Despite the development of anti-myeloma therapeutics, such as proteasome inhibitors, immunomodulatory drugs, anti-CD38 monoclonal antibodies, and autologous stem cell transplantation (ASCT), multiple ...myeloma remains incurable. A trial treatment combining four drugs-daratumumab, carfilzomib, lenalidomide, and dexamethasone-followed by ASCT frequently results in minimal residual disease (MRD) negativity and prevents progressive disease in patients with standard- and high-risk cytogenetics; however, it is insufficient to overcome the poor outcomes in patients with ultra-high-risk chromosomal aberration (UHRCA). In fact, MRD status in autografts can predict clinical outcomes after ASCT. Therefore, the current treatment strategy might be insufficient to overcome the negative impact of UHRCA in patients with MRD positivity after the four-drug induction therapy. High-risk myeloma cells lead to poor clinical outcomes not only by aggressive myeloma behavior but also via the generation of a poor bone marrow microenvironment. Meanwhile, the immune microenvironment effectively suppresses myeloma cells with a low frequency of high-risk cytogenetic abnormalities in early-stage myeloma compared to late-stage myeloma. Therefore, early intervention might be key to improving clinical outcomes in myeloma patients. The purpose of this review is to improve clinical outcomes in patients with UHRCA by considering MRD assessment results and improvement of the microenvironment.
This review discusses immunomodulatory drug (IMiDs) sequencing and IMiD-free interval strategies for lenalidomide-refractory myeloma. IMiDs and proteasome inhibitors (PIs) improve clinical outcomes ...in patients with myeloma; however, refractoriness to lenalidomide, a category of IMiD, predicts poor outcomes. Next-generation IMiDs, such as pomalidomide, are effective even for lenalidomide-refractory myeloma. Therefore, an IMiD-sequencing strategy from lenalidomide to pomalidomide would be desirable. PIs are an antimyeloma therapeutic agent with another mode of action that might restore cereblon, a target of IMiDs; therefore, an IMiD-free interval via class switching from lenalidomide to PIs may be a promising alternative for lenalidomide-refractory myeloma. Additionally, the anti-CD38 monoclonal antibody is a key drug for salvage therapy in anti-CD38 monoclonal antibody-naïve patients. In clinical practice, safety profiles and social convenience can play important roles in the choice of combination therapy. In the future, the selection of optimal treatments should be based on the status of the immunological environment and genetic alterations. This review aims to discuss IMiDs sequencing and IMiD-free interval strategies for lenalidomide- refractory myeloma.
Multiple myeloma is an uncurable hematological malignancy because of obtained drug resistance. Microenvironment and clonal evolution induce myeloma cells to develop de novo and acquired drug ...resistance, respectively. Cell adhesion-mediated drug resistance, which is induced by the interaction between myeloma and bone marrow stromal cells, and soluble factor-mediated drug resistance, which is induced by cytokines and growth factors, are two types of de novo drug resistance. The microenvironment, including conditions such as hypoxia, vascular and endosteal niches, contributes toward de novo drug resistance. Clonal evolution was associated with acquired drug resistance and classified as branching, linear, and neutral evolutions. The branching evolution is dependent on the microenvironment and escape of immunological surveillance while the linear and neutral evolution is independent of the microenvironment and associated with aggressive recurrence and poor prognosis. Proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibody agents (MoAbs), and autologous stem cell transplantation (ASCT) have improved prognosis of myeloma via improvement of the microenvironment. The initial treatment plays the most important role considering de novo and acquired drug resistance and should contain PIs, IMIDs, MoAb and ASCT. This review summarizes the role of anti-myeloma agents for microenvironment and clonal evolution and treatment strategies to overcome drug resistance.
Remarkable advancements have been made in the treatment outcomes of multiple myeloma (MM) patients; however, for frail elderly patients, these treatment outcomes are still insufficient. Elderly MM ...patients are increasing, as are their treatment regimens. There is a heightened demand to assess these patients in order to provide optimized treatments. While continuous treatment is more common for MM patients when compared to fixed-duration treatment, due to the risk of treatment interruption causing reduced survival rates, effectiveness and safety are essential. Treatment goals vary for each patient, but must preserve their quality of life (QOL). When planning treatments for these patients, frailty evaluation is increasingly emphasized as a stratification factor which helps develop accurate screening tools. Daratumumab (DARA) therapy, used globally, is not only effective in frail elderly MM patients, but also has QOL benefits. Proficiency in utilizing DARA regimens is potentially advantageous for patients not included in clinical trials, and innovative usage can further broaden its scope. The development of tools to accurately assess frailty and the establishment of optimal treatments for frail elderly MM patients are imperative. This review is an overview, challenging the frailty assessments for MM patients, re-examining the evidence for DARA regimens in frail elderly MM patients, and discussing potential areas for improvement.
Improving the immunological environment and eradicating minimal residual disease (MRD) are the two main treatment goals for long-term survival in patients with multiple myeloma (MM). Immunomodulatory ...drugs (IMiDs), monoclonal antibody drugs (MoAbs), and autologous grafts for autologous stem cell transplantation (ASCT) can improve the immunological microenvironment. ASCT, MoAbs, and proteasome inhibitors (PIs) may be important for the achievement of MRD negativity. An improved immunological environment may be useful for maintaining MRD negativity, although the specific treatment for persistent MRD negativity is unknown. However, whether the ongoing treatment should be continued or changed if the MRD status remains positive is controversial. In this case, genetic, immunophenotypic, and clinical analysis of residual myeloma cells may be necessary to select the effective treatment for the residual myeloma cells. The purpose of this review is to discuss the MM treatment strategy to “cure MM” based on currently available therapies, including IMiDs, PIs, MoAbs, and ASCT, and expected immunotherapies, such as chimeric antigen receptor T cell (CAR-T) therapy, via improvement of the immunological environment and maintenance of MRD negativity.
Background
Heart failure (HF) prevalence increases with age, and sarcopenia is a poor prognostic factor in patients with HF. We aimed to evaluate the characteristics and prognostic factors in ...patients with HF and sarcopenia.
Results
We retrospectively reviewed 256 consecutive patients admitted to our hospital for HF between May 2018 and May 2021, underwent dual-energy X-ray absorptiometry, and were diagnosed with sarcopenia. The primary endpoint was all-cause mortality. The prognoses and characteristics were evaluated and compared between patients with left ventricular ejection fraction (LVEF) < 50% (reduced LVEF, HF with reduced ejection fraction HFrEF) and those with LVEF ≥ 50% (preserved LVEF, HF with preserved ejection fraction HFpEF). 83 (32%) and 173 (68%) patients had HFrEF and HFpEF, respectively. The HFrEF group had fewer women, lower hypertension rates, higher ischemic heart disease rates, and brain natriuretic peptide (BNP) levels than did the HFpEF group. Kaplan–Meier analysis for all-cause death showed that the HFrEF group had a significantly worse prognosis than the HFpEF group log-rank
p
= 0.002.
Conclusions
In patients with HF and sarcopenia, older age, higher New York Heart Association (NYHA) class, BNP levels, and reduced LVEF were independent predictors of death after evaluation. During the treatment of patients with HF and sarcopenia, it is necessary to manage treatment with close attention to BNP and LVEF.
A 48-year-old woman with polyneuropathy, organomegaly, endocrinopathy, M-protein, skin change (POEMS) syndrome suddenly presented with numbness of her right upper limb. Magnetic resonance imaging ...showed multiple acute infarctions in her left cerebrum, and magnetic resonance angiography (MRA) showed multiple intra-cranial vascular lesions, which contrasted with previously normal MRA results obtained eight months prior to the stroke. After completing successful treatment for POEMS syndrome, there were no recurrent stroke episodes. A six-month follow-up scan showed that although the vascular lesions did not progress, they did not improve much either. POEMS syndrome is associated with the rapid extension of large blood vessels-vasculopathy-resulting in nearly irreversible brain lesions.
New drugs for multiple myeloma (MM) have dramatically improved patients’ overall survival (OS). Autologous stem cell transplantation (ASCT) remains the mainstay for transplant‐eligible MM patients. ...To investigate whether the post‐ASCT prognosis of MM patients has been improved by new drugs, we undertook a retrospective observational analysis using the Transplant Registry Unified Management Program database in Japan. We analyzed 7323 patients (4135 men and 3188 women; median age, 59 years; range 16‐77 years) who underwent upfront ASCT between January 2007 and December 2018. We categorized them by when they underwent ASCT according to the drugs’ introduction in Japan: group 1 (2007‐2010), group 2 (2011‐2016), and group 3 (2017‐2018). We compared the groups’ post‐ASCT OS. The 2‐year OS rates (95% confidence interval CI) of groups 1, 2, and 3 were 85.8% (84.1%‐87.4%), 89.1% (88.0%‐90.1%), and 92.3% (90.0%‐94.2%) (P < .0001) and the 5‐year OS (95% CI) rates were 64.9% (62.4%‐67.3%), 71.6% (69.7%‐73.3%), and not applicable, respectively (P < .0001). A multivariate analysis showed that the post‐ASCT OS was superior with these factors: age less than 65 years, performance status 0/1, low International Staging System (ISS) stage, receiving SCT for 180 days or less post‐diagnosis, better treatment response pre‐ASCT, later year of ASCT, and receiving SCT twice. A subgroup analysis showed poor prognoses for the patients with unfavorable karyotype and poor treatment response post‐ASCT. The post‐ASCT OS has thus improved over time (group 1 < 2 < 3) with the introduction of new drugs for MM. As the prognosis of high‐risk‐karyotype patients with ISS stage III remains poor, their treatment requires improvement.
The overall survival of patients with multiple myeloma (MM) after autologous stem cell transplantation has improved over time along with the introduction of new drugs for the treatment of MM.
Minimal residual disease (MRD) is a surrogate marker for survival in multiple myeloma (MM), while the lymphocyte-to-monocyte ratio (LMR) is a prognostic factor associated with the patients’ ...immunological status. We retrospectively evaluated the clinical impact of MRD negativity and LMR. MRD was analyzed by multicolor flowcytometry (threshold, 1 × 10–5). Fifty-eight patients (median age 70 years) who achieved complete response were included in this study. Twenty-two patients received autologous stem cell transplantation, 14 received daratumumab-based chemotherapy, and 22 received another treatment. Forty-one (70.7%) patients achieved MRD negativity. Over the median follow-up time of 15.1 months, PFS in MRD-negative patients was significantly longer than in MRD-positive patients (
P
= 0.020). In addition, a high LMR at MRD assessment was associated with MRD negativity (
P
= 0.019) and long PFS (
P
= 0.009). Finally, neither MRD negativity nor high LMR at MRD assessment was associated with significantly shorter PFS compared with MRD positivity or low LMR (
P
= 0.002). In conclusion, high LMR was associated with MRD negativity and can be used as a predictor of long PFS. Change of treatment strategy might be essential for patients with MRD positivity and high LMR at MRD assessment due to their short PFS.
Assembly and installation of the Belle II TOP detector Suzuki, Kazuhito
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
12/2017, Letnik:
876
Journal Article
Recenzirano
The Time-of-Propagation (TOP) detector is a new type of ring-imaging Cherenkov detector developed for particle identification in the barrel region of the Belle II spectrometer. In the assembly and ...installation, it is crucial for the detector performance to achieve precision alignment and secure gluing of the optical components as well as to mechanically support them managing the stress, attitude, optical and electrical contacts, and limited installation space. Various efforts were made to develop the procedures and jigs along with the development of the mechanical structure. Such efforts accomplished the assembly and installation in April and May 2016, respectively, without a significant incident.
•A new type of ring-imaging Cherenkov detector has been implemented.•Sixteen detector modules were assembled and installed without a significant incident.•Precision alignment and secure gluing of the optical components were accomplished.•A flexible scheme of the optical and electrical contacts was realized.•Mechanical stress on the optical components were managed well.
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