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Zhongguo Shi Yan Xue Ye Xue Za Zhi Dec 2023To investigate the clinical characteristics, diagnosis, and treatment of one patient with TAFRO syndrome, and to strengthen the understanding of this rare type.
OBJECTIVE
To investigate the clinical characteristics, diagnosis, and treatment of one patient with TAFRO syndrome, and to strengthen the understanding of this rare type.
METHODS
The clinical manifestations, diagnosis and treatment process, and prognosis of the patient admitted in Gansu Provincial People's Hospital were retrospectively analyzed.
RESULTS
Combined with laboratory tests, bone marrow examination, imaging, pathology, etc, the patient was diagnosed with TAFRO syndrome. After three cycles of treatment with pomalidomide (2-3 mg/d, d1-21), cyclophosphamide (300 mg/m, 0.54 g once a week) and dexamethasone (20 mg/d, two days a week), platelet count, serum creatinine and procalcitonin returned to normal, the systemic edema disappeared, and the patient's condition was alleviated. The therapeutic effect was good.
CONCLUSION
TAFRO syndrome is rare, involves multiple systems, progresses rapidly, and has a worse prognosis. The choice of the "Pomalidomide+cyclophosphamide+dexamethasone" regimen is help to improve the survival prognosis of patient with TAFRO syndrome.
Topics: Humans; Thrombocytopenia; Retrospective Studies; Castleman Disease; Dexamethasone; Cyclophosphamide
PubMed: 38071075
DOI: 10.19746/j.cnki.issn.1009-2137.2023.06.042 -
EJHaem Nov 2023Pomalidomide-dexamethasone (Pd) has been a standard care treatment for relapsed and refractory multiple myeloma since 2013. However, the outcomes of Pd after exposure to...
Pomalidomide-dexamethasone (Pd) has been a standard care treatment for relapsed and refractory multiple myeloma since 2013. However, the outcomes of Pd after exposure to CD38 antibodies are not known. Here we describe the real-world use and efficacy of pomalidomide in a Danish, nationwide cohort of daratumumab-exposed patients. We identified 328 patients that were treated with pomalidomide. Of these, 137 received Pd, 65 daratumumab-pomalidomide-dexamethasone (DPd), 43 pomalidomide-cyclophosphamide-dexamethasone (PCd), 19 carfilzomib-pomalidomide-dexamethasone (KPD), 11 pomalidomide-bortezomib-dexamethasone (PVd), and 52 pomalidomide in other combinations. Patients treated with Pd in this cohort had a partial response or better (≥ PR) rate of 35.8% and median time to next treatment (mTNT) of 4.9 months, almost identical to the results of previous prospective clinical trials. Although treatment with the various pomalidomide-containing triplet regimens resulted in higher ≥ PR rates (PCd: 46.5%, PVd: 63.6%, DPd: 55.4%, KPd: 63.2%), the mTNT achieved was not significantly better than with Pd in most cases (PCD: 5.4, PVD: 5.3, DPD: 4.7 months). The exception to this was KPd (mTNT 7.4 months), but this regimen was mainly used earlier in the course of the disease (median time from diagnosis 2.3 years vs. 3.7-4.3 years). The most important predictor of outcomes was not the choice of index regimen ( = 0.72), but prior exposure ( = 0.0116). Compared to CD38 antibody-naïve patients, triple-class-exposed patients achieved reduced ≥ PR rate (38.0% vs. 47.3%), shorter mTNT (4.0 vs. 5.9 months), and shorter median overall survival (12.4 vs. 24.2 months) with pomalidomide treatment.
PubMed: 38024635
DOI: 10.1002/jha2.774 -
EJHaem Nov 2023In this single-center study, we aimed to describe the characteristics, treatment patterns, and outcomes of patients with multiple myeloma (MM) following treatment with...
In this single-center study, we aimed to describe the characteristics, treatment patterns, and outcomes of patients with multiple myeloma (MM) following treatment with bortezomib, carfilzomib, daratumumab, ixazomib, lenalidomide or pomalidomide-based regimens. Data were collected retrospectively from a study cohort of patients receiving a MM treatment in the Hospital District of Helsinki and Uusimaa (HUS) in Finland between 2016-2020. In total, 472 patients were included in the study. Median age was 68.2 years and nearly 25% had a high cytogenetic risk according to the International Myeloma Working Group categorization. In 2018-2020, the spectrum of regimens used as third- or later-line therapy was notably broader than in 2016-2017. The overall response rates for patients who received the most novel regimens (available ≤ 5 years) in second or third line of therapy ( = 67/430) and fourth line or later ( = 78/151) were 53.3% and 25.0%, respectively. In this real-world MM patient cohort, the response rates for these novel agents were lower compared to those reported in clinical trials. Given the higher cytogenetic risk profile and more advanced disease stage at the time when treated with novel agents, patients could have benefited from effective novel therapies earlier in their treatment pathway. What is the NEW aspect of your work? (ONE sentence) This study characterized the treatment of Finnish multiple myeloma patients during the era of most novel therapies (after 2016) and also included information on the cytogenetic risk profile of this real-world population.What is the CENTRAL finding of your work? (ONE sentence) There are clear differences between real-world populations treated with most novel combinations and those of randomized controlled trials (RCTs), which is reflected by the poorer treatment outcomes in the real-world setting.What is (or could be) the SPECIFIC clinical relevance of your work? (ONE sentence) Given the high cytogenetic risk profile and advanced disease stage at the time when treated with novel agents, patients could have benefited from effective novel therapies earlier in their treatment pathway.
PubMed: 38024616
DOI: 10.1002/jha2.802 -
Chemical Communications (Cambridge,... Dec 2023Optimisation of protein degraders requires balancing multiple factors including potency, cell permeability and solubility. Here we show that the fluorescence of...
Optimisation of protein degraders requires balancing multiple factors including potency, cell permeability and solubility. Here we show that the fluorescence of pomalidomide can be used in high-throughput screening assays to rapidly assess cellular penetration of degrader candidates. In addition, this technique can be paired with endocytosis inhibitors to gain insight into potential mechanisms of candidates entering a target cell. A model library of pomalidomide conjugates was synthesised and evaluated using high-throughput fluorescence microscopy. This technique based on intrinsic fluorescence can be used to guide rational design of pomalidomide conjugates without the need for additional labels or tags.
Topics: Thalidomide; Microscopy, Fluorescence
PubMed: 38019727
DOI: 10.1039/d3cc04314b -
Life (Basel, Switzerland) Nov 2023This review discusses immunomodulatory drug (IMiDs) sequencing and IMiD-free interval strategies for lenalidomide-refractory myeloma. IMiDs and proteasome inhibitors... (Review)
Review
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.
PubMed: 38004369
DOI: 10.3390/life13112229 -
European Journal of Medicinal Chemistry Jan 2024Zinc-dependent histone deacetylases (HDACs) play an essential role as epigenetic regulators and are becoming increasingly important drug targets for the treatment of...
Zinc-dependent histone deacetylases (HDACs) play an essential role as epigenetic regulators and are becoming increasingly important drug targets for the treatment of cancer. Although five HDAC inhibitors have been approved for treating several cancers, only one of them is a Class I HDAC inhibitor, which may have advantages over pan-HDAC inhibitors due to the various side effects associated with the latter. On the other hand, the emerging strategy of molecular glue degraders offers a unique advantage for targeting therapeutic proteins. In this study, we synthesized a series of candidate compounds based on the molecule glue, pomalidomide, using a "merger principle", initially aiming to obtain molecular glue degraders that can target HDAC degradation. However, we serendipitously discovered that compounds 2f and 3f may be potent Class I HDAC selective inhibitors. After further evaluation, we found that compounds 2f and 3f exhibit selective inhibitory effects on Class I HDAC in cancer cells. Moreover, they showed the robust antiproliferative activities against various hematological tumor cells, comparable to that of the approved Class I HDAC inhibitor, Chidamide. These results suggest that pomalidomide-derivatized compounds have promising potential as Class I HDAC inhibitors with therapeutic applications in cancer treatment.
Topics: Humans; Histone Deacetylase Inhibitors; Neoplasms; Thalidomide
PubMed: 37995564
DOI: 10.1016/j.ejmech.2023.115926 -
Current Drug Safety Nov 2023Drugs are related with various adverse drug reactions (ADRs), however, many unexpected ADRs of drugs are reported through post-marketing surveillance.
BACKGROUND
Drugs are related with various adverse drug reactions (ADRs), however, many unexpected ADRs of drugs are reported through post-marketing surveillance.
AIM
The current study's goal is to uncover potential signals connected with FDA-approved medications in the United States (2013).
METHODOLOGY
Open Vigil 2.1-MedDRA-v24 (data 20004Q1-2021Q3) was used as a tool to query the FAERS data. To find possible signals, disproportionality measures such as Proportional Reporting Ratio (PRR 2) with associated Chi-square value, Reporting Odds Ratio (ROR 2) with 95% confidence interval, and case count (3) were calculated.
RESULTS
A total of eight potential signals were identified with five drugs. Positive signals were found with pomalidomide, canagliflozin, dolutegravir sodium, macitentan and ibrutinib.
CONCLUSION
However, further causality assessment is required to confirm the association of these drugs with identified potential signals.
PubMed: 37990902
DOI: 10.2174/0115748863276447231108092936 -
European Journal of Haematology Mar 2024Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS), but not...
Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS), but not overall survival (OS), versus pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma in the OCEAN study. Time to progression (TTP) <36 months after a prior autologous stem cell transplantation (ASCT) was a negative prognostic factor for OS with melflufen. This post hoc exploratory analysis evaluated patients refractory to prior alkylators (e.g., cyclophosphamide and melphalan) in OCEAN. In 153 patients refractory to prior alkylators (melflufen, n = 78; pomalidomide, n = 75), the melflufen and pomalidomide arms had similar median PFS (5.6 months [95% CI, 4.2-8.3] vs. 4.7 months [95% CI, 3.1-7.3]; hazard ratio [HR], 0.92 [95% CI, 0.63-1.33]) and OS (23.4 months [95% CI, 14.4-31.7] vs. 20.0 months [95% CI, 12.0-28.7]; HR, 0.92 [95% CI, 0.62-1.38]). Among alkylator-refractory patients with a TTP ≥ 36 months after a prior ASCT or no prior ASCT (melflufen, n = 54; pomalidomide, n = 53), the observed median PFS and OS were longer in the melflufen arm than the pomalidomide arm. The safety profile of melflufen was consistent with previous reports. These results suggest that melflufen is safe and effective in patients with alkylator-refractory disease, suggesting differentiated activity from other alkylators.
Topics: Humans; Multiple Myeloma; Melphalan; Alkylating Agents; Hematopoietic Stem Cell Transplantation; Dexamethasone; Transplantation, Autologous; Antineoplastic Combined Chemotherapy Protocols; Phenylalanine; Thalidomide
PubMed: 37968873
DOI: 10.1111/ejh.14127 -
Frontiers in Oncology 2023Pegylated granulocyte colony-stimulating factor (G-CSF) has been widely used for preventing febrile neutropenia in various types of cancer treatment. In the present...
Open-labeled, multicenter phase II study of prophylactic administration of pegylated granulocyte colony-stimulating factor in relapsed or refractory multiple myeloma who received pomalidomide-based regimens (KMM170).
INTRODUCTION
Pegylated granulocyte colony-stimulating factor (G-CSF) has been widely used for preventing febrile neutropenia in various types of cancer treatment. In the present study, we prospectively evaluated the safety and efficacy of pegfilgrastim as a primary prophylaxis of febrile neutropenia and infection among patients with relapsed refractory multiple myeloma (RRMM) treated with pomalidomide-based regimens.
METHODS
Thirty-three patients with RRMM who received pomalidomide and dexamethasone (Pd) with or without cyclophosphamide (PCd) were enrolled in this study. Twenty-eight patients were treated with PCd and 5 patients were treated with Pd. All patients were given pegfilgrastim subcutaneously with a single administration performed on the first day of each cycle as primary prophylaxis until the fourth cycle.
RESULTS
The median age of the patients was 75 (range 56-85), and the median prior line of therapy was 2 (range 2-6). Seventeen patients (51.5%) had any grade of neutropenia and 20 (60.6%) had any grade of thrombocytopenia before starting pomalidomide treatment. During the 4 cycles of treatment, grade 3 or more neutropenia occurred in 17 patients (51.5%), and 4 (12.1%) experienced grade 3 or more febrile neutropenia. Grade 3 or more infections occurred in 5 patients (15.2%). Interestingly, the patients with markedly increased ANC of more than 2 x 109/L compared to baseline ANC after 7 days of pegfilgrastim at 1st cycle of treatment showed a significantly lower incidence of grade 3-4 neutropenia. The most common adverse event of pegfilgrastim was fatigue, and all the adverse events caused by pegfilgrastim were grade 1 or 2. And there was no significant change in the immune cell population and cytokines during the administration of pegfilgrastim.
DISCUSSION
Considering that this study included elderly patients with baseline neutropenia, pegylated G-CSF could be helpful to prevent severe neutropenia, febrile neutropenia, or infection in patients with RRMM.
PubMed: 37965454
DOI: 10.3389/fonc.2023.1209110