TF. No genes were under expressed in MDD. Only TF was under expressed in BPD and only in the IC. In contrast, two astrocyte-associated genes (GFAP and ALDH1L1) had higher mean expression levels across regions in all psychiatric groups relative to NCs. These differences reached statistical significance for SZ and MDD relative to NCs. There were no age by diagnosis interactions. The majority of age regressions had negative slopes for the expression of oligodendrocyte-associated genes. GFAP but not ALDH1L1 expression was significantly and positively correlated with age in the MDN, AV and Put. Across subject groups the expression of both astrocyte genes was highly correlated with cumulative neuroleptic exposure in all regions except the Put. Significant positive correlations were also observed in some regions between cumulative neuroleptic exposure and the expression of genes associated with mature oligodendrocytes as well as with bipotential OLPs. Multiple negative correlations were observed between the mRNA expression of astrocyte genes and genes expressed by terminally differentiated oligodendrocytes. These data are discussed in the context of myelin turnover and potential effects of psychiatric illness as well as medications on the developmental fate of OLPs.

Editing of serotonin 2C receptor mRNA in the prefrontal cortex characterizes high-novelty locomotor response behavioral trait.

Serotonin 2C receptor (5-HT(2C)R) exerts a major inhibitory influence on dopamine (DA) neurotransmission within the mesocorticolimbic DA pathway that is implicated in drug reward and goal-directed behaviors. 5-HT(2C)R pre-mRNA undergoes adenosine-to-inosine editing, generating numerous receptor isoforms in brain. As editing influences 5-HT(2C)R activity, individual differences in editing might influence dopaminergic function and, thereby, contribute to interindividual vulnerability to drug addiction. Liability to drug-related behaviors in rats can be predicted by their level of motor activity in response to a novel environment. Rats with a high locomotor response (high responders; HRs) exhibit enhanced acquisition and maintenance of drug self-administration compared to rats with a low response (low responders; LRs). We here examined 5-HT(2C)R mRNA editing and expression in HR and LR phenotypes to investigate the relationship between 5-HT(2C)R function and behavioral traits relevant to drug addiction vulnerability. Three regions of the mesocorticolimbic circuitry (ventral tegmental area (VTA), nucleus accumbens (NuAc) shell, and medial prefrontal cortex (PFC)) were examined. 5-HT(2C)R mRNA expression and editing were significantly higher in the NuAc shell compared with both the PFC and VTA, implying significant differences in function (including constitutive activity) among 5-HT(2C)R neuronal populations within the circuitry. The regional differences in editing could, at least in part, arise from the variations in expression levels of the editing enzyme, ADAR2, and/or from the variations in the ADAR2/ADAR1 ratio observed in the study. No differences in the 5-HT(2C)R expression were detected between the behavioral phenotypes. However, editing was higher in the PFC of HRs vs LRs, implicating this region in the pathophysiology of drug abuse liability.

Redox transformations of bis(2,2'-bipyridine)(1-methyl-1-pyridin-2-yl-ethylamine)ruthenium(II).

The amineruthenium(II) complex Ru(bpy)2(mpea)2+ has been prepared by the direct reaction of 1-methyl-1-pyridin-2-yl-ethylamine (mpea) with Ru(bpy)2Cl2 in ethanol/water and isolated as the hexafluorophosphate salt. Electrochemical analysis of this complex shows that it undergoes sequential one-electron oxidations to an amidoruthenium(III) intermediate (E degrees' = 1.086 V vs NHE) and then to an amidoruthenium(IV) (E degrees' = 0.928 V) or imidoruthenium(IV) (E degrees' = 1.083 V) complex, depending upon the solution pH (pKa = 2.62 for the amidoruthenium(IV) species). At higher potentials ( Epa = 1.5 V in 1.0 M H2SO4), the amido- or imidoruthenium(IV) species is irreversibly oxidized to the corresponding nitrosoruthenium(II) complex. The mechanism for this transformation appears, on the basis of b3lyp/cpcm/cep-31g(d) computations, to proceed through an imidoruthenium(V) intermediate, which is rapidly attacked by water to yield a Ru(II)-bound hydroxylamine radical, which is readily oxidized and deprotonated to produce the nitrosoruthenium(II) complex. The nitrosoruthenium(II) complex is quantitatively reduced to the original [Ru(bpy)2(mpea)]2+ complex at relatively negative potentials ( Epc = -0.2 V in 1.0 M H2SO4).