Approximately 4%-7% of patients diagnosed with pancreatic adenocarcinoma (PDAC) are found to harbor deleterious germline mutations in BRCA1 and/or BRCA2. Loss of function of BRCA1 and/or BRCA2 results in deficiency in ho...Approximately 4%-7% of patients diagnosed with pancreatic adenocarcinoma (PDAC) are found to harbor deleterious germline mutations in BRCA1 and/or BRCA2. Loss of function of BRCA1 and/or BRCA2 results in deficiency in homologous recombination repair (HRR), a critical DNA repair pathway, and confers sensitivity to certain DNA damaging agents, including platinum chemotherapy and PARP inhibitors. The PARP inhibitor olaparib is food and drug administration (FDA) approved for use in pancreatic cancer based on the POLO trial, which found that maintenance olaparib significantly prolonged progression free survival compared to placebo among patients with germline BRCA1 or BRCA2 mutations and metastatic PDAC that had not progressed following frontline platinum-based chemotherapy. Recently, there has been considerable interest in identifying patients without BRCA inactivation whose tumors also exhibit properties of HRR deficiency and thus may be susceptible to therapies with proven benefit in cancers harboring BRCA mutations. Here, we discuss methods for identification of HRR-deficiency and review the management of HRR-deficient cancers with a focus on HRR-deficient PDAC.
Shain J, Michel A, May MS
… +7 more, Qunaj L, El-Sadr W, Chung WK, Appelbaum PS, Jacobson JS, Justman J, Neugut AI
Semin Oncol
· 2023 Dec · PMID 38171987
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Full text
BACKGROUND: Cancer represents a leading cause of death worldwide. Germline mutations in several genes increase the risk of developing several cancers, including cancers of the breast, ovary, pancreas, colorectum, and mel...BACKGROUND: Cancer represents a leading cause of death worldwide. Germline mutations in several genes increase the risk of developing several cancers, including cancers of the breast, ovary, pancreas, colorectum, and melanoma. An understanding of the population prevalence of pathogenic germline variants can be helpful in the design of public health interventions, such as genetic testing, which has downstream implications for cancer screening, prevention, and treatment. While population-based studies of pathogenic germline variants exist, most such studies have been conducted in White populations. Limited data exist regarding the prevalence of germline mutations within sub-Saharan African populations. MATERIALS AND METHODS: We identified countries defined as sub-Saharan Africa by the World Bank and conducted a scoping literature review using PubMed. For each country, we identified and summarized studies that focused on the prevalence of germline genetic mutations with sample sizes >10 and in a population directly from sub-Saharan Africa, either with or without diseases associated with the relevant genetic mutations. Studies that evaluated the prevalence of somatic or likely benign variants were excluded. RESULTS: Within the 48 countries in sub-Saharan Africa, we identified 34 studies which meet the inclusion criteria. Twenty studies were conducted in South Africa, Nigeria, or Burkina Faso; four countries had more than two published papers. We found that 33 of 48 countries in sub-Saharan Africa lacked any genetic studies. Notably, there has been an increase in relevant studies starting in 2020. Importantly, of the 34 studies identified, 29 included data on BRCA1 or BRCA2. Data on the prevalence of mutations contributing to familial cancer syndromes other than BRCA1 and BRCA2 was limited. CONCLUSIONS: While some progress has been made towards understanding the prevalence of germline mutations in cancer susceptibility genes, the characterization of genetic mutations among sub-Saharan African populations remains strikingly incomplete. Given the genetic diversity in the region, there remains a great need for large-scale, population-based studies to understand the prevalence of germline pathogenic variants and adequately capture all the subpopulations in this part of the world.
Martella S, Lucas M, Porcu M
… +12 more, Perra L, Denaro N, Pretta A, Deias G, Willard-Gallo K, Parra HS, Saba L, Scartozzi M, Wekking D, Kok M, Aiello MM, Solinas C
Immune checkpoint inhibitors (ICI) have become a cornerstone in medical oncology, with evolving therapeutic strategies and applications. These monoclonal antibodies, designed to enhance immune responses, have revealed a...Immune checkpoint inhibitors (ICI) have become a cornerstone in medical oncology, with evolving therapeutic strategies and applications. These monoclonal antibodies, designed to enhance immune responses, have revealed a spectrum of immune-related adverse events (irAEs). While many irAEs exhibit favorable responses to corticosteroid or immunosuppressive therapy, most ICI-related endocrinopathies necessitate lifelong replacement therapy and pose significant clinical challenges. Adrenal insufficiency (AI), a noteworthy endocrine irAE, can manifest as primary AI (PAI) or secondary AI (SAI), resulting from adrenal or pituitary gland dysfunction, respectively. ICI-induced AI, albeit relatively infrequent, occurs in 1-2% of patients receiving single-agent anti-Programmed Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) or Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) therapies and in a higher range of 4-9% when ICIs are used in combinations. Recognizing and addressing ICI-induced PAI is crucial, as it often presents with acute and potentially life-threatening symptoms, especially considering the expanding use of ICI therapy. This review provides an updated overview of ICI-induced PAI, exploring its clinical, diagnostic, and radiological aspects.
INTRODUCTION: Squamous cell carcinoma of the anus (SCCA) is a rare tumor. While most patients with locally advanced disease are cured with chemo-radiotherapy, about a quarter eventually experience metastatic recurrence....INTRODUCTION: Squamous cell carcinoma of the anus (SCCA) is a rare tumor. While most patients with locally advanced disease are cured with chemo-radiotherapy, about a quarter eventually experience metastatic recurrence. Standard treatment for advanced disease is chemotherapy, but recently evidence on the activity of immunotherapy has been reported. We performed a systematic review and meta-analysis of prospective trials testing immune-checkpoint inhibitors (ICIs) in patients with SCCA. OBJECTIVE: We aimed to evaluate the overall response rate (ORR) and the disease control rate (DCR) of ICIs in patients with advanced SCCA. METHODS: We systematically searched PubMed, Embase, and Scopus, through December 31, 2022, for prospective trials assessing ICIs in patients with advanced SCCA. The primary and secondary endpoints were respectively ORR and DCR. RESULTS: Six prospective trials were included in the analysis, one of which was randomized. Overall, seven treatment arms and 347 patients have been analyzed. Five treatment arms tested ICIs as monotherapy and two arms examined ICIs in combination with cetuximab and bevacizumab, respectively. The pooled ORR was 13% (95%CI, 10%-17%), with a DCR of 57% (95%CI, 40%-74%). Results did not change in a sensitivity analysis, which excluded the two treatment arms testing the combination of ICIs with other drugs. CONCLUSIONS: The efficacy of ICIs in SCCAs is low. Combination strategies with targeted drugs or chemotherapy might represent a better therapeutic strategy for these patients. Further studies are awaited to identify resistance mechanisms to ICIs and optimize their efficacy.
PURPOSE: Opioid-induced constipation (OIC) is a common adverse effect of opioid therapy. We aim to identify the main barriers hindering clinical recommendations implementation and propose consensus solutions to improve O...PURPOSE: Opioid-induced constipation (OIC) is a common adverse effect of opioid therapy. We aim to identify the main barriers hindering clinical recommendations implementation and propose consensus solutions to improve OIC control in cancer patients. METHODS: Following collaborative and prioritization techniques, a scientific committee generated statements addressing possible barriers to optimal OIC management (related to patients, health providers and health care system), and potential interventions to overcome these barriers. An expert panel of 36 oncologists assessed the statements to reach a consensus. RESULTS: The survey consisted of 70 statements. Consensus was reached on 12/45 items related to barriers (26.6%) and on 19/25 items about corrective interventions (76%). The panel considered that patients are unaware of the existence of a specific OIC treatment, and their information sources are highly variable and unreliable. Regarding health providers, the panel considered that the oncologists prioritize symptoms such as diarrhea, pain, anxiety, or other treatment toxicities, over constipation. Work overload and bureaucratic requirements were the main barriers related to health care system. Regarding potential interventions, best-rated proposals included specific training programs development for primary care physicians and nurses, and multiplatform informative resources development for patients and caregivers, including precisely written instructions about OIC recognition and management. Oncologists assessed positively measures aiming to improve coordination between primary care physicians and oncologists, and nursing consultations implementation. The panel considered useful the OIC treatment algorithms simplification. CONCLUSIONS: The expert panel identified the main barriers to optimal OIC management and suggested some feasible approaches to overcome these barriers.
PARP inhibitors have emerged as a promising class of anticancer agents approved for the treatment of ovarian, breast, prostate, and pancreatic cancer. These inhibitors target PARP enzymes involved in DNA repair pathways...PARP inhibitors have emerged as a promising class of anticancer agents approved for the treatment of ovarian, breast, prostate, and pancreatic cancer. These inhibitors target PARP enzymes involved in DNA repair pathways and exhibit remarkable efficacy in cancers with genetic deficiencies in the homologous recombination pathway responsible for mending DNA double-strand breaks. While all PARP inhibitors demonstrate potent and selective inhibition of PARP1 and PARP2, the key enzymes involved in DNA repair, each agent within the class possesses unique pharmacological profiles distinguishing them from one another. This review aims to comprehensively examine the properties of the entire PARP inhibitor class while emphasizing individual pharmacologic and pharmacokinetic distinctions that inform clinical recommendations. Currently, four agents, namely olaparib, rucaparib, niraparib, and talazoparib, have obtained approval in the United States and Europe. Olaparib, the first approved PARP inhibitor, has been extensively studied and is indicated for a wider range of cancer types. Niraparib and talazoparib, the more recent additions to the PARP inhibitor class, possess the longest half-lives and are formulated for convenient once-daily dosing, alleviating the pill burden for patients when compared to older agents. Moreover, talazoparib undergoes minimal hepatic metabolism, reducing the potential for drug-drug interactions. Notably, niraparib is the sole PARP inhibitor recommended for dose reduction in hepatically impaired populations, whereas talazoparib and olaparib should be dose reduced in renally impaired populations. The mechanisms underlying these dose adjustment recommendations are further explored in this review. Additionally, this review briefly covers veliparib, a PARP inhibitor under development, and two recently approved PARP inhibitors in China, fuzuloparib and pamiparib. Although significant progress has been made in understanding PARP inhibitors, there are several unanswered questions that remain, necessitating further research across a broader spectrum of cancer types within this evolving class of anticancer agents.
Poly(ADP-ribose) polymerase (PARP) inhibitors have transformed the treatment landscape for patients with metastatic castration-resistant prostate cancer (mCRPC) and alterations in DNA damage response genes. This has also...Poly(ADP-ribose) polymerase (PARP) inhibitors have transformed the treatment landscape for patients with metastatic castration-resistant prostate cancer (mCRPC) and alterations in DNA damage response genes. This has also led to widespread use of genomic testing in all patients with mCRPC. The current review will give an overview of (1) the current understanding of the interplay between DNA damage response and PARP enzymes; (2) the clinical landscape of PARP inhibitors, including the combination of PARP inhibitors with other agents such as androgen-receptor signaling agents; (3) biomarkers related to PARP inhibitor response and resistance; and (4) considerations for interpreting genomic testing results and treating patients with PARP inhibitors.
PURPOSE: About 50%-90% of patients with brain metastases who receive radiation therapy experience cognitive impairment. This systematic review aims to gather credible sources of comprehensive information on the efficacy...PURPOSE: About 50%-90% of patients with brain metastases who receive radiation therapy experience cognitive impairment. This systematic review aims to gather credible sources of comprehensive information on the efficacy of memantine in preventing cognitive dysfunction. METHODS: A comprehensive review conducted in compliance with the PRISMA statement and systematic search was performed across five databases included PubMed, Embase, Scopus, Cochrane Library, and ClinicalTrial.gov.in from inception until November 2021. RESULTS: A total of four eligible studies were selected in this review that included 1,444 patients with brain metastases who received radiation therapy (Intervention group [n = 729] and control group [n = 715]). Overall, three of the four studies reported some improvement in neurocognitive function in at least one or more parameters such as recall and recognition (P = .39, P = .10 and P = .05), verbal fluency (P = .03 and P < .0001), complex attention (P = .59) executive function (P = .92) and normal appearing white matter (P = .01) following memantine therapy compared to control group. Further, two of the four studies reported an improvement in the patients' quality of life following memantine therapy compared to the control group, and there was no significant difference in the toxicity profile of the interventional compared to the control group as reported from two studies. CONCLUSION: This review embraces the comprehensive evidence that the use of memantine therapy in patients with brain metastases to prevent radiation-induced neurocognitive dysfunction has a modest and statistically significant beneficial impact in improving quality of life and preserving some neurocognitive function without any complications. Pending the completion of additional ongoing studies, one can argue that memantine is a reasonable treatment to consider in patients with brain metastases while they receive whole brain radiation therapy.
During the course of lung cancer progression, bone metastases occur in about 40% of patients. Common complications associated with bone metastases in lung cancer patients include musculoskeletal pain, pathologic fracture...During the course of lung cancer progression, bone metastases occur in about 40% of patients. Common complications associated with bone metastases in lung cancer patients include musculoskeletal pain, pathologic fractures, spinal cord compression, and hypercalcemia. We discuss the efficacy of bone-modifying agents (BMAs) in reducing skeletal-related events (SREs) and improving cancer-related outcomes, particularly in patients with stage IV non-small-cell lung cancer with bone metastases. In addition, the combined effects of BMAs with radiotherapy or immunotherapy in reducing SREs in patients with lung cancer and bone metastases are explored.
For many decades, extended pelvic lymph node dissection has been an integral part during radical cystectomy for patients with muscle invasive bladder cancer. This practice was based on large retrospective meta-analyses s...For many decades, extended pelvic lymph node dissection has been an integral part during radical cystectomy for patients with muscle invasive bladder cancer. This practice was based on large retrospective meta-analyses suggesting an oncologic benefit to an extended dissection. This mini review and meta-analysis includes the two available randomized trials in the current literature. Therefore, it can be considered as the strongest level of evidence regarding the prognostic benefit of an extended pelvic lymphadenectomy. Based on current randomized data, standard pelvic lymph node dissection up to the level of iliac bifurcation is sufficient, and extension of the dissection above this level does not provide any additional oncologic benefit.
Genome integrity is under constant insult from endogenous and exogenous sources. In order to cope, eukaryotic cells have evolved an elaborate network of DNA repair that can deal with diverse lesion types and exhibits con...Genome integrity is under constant insult from endogenous and exogenous sources. In order to cope, eukaryotic cells have evolved an elaborate network of DNA repair that can deal with diverse lesion types and exhibits considerable functional redundancy. PARP1 is a major sensor of DNA breaks with established and putative roles in a number of pathways within the DNA repair network, including repair of single- and double-strand breaks as well as protection of the DNA replication fork. Importantly, PARP1 is the major target of small-molecule PARP inhibitors (PARPi), which are employed in the treatment of homologous recombination (HR)-deficient tumors, as the latter are particularly susceptible to the accumulation of DNA damage due to an inability to efficiently repair highly toxic double-strand DNA breaks. The clinical success of PARPi has fostered extensive research into PARP biology, which has shed light on the involvement of PARP1 in various genomic transactions. A major goal within the field has been to understand the relationship between catalytic inhibition and PARP1 trapping. The specific consequences of inhibition and trapping on genomic stability as a basis for the cytotoxicity of PARP inhibitors remain a matter of debate. Finally, PARP inhibition is increasingly recognized for its capacity to elicit/modulate anti-tumor immunity. The clinical potential of PARP inhibition is, however, hindered by the development of resistance. Hence, extensive efforts are invested in identifying factors that promote resistance or sensitize cells to PARPi. The current review provides a summary of advances in our understanding of PARP1 biology, the mechanistic nature, and molecular consequences of PARP inhibition, as well as the mechanisms that give rise to PARPi resistance.
Endocrine therapy (ET) targeting estrogen receptor (ER) signaling is still the mainstay treatment option for early or advanced ER-positive breast cancer (BC) and may involve suppressing estrogen production by means of ar...Endocrine therapy (ET) targeting estrogen receptor (ER) signaling is still the mainstay treatment option for early or advanced ER-positive breast cancer (BC) and may involve suppressing estrogen production by means of aromatase inhibitors or directly blocking the ER pathway through selective estrogen receptor modulators such as tamoxifen or selective estrogen receptor degraders such as fulvestrant. However, despite the availability of this armamentarium in clinical practice, de novo or acquired resistance to ET is the main cause of endocrine-based treatment failure leading to the progression of the BC. Recent advances in targeting, modulating, and degrading ERs have led to the development of new drugs capable of overcoming intrinsic or acquired ET resistance related to alterations in the ESR1 gene. The new oral selective estrogen receptor degraders, which are capable of reducing ER protein expression and blocking estrogen-dependent and -independent ER signaling, have a broader spectrum of activity against ESR1 mutations and seem to be a promising means of overcoming the failure of standard ET. The aim of this review is to summarize the development of oral selective estrogen receptor degraders, their current status, and their future perspectives.
Anti-cancer treatment is considered an independent risk factor for emergent bleeding during anticoagulant treatment in patients with cancer-associated thrombosis. This increased bleeding risk is perceived as major concer...Anti-cancer treatment is considered an independent risk factor for emergent bleeding during anticoagulant treatment in patients with cancer-associated thrombosis. This increased bleeding risk is perceived as major concern particularly when tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial derived growth factor receptor (VEGFR-TKIs) are co-administered with anticoagulants. We evaluated the effects of the combined administration of a VEGF-TKI and the oral direct anticoagulant (apixaban) or the low-molecular weight-heparin dalteparin in a sub-analysis of the Caravaggio study in patients with a diagnosis of cancer patients with venous thromboembolism. The rate of major bleeding was 4.2% in the 668 patients who received any type of anti-cancer treatment and 3.5% in the 487 patients who did not receive any anti-cancer treatment. The relative risk for patients treated with a VEGF-TKI was 1.58 (95% CI: 0.69-3.68), compared to patients treated with anticancer agents other than a VEGF-TKI and 1.73 (95% CI: 0.73-4.07) compared to patients who did not receive any anticancer treatment. The administration of a VGEF-TKI did not have any impact on the recurrence rate of venous thromboembolism. We observed a numerically not statistically significant increase in major bleeding events in patients on concurrent VEGF-TKI and therapeutic anticoagulation with no excess in those who received apixaban. Further prospective well-designed studies are needed to evaluate whether the concomitant administration of VGEF-TKI and anticoagulant agents may result in an increase of bleeding in patients with a diagnosis of cancer treated for venous thromboembolism.
BACKGROUND: Classic Hodgkin lymphoma (cHL) is a highly-curable disease. However, relapses after bone marrow transplant are challenging especially relapses after allogeneic transplant. METHODS: A retrospective chart revie...BACKGROUND: Classic Hodgkin lymphoma (cHL) is a highly-curable disease. However, relapses after bone marrow transplant are challenging especially relapses after allogeneic transplant. METHODS: A retrospective chart review of the institution transplant database to summarize the safety and efficacy of checkpoint inhibitors (CPIs) use for cHL relapses postallo-HCT in patients who already failed to derive sustained benefit from CPIs received prior to allo-HCT. RESULTS: Six cases were identified and reviewed. All patients received and failed to derive sustained benefit from CPIs and brentuximab vedotin preallo-HCT. The median age at the time of allo-HCT was 28.6 years (IQR 23.6-34.2), the median number of lines received prior to allo-HCT was 6.5 (range 5-9). The median duration of CPI therapy prior to allo-HCT was 8.1 months (IQR 6.7-12.9). The median time between the discontinuation of CPI and allo-HCT was 5.78 months (IQR 3.15-15.8). The median time to progression postallo-HCT was 5.75 months (IQR 2.6-11.7). The median time between allo-HCT and re-challenge with a CPI was 7.6 months (IQR 3.2-28.6). The median time of follow up after starting postallo-HCT CPIs was 16 months (IQR 7.25-25.75). Five out six patients responded and two patients developed GvHD. CONCLUSION: Our report shows preserved efficacy without any new safety signals by using CPIs postallo-HCT despite using and having failed to derive sustained benefit from CPIs preallo-HCT.
Acute liver failure (ALF) requires early and very precise treatment decisions for a diagnosis that is not often easy and may lead to erroneous decisions. Accordingly, we undertook a review of ALF secondary to malignant i...Acute liver failure (ALF) requires early and very precise treatment decisions for a diagnosis that is not often easy and may lead to erroneous decisions. Accordingly, we undertook a review of ALF secondary to malignant infiltration given the rarity of the condition, plus its singularity and therapeutic implications. This review should aid in establishing future frameworks for action. Analyze cases of ALF secondary to malignant infiltration in our center during the last 5 years and review the literature. We undertook a retrospective review of all cases of ALF due to malignant infiltration in our center between January 2015 and December 2019. Data were recorded on demographic characteristics, clinical presentation, type of tumor, diagnostic techniques used, treatment and evolution. We also undertook a literature review on the subject and compared the results. AFL secondary to malignant infiltration was diagnosed in five patients, four women and one man with a median age 58 years. The most common clinical presentation was jaundice. Three cases were due to infiltration by hematological tumors (non-Hodgkin lymphoma and histiocytosis), one a cholangiocarcinoma and one lung cancer. In all cases a liver biopsy was required for diagnosis, this being conclusive in four cases; diagnosis in the non-conclusive case was by analysis of the hepatectomy sample after transplantation. Three patients died due to AFL in a mean of 13.8 days, another died 5 months after diagnosis as a consequence of the tumor while the patient with a diagnosis of non-Hodgkin lymphoma and transplant recipient remains alive after a follow-up of 6 years and after receiving chemotherapy. AFL due to malignant infiltration is a very unusual condition but with a high rate of mortality. It requires a rapid and precise diagnosis given the relevant treatment options.
Hung A, Candelieri D, Li Y
… +13 more, Alba P, Robison B, Agiri F, Perez C, Lee KM, Maxwell KN, Li W, Aggarwal H, Pridgen K, Reed SD, DuVall S, Wong YN, Lynch JA
INTRODUCTION: In 2016, the Department of Veterans Affairs (VA) and Prostate Cancer Foundation (PCF) began a partnership to improve access to testing. The primary objective of this analysis was to describe the use of tumo...INTRODUCTION: In 2016, the Department of Veterans Affairs (VA) and Prostate Cancer Foundation (PCF) began a partnership to improve access to testing. The primary objective of this analysis was to describe the use of tumor testing and treatment patterns in Veterans who progressed to metastatic castration-resistant prostate cancer (mCRPC) from 2016 to 2021. Secondary objectives including identifying factors associated with receipt of tumor testing, and reporting HRR mutation results among a subset who were tested. METHODS AND MATERIALS: Natural language processing algorithms were applied to VA electronic health record data to identify a nationwide cohort of veterans with mCRPC. Tumor testing over time and by region were reported, alongside first-, second-, and third-line treatment patterns. Factors associated with receipt of tumor testing were identified using generalized linear mixed models with binomial distributions and logit links to account for clustering by VA facility. RESULTS: Of the 9,852 veterans analyzed, 1,972 (20%) received tumor testing, with 73% of testing occurring in 2020-2021. Factors associated with tumor testing included younger age, later diagnosis year, being treated in the Midwest, or Puerto Rico or other compared to the South, and being treated at a PCF-VA Center of Excellence. Fifteen percent of tests were positive for a pathogenic HRR mutation. Seventy-six percent of the study cohort received first-line treatment, and among those, a subsequent 52% received second-line treatment. A subsequent 46% received third-line treatment. CONCLUSION: After the VA-PCF partnership, one-fifth of veterans with mCRPC received tumor testing, with most tests occurring in 2020-2021.
Colorectal cancer (CRC) is a common cause of cancer-related death worldwide, with high rates of late diagnosis and increased mortality in sub-Saharan Africa. Furthermore, there is an alarming uptrend in the incidence of...Colorectal cancer (CRC) is a common cause of cancer-related death worldwide, with high rates of late diagnosis and increased mortality in sub-Saharan Africa. Furthermore, there is an alarming uptrend in the incidence of early onset colorectal cancer (EOCRC) across the globe, thus necessitating the need for early screening in general and special populations. There is, however, limited data available on the incidence and genetic characteristics of EOCRC from resource-poor countries, particularly Africa. Moreover, there is lack of clarity if recommendations and mechanisms proposed based on data from resource-rich countries applies to other regions of the world. In this review, we appraise the literature on EOCRC, its overall incidence, and genetic components as it pertains to sub-Saharan Africa. In addition, we highlight epidemiologic and epigenetic findings of our EOCRC cohort in Ethiopia.
Panobinostat is an oral pan histone-deacetylase inhibitor used in the treatment of relapsed and refractory multiple myeloma. Previously published studies of panobinostat demonstrated synergy with bortezomib but included...Panobinostat is an oral pan histone-deacetylase inhibitor used in the treatment of relapsed and refractory multiple myeloma. Previously published studies of panobinostat demonstrated synergy with bortezomib but included few patients exposed to newer agent combinations (ie, panobinostat plus daratumumab or carfilzomib). Here, we report outcomes of panobinostat-based combinations at an academic medical center among patients whose disease had been heavily pretreated with modern agents. We retrospectively analyzed 105 patients with myeloma treated with panobinostat at The Mount Sinai Hospital in New York City between October 2012 and October 2021. These patients had a median age of 65 (range 37-87) and had received a median of 6 prior lines of therapy while in 53% the disease was classified as triple class refractory and in 54% the disease had high-risk cytogenetics. Panobinostat was most commonly utilized at 20 mg (64.8%) as part of a triplet (61.0%) or quadruplet (30.5%). Aside from steroids, panobinostat was most commonly administered in combination with lenalidomide, pomalidomide, carfilzomib, and daratumumab in descending order of frequency. Among the 101 response-evaluable patients, the overall response rate was 24.8%, clinical benefit rate (≥minimal response) was 36.6%, and median progression-free survival was 3.4 months. Median overall survival was 19.1 months. The most common toxicities ≥grade 3 were hematologic, primarily neutropenia (34.3%), thrombocytopenia (27.6%), and anemia (19.1%). Panobinostat-based combinations produced modest response rates in patients with heavily pretreated multiple myeloma, over half of whom had triple-class refractory disease. Panobinostat warrants continued investigation as a tolerable oral option for recapturing responses in patients whose disease has progressed after receipt of standard-of-care therapies.