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Simple Summary: Induction regimens using 4-drugs for patients with newly diagnosed multiple myeloma have shown impressive results in multiple trials. However, trials of 4-drug regimens typically use a 3-drug regimen as their comparator, which limits our ability to determine whether the benefit is from the specific combination of drugs or just the addition of more agents. We performed a meta-analysis to compare all trials that compared 4-drug to 3-drug regimens and found that the addition of an anti-CD38 antibody (daratumumab or isatuximab) resulted in improved responses, while 4-drug regimens without an anti-CD38 antibody performed similarly to 3-drug regimens. While the addition of an anti-CD38 antibody led to increased adverse effects, these were predominantly mild and easily managed. These data suggest that an anti-CD38 antibody should be part of all 4-drug induction regimens for newly diagnosed myeloma patients. The use of 4-drug induction regimens for treatment naïve newly diagnosed multiple myeloma (NDMM) is associated with improved depth of response and progression-free survival (PFS). However, head-to-head trials of 4-drug combinations are lacking, and instead, these regimens are typically compared to 3-drug backbones; limiting the ability to discern whether any additional benefit (or toxicity) is simply additive or represents a synergy (or interaction). We conducted a meta-analysis of phase 2 and phase 3 clinical trials that randomized treatment naïve NDMM patients to either a 4-drug or 3-drug induction regimen. We included 11 trials which represented 6509 unique patients. PFS for all trials in the meta-analysis was 54 months with a 4-drug induction and 8.9 months with a 3-drug induction (HR: 0.49; 95% CI: 0.45; 0.54), but there was no benefit to using a 4-drug induction that did not include an anti-CD38 antibody (PFS 4-drug 8.1 months, PFS 3-drug 8.0 months; HR 0.95; 95% CI 0.86; 1.06). Adverse events were more frequent with the quadruplet regimens but were predominately mild. High-grade (≥3) adverse events (AEs) that were more common with 4-drug regimens were infections (RR: 1.34; 95% CI 1.17; 1.54) and thrombocytopenia (RR: 1.39; 95% CI 1.12; 1.74). This study suggests that 4-drug induction regimens which include an anti-CD38 antibody improve efficacy although with additional toxicity in NDMM patients. [ABSTRACT FROM AUTHOR]

• Daratumumab (Dara) is an anti-CD38 mAb that targets CD38 expressed in high concentration on malignant plasma cells. • Dara leads to early and deep hematological responses with acceptable toxicity profile in patients with light chain amyloidosis. • Future studies should define the preferable agents to combine with Dara in rescue setting and role of maintenance therapy. Outcomes for patients with systemic light-chain (AL) amyloidosis have improved over the last two decades with timely diagnosis, use of novel chemotherapeutic agents, risk stratification and better patient selection criteria before hematopoietic autologous stem cell transplant (ASCT). However, majority of patients have advanced stage disease at initial presentation and at relapse rendering them ineligible for intensive cytotoxic chemotherapy or ASCT. Daratumumab (Dara) with or without standard chemotherapy appears to be an excellent treatment option for newly diagnosed and relapsed refractory AL amyloidosis. This is largely due to its tolerable safety and remarkable efficacy as seen in multiple retrospective, small phase II studies as well as a phase III randomized controlled trial. Here we review published clinical trials and retrospective data of Dara in AL amyloidosis that explore its role as a valuable addition to the treatment armamentarium for this challenging disease. [ABSTRACT FROM AUTHOR]

Severe refractory ITP is clinically challenging and a variety of single or combination chemotherapies have been tried with limited outcome. We report a case of ITP that was unresponsive to multiple agents including high-dose steroid, IVIG, Rho(D) immune globulin, rituximab, cyclosporine, azathioprine, vincristine, mycophenolate mofetil, romiplostim, and eltrombopag; however, it achieved complete remission with combination treatment of cyclophosphamide and eltrombopag. [ABSTRACT FROM AUTHOR]

Background: Daratumumab's incorporation in the upfront treatment of light chain (AL) amyloidosis has led to daratumumab (dara) refractoriness early in disease course. Patients who experience relapse or have suboptimal response to dara-based-therapy, have limited options. Objective: This study aimed to evaluate the outcomes of venetoclax-based therapy in t(11;14) positive AL patients who previously failed dara. Methods: Thirty-one patients with AL were included in this bi-institutional retrospective analysis. Results: Dara failure was due to inadequate response in 20 (65%) patients, haematologic relapse in 7 (22%), and both haematologic plus organ relapse in 4 (13%). Overall haematologic response rate to venetoclax-based therapy was 97%, with ≥ VGPR being 91%. Of the 19 evaluable patients with cardiac involvement, 14 (74%) achieved organ response. Of the 13 evaluable patients with renal involvement, 6 (46%) achieved organ response. With a median follow-up of 22 months, median time-to-next-treatment (TTNT) and overall survival (OS) were not reached. The 12- and 24-month TTNT rates were 74% and 56%, respectively. At data-cut-off, four patients had died, all from AL-related organ complications. The 12- and 24-month OS rates were 89% and 85%, respectively. Grade ≥3 adverse events occurred in 26% of patients, with 6% due to infections. Conclusion: These findings are encouraging for the use of venetoclax as salvage therapy post-dara failure. [ABSTRACT FROM AUTHOR]

Clinical trials evaluating chimeric antigen receptor (CAR) T‐cell therapy in relapsed/refractory multiple myeloma (RRMM) have typically excluded patients with AL amyloidosis. As a result, there are limited data on the safety and efficacy of CAR T‐cell therapy in this patient population. We retrospectively reviewed eight consecutive patients with RRMM and AL amyloidosis who were treated with standard of care CAR T‐cell therapy. Cytokine release syndrome was seen in 75% of patients (grade ≥3: 0%) and immune effector cell‐associated neurotoxicity syndrome (grade 1) in only one patient. Low‐grade cytopenias were common (any grade/grade ≥3: neutropenia 62.5%/37.5%, anemia 37.5%/0%, thrombocytopenia 25%/0%). CAR T‐cell therapy led to rapid and deep responses with a median time to best response of 43 days and a hematologic very good partial response or better rate of 62.5%. Overall, we found that commercial CAR T‐cell therapy was feasible, and effective in patients with RRMM and concurrent AL amyloidosis. [ABSTRACT FROM AUTHOR]

Introduction: This study explored the efficacy of repeat blood cultures in bacteremic acute myeloid leukemia (AML) patients following allogeneic hematopoietic stem cell transplantation (HSCT). Methods: This was a retrospective study of AML patients who experienced febrile neutropenia (FN) and bacteremia following HSCT at the Taussig Cancer Center from January 1, 2019, to December 31, 2022. The primary endpoint was the rate of positive repeat blood cultures following initial positive blood culture. Results: Fifty patients were included in the study. There were 50 occurrences of FN with positive initial blood cultures that were diagnosed following HSCT. Fifty initial sets of blood cultures and 96 sets of repeat blood cultures were drawn between the 50 occurrences of FN. Twelve of 96 (12.5%) repeat blood culture sets were positive for a pathogen, which occurred over nine of 50 (18.0%) episodes of FN. Three of 96 (3.2%) repeat blood culture sets grew a pathogen that differed from the pathogen that grew in the preceding positive blood culture. Conclusion: Among bacteremic AML patients in the post‐HSCT period, the yield of repeat blood cultures for detecting previously detected and new pathogens was low. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a hematologic malignancy caused by the clonal expansion of immunoglobulin-producing plasma cells in the bone marrow and/or extramedullary sites. Common manifestations of MM include anemia, renal dysfunction, infection, bone pain, hypercalcemia, and fatigue. Despite numerous recent advancements in the MM treatment paradigm, current therapies demonstrate limited long-term effectiveness and eventual disease relapse remains exceedingly common. Myeloma cells often develop drug resistance through clonal evolution and alterations of cellular signaling pathways. Therefore, continued research of new targets in MM is crucial to circumvent cumulative drug resistance, overcome treatment-limiting toxicities, and improve outcomes in this incurable disease. This article provides a comprehensive overview of the landscape of novel treatments and emerging therapies for MM grouped by molecular target. Molecular targets outlined include BCMA, GPRC5D, FcRH5, CD38, SLAMF7, BCL-2, kinesin spindle protein, protein disulfide isomerase 1, peptidylprolyl isomerase A, Sec61 translocon, and cyclin-dependent kinase 6. Immunomodulatory drugs, NK cell therapy, and proteolysis-targeting chimera are described as well. [ABSTRACT FROM AUTHOR]

Waldenström macroglobulinemia (WM) is a chronic B-cell lymphoproliferative disorder characterized by lymphoplasmacytic cell overgrowth in the bone marrow and increased secretion of IgM immunoglobulins into the serum. Patients with WM have a variety of clinical outcomes, including long-term survival but inevitable recurrence. Recent advances in disease knowledge, including molecular and genetic principles with the discovery of MYD88 and CXCR4 mutations, have rapidly increased patient-tolerable treatment options. WM patients may benefit from chemotherapy regimens that include rituximab-based regimens, alkylating drugs, proteasome inhibitors, monoclonal antibodies, and drugs targeting Bruton tyrosine kinase inhibitors. In light of these advancements, patients can now receive treatment customized to their specific clinical characteristics, focusing on enhancing the depth and durability of their response while limiting the adverse effects. Despite the rapidly developing therapeutic armament against WM, a lack of high-quality evidence from extensive phase 3 trials remains a significant challenge in the research. We believe clinical outcomes will keep improving when new medicines are introduced while preserving efficacy and minimizing toxicity. [ABSTRACT FROM AUTHOR]

Light chain amyloidosis is a plasma–cell disorder with a poor prognosis. It is a progressive condition, causing worsening pain, disability, and life-limiting complications involving multiple organ systems. The medical regimen can be complex, including chemotherapy or immunotherapy for the disease itself, as well as treatment for pain, gastrointestinal and cardiorespiratory symptoms, and various secondary symptoms. Patients and their families must have a realistic awareness of the illness and of the goals and limitations of treatments in making informed decisions about medical therapy, supportive management, and end-of-life planning. Palliative care services can thus improve patients' quality of life and may even reduce overall treatment costs. Light chain (AL) amyloidosis is a clonal plasma cell disorder characterized by the excessive secretion of light chains by an indolent plasma cell clone that gradually accumulates in vital organs as amyloid fibrils and leads to end-organ damage. With progressive disease, most patients develop diverse clinical symptoms and complications that negatively impact quality of life and increase mortality. Complications include cardiac problems including heart failure, hypotension, pleural effusions, renal involvement including nephrotic syndrome with peripheral edema, gastrointestinal symptoms leading to anorexia and cachexia, complex pain syndromes, and mood disorders. The prognosis of patients with advanced AL amyloidosis is dismal. With such a complex presentation, and high morbidity and mortality rates, there is a critical need for the establishment of a palliative care program in clinical management. This paper provides an evidence-based overview of the integration of palliative care in the clinical management of AL amyloidosis as a means of reducing ER visits, rehospitalizations, and in-hospital mortality. We also discuss potential future collaborative directions in various aspects of clinical care related to AL amyloidosis. [ABSTRACT FROM AUTHOR]

Summary: Ide‐cel received approval for relapsed–refractory multiple myeloma based on the results of the KarMMa‐1 trial. However, patients with significant comorbidities, aggressive disease and prior B‐cell maturation antigen‐directed therapy (BCMA‐DT) were excluded. This retrospective study evaluated real‐world outcomes of patients who did not meet the KarMMa‐1 eligibility criteria and were treated with standard of care (SOC) ide‐cel. A total of 69 patients from three US centres who did not meet the KarMMa‐1 criteria underwent ide‐cel infusion. The main reasons for trial ineligibility included baseline grade 3–4 cytopenia (39%), prior BCMA‐DT (26%), renal impairment (19%) and Eastern Cooperative Oncology Group performance status ≥2 (14.5%). Cytokine‐release syndrome occurred in 81% vs. 84%, and immune effector cell‐associated neurotoxicity syndrome occurred in 28% vs. 18% of SOC versus KarMMa‐1 patients, respectively. Early infection (≤8 weeks post‐infusion) and severe infection rates were 42% vs. 49% and 30% vs. 22% for the SOC versus KarMMa‐1 cohorts, respectively. Grade 3–4 cytopenias for SOC versus KarMMa‐1 cohorts were: neutropenia (87% vs. 89%), anaemia (51% vs. 60%) and thrombocytopenia (65% vs. 52%). Overall response rate was higher for the SOC cohort (93% vs. 73%), as was the complete response or better rate (48% vs. 33%). However, median progression‐free survival and overall survival were comparable between the two groups. Our findings support broadening the inclusion criteria of future trials evaluating ide‐cel. [ABSTRACT FROM AUTHOR]

AL amyloidosis is caused by the excessive production of nonfunctional immunoglobulins, leading to the formation of amyloid fibrils that damage vital organs, especially the heart and kidneys. AL amyloidosis presents with non-specific symptoms such as fatigue, weight loss, numbness, pain, and nephrotic syndrome. Consequently, diagnosis is often delayed, and patients typically present with advanced disease at diagnosis. The Pavia renal staging model stratifies patients based on their likelihood of progressing to dialysis. Treatment with daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (i.e., Dara-CyBorD) was effective in inducing renal response in the landmark phase III ANDROMEDA trial and reducing early mortality. However, determining the most appropriate treatment regimen for relapsed or refractory cases remains a challenge due to various patient- and disease-related factors. Encouragingly, t(11:14) may be a positive indicator of therapy responses to the anti-BCL2 therapy venetoclax. Moreover, it is increasingly possible—for the first time—to clear AL amyloid fibrils from peripheral organs by leveraging novel anti-fibril immunotherapeutic approaches, although these medications are still under investigation in clinical trials. Given these advancements, this review provides a comprehensive overview of the current strategies for diagnosing, staging, treating, and monitoring AL amyloidosis, emphasizing renal involvement. [ABSTRACT FROM AUTHOR]

The incidence and relative risk of kidney toxicity with carfilzomib in multiple myeloma (MM) has been incompletely characterized. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing carfilzomib-based with non-carfilzomib-based regimens in MM to investigate the risk of kidney toxicity. Point estimates were pooled in the form of risk ratios (RR) with 95% confidence intervals (CI) using the random-effects model. We identified four RCTs with 2954 patients. The median duration of treatment ranged from 16.3 to 88 weeks in carfilzomib arms. The cumulative rate of kidney toxicities in the carfilzomib arms was 21.3% for all grades and 8.3% for grades 3-5 toxicities, with acute kidney injury being the predominantly reported event. Patients receiving a carfilzomib-based regimen had a significantly higher risk of total kidney toxicity compared with those in the control arms, with pooled RR of 1.79 (95% CI, 1.43-2.23, p < 0.001) and 2.29 (95% CI, 1.59-3.30; p < 0.001), for all grades and grades 3-5 toxicities, respectively. Despite adjustment for the duration of exposure in treatment arms, pooled incidence rate ratios (IRR) for kidney toxicity was significantly increased in the carfilzomib arm compared with control (pooled IRR of 1.28 for all grades and 1.66 for grades 3-5 toxicity). Subgroup analysis based on carfilzomib dose, infusion length, and treatment setting did not identify any significant subgroup effect. Kidney toxicity is an important adverse effect of carfilzomib-based regimens. Prospective studies should investigate patient-, disease-, and treatment-related risk factors for severe kidney toxicities and impact on long-term outcome. [ABSTRACT FROM AUTHOR]

This article validates the use of the GATMO score in predicting non-relapse mortality (NRM) in multiple myeloma (MM) patients after autologous hematopoietic cell transplant (AHCT). The study included 513 MM patients who underwent AHCT, and the GATMO score reliably stratified the patients' risk of NRM. The score was found to be useful in identifying patients at higher risk of NRM, although its ability to predict overall survival (OS) was modest. The authors suggest that the GATMO score may be a useful tool for evaluating MM patients being considered for AHCT, but further prospective validation is needed. [Extracted from the article]

Brain metastasis in gastric cancer (GC) patients is a rare phenomenon that is associated with adverse clinical outcomes and poor survival rates. We conducted a retrospective cohort study to investigate the incidence, risk factors and prognostic factors of brain metastasis in GC patients. Data on sociodemographic and tumor characteristics of GC patients from 2010 to 2019 was extracted from the Surveillance, Epidemiology and End-Results (SEER) database. Descriptive statistics, multivariable logistic and Cox regression were applied on SPSS. Kaplan–Meier-Survival curves and ROC curves were constructed. A total of 59,231 GC patients, aged 66.65 ± 13.410 years were included. Brain metastasis was reported in 368 (0.62%) patients. On logistic regression, the risk of brain metastasis was significantly greater in males, patients aged < 60 years and patients having concurrent bone and lung metastasis. High grade and high N stage were significant risk factors for development of brain metastasis. Patients who had undergone surgery for the primary tumor were at reduced risk for brain metastasis (adjusted odds ratio 0.210, 95% CI 0.131–0.337). The median OS was 3 months in patients with brain metastasis and 17 months in patients without brain metastasis (p < 0.05). On Cox regression, Grade IV tumors and primary antral tumors were significant predictable parameters for poor prognosis. Overall Survival (OS) and Cancer-Specific Survival (CSS) were prolonged in patients who had undergone surgery. Brain metastasis in gastric cancer is associated with significantly worse survival. Employing large-scale screening for high-risk patients holds a promising impact to improve survival rates, but it must be accurately balanced with a comprehensive understanding of clinicopathological aspects for accurate diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Anti-B-cell maturation antigen therapies consisting of bispecific antibodies, antibody–drug conjugates, and chimeric antigen receptor T cells have shown promising results in relapsed refractory multiple myeloma (RRMM). However, the severe side effects include cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, cytopenia(s), infections, hemophagocytic lymphohistiocytosis, and organ toxicity, which could sometimes be life-threatening. This review focuses on these most common complications post-BCMA therapy. We discussed the risk factors, pathogenesis, clinical features associated with these complications, and how to prevent and treat them. We included four original studies for this focused review. All four agents (idecabtagene vicleucel, ciltacabtagene autoleucel, teclistamab, belantamab mafodotin) have received FDA approval for adult RRMM patients. We went through the FDA access data packages of the approved agents to outline stepwise management of the complications for better patient outcomes. [ABSTRACT FROM AUTHOR]

Multiple myeloma is the second-most common hematologic malignancy in adults worldwide. Despite ongoing advancement in therapeutic modalities, it remains an incurable disease with a 5-year survival rate of approximately 50%. The recent development and introduction of anti-BCMA immunotherapies into clinical practice, including chimeric antigen receptor T-cell (CAR-T) therapies and bispecific antibodies, has radically shifted the treatment paradigm. However, despite the promising potential of these therapies for broader application, frequent and significant adverse effects have been reported, both in short- and in long-term settings, requiring increasing awareness and vigilance in the treating team, close monitoring, and prompt interventions with a multidisciplinary approach. In this review, we will discuss the toxicities associated with CAR-T cell and bispecific antibody therapies, focusing on results from major clinical studies and real-world observations. In addition, we will emphasize on effective strategies for prevention, monitoring and management, and provide expert recommendations. [ABSTRACT FROM AUTHOR]

Multiple myeloma is a heterogeneous clonal malignant plasma cell disorder, which remains incurable despite the therapeutic armamentarium's evolution. Bispecific antibodies (BsAbs) can bind simultaneously to the CD3 T-cell receptor and tumor antigen of myeloma cells, causing cell lysis. This systematic review of phase I/II/III clinical trials aimed to analyze the efficacy and safety of BsAbs in relapsed refractory multiple myeloma (RRMM). A thorough literature search was performed using PubMed, Cochrane Library, EMBASE, and major conference abstracts. A total of 18 phase I/II/III studies, including 1283 patients, met the inclusion criteria. Among the B-cell maturation antigen (BCMA)-targeting agents across 13 studies, the overall response rate (ORR) ranged between 25% and 100%, with complete response/stringent complete response (CR/sCR) between 7 and 38%, very good partial response (VGPR) between 5 and 92%, and partial response (PR) between 5 and 14%. Among the non-BCMA-targeting agents across five studies, the ORR ranged between 60 and 100%, with CR/sCR seen in 19–63%, and VGPR in 21–65%. The common adverse events were cytokine release syndrome (17–82%), anemia (5–52%), neutropenia (12–75%), and thrombocytopenia (14–42%). BsAbs have shown promising efficacy against RRMM cohorts with a good safety profile. Upcoming phase II/III trials are much awaited, along with the study of other agents in concert with BsAbs to gauge response. [ABSTRACT FROM AUTHOR]

A total of 475 patients were included in our study, of which 46 patients had a DLCOc <= 60% and 429 had a DLCOc > 60% of the predicted value. Subgroup analysis confirmed that mOS was significantly shorter in the DLCOc <= 60% group irrespective of relapse, with mOS of 27.3 versus 77.2 months ( I p i = .0002) in relapsed patients with DLCOc <= 60% ( I n i = 22) and DLCOc > 60% ( I n i = 193), respectively. Patients with DLCOc <= 60% survived for a significantly shorter period with median overall survival (mOS) of 43 versus 91.7 months ( I p i < .0001) in patients with DLCOc > 60% (Figure 1A). [Extracted from the article]

Summary: Selective patients with multiple myeloma (MM) receiving immunomodulatory drugs (IMiD) are at high risk for venous thromboembolism (VTE). The SAVED score is a VTE risk prediction model recently incorporated into the National Comprehensive Cancer Network (NCCN) guidelines. Using retrospective data from 501 MM patients with new IMiD initiation between 2010 and 2019, we performed the first independent external validation of this model. The cumulative incidence of VTE after IMiD initiation at 6 and 12 months was 32% and 42% in the high‐risk group, versus 6% and 9% in the low‐risk group respectively. The C‐statistic of the SAVED score to predict VTE within 12 months of IMiD‐based treatment start was 0.74 [95% confidence interval (CI): 0.69–0.78], which outperformed several other VTE risk models in MM patients. Our findings suggest that the SAVED score is an accurate risk assessment tool for VTE stratification in patients initiating IMiD‐containing regimens. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple myeloma is an incurable hematologic malignancy arising from terminally differentiated B-cells. Over the last decade, advancements in therapeutics have radically shifted the treatment landscape of MM, significantly improving the survival of patients. In this review, we will discuss the available therapeutic modalities for relapsed–refractory disease, highlighting critical factors that guide the therapy selection process. Multiple myeloma (MM) is the second most common hematologic malignancy in adults worldwide. Over the past few years, major therapeutic advances have improved progression-free and overall survival, as well as quality of life. Despite this recent progress, MM remains incurable in the vast majority of cases. Patients eventually relapse and become refractory to multiple drug classes, making long-term management challenging. In this review, we will focus on the treatment paradigm of relapsed/refractory MM (RRMM) in the era of advanced therapies emphasizing the available novel modalities that have recently been incorporated into routine practice, such as chimeric antigen receptor T-cell therapy, bispecific antibodies, and other promising approaches. We will also discuss major factors that influence the selection of appropriate drug combinations or cellular therapies, such as relapse characteristics, and other disease and patient related parameters. Our goal is to provide insight into the currently available and experimental therapies for RRMM in an effort to guide the therapeutic decision-making process. [ABSTRACT FROM AUTHOR]

Objectives: Treatment options for multicentric Castleman disease (MCD) remain limited. The only FDA‐approved drug is siltuximab for idiopathic MCD (iMCD), but the response rate with siltuximab is less than 50%. We performed a systematic review to examine the efficacy and safety of various regimens used for the treatment of MCD. Methods: A database search on PubMed, Embase, Cochrane, Web of Science, and Clinicaltrials.gov using the terms "Castleman disease," "treatment outcome," and "patient safety" was done. Results and Conclusions: Results from a randomized controlled trial and an extension study highlighted the efficacy and long‐term safety of siltuximab for iMCD; other trials showed tocilizumab to be a suitable alternative. A recent trial reported high response rates with thalidomide in iMCD patients. Promising results were reported for bortezomib in relapsed/ refractory MCD. For human herpesvirus‐8 (HHV8)‐associated MCD, rituximab along with doxorubicin therapy followed by maintenance with zidovudine and valganciclovir is the most effective therapy. A single‐arm trial has highlighted the potential role of tocilizumab in HHV8‐MCD. Data for these regimens are limited and mostly comprise nonrandomized trials. Further research on emerging agents could have a major impact on the treatment of this rare disease. [ABSTRACT FROM AUTHOR]

Background: Despite routine evaluation of cytogenetics in myeloma, little is known regarding the impact of high‐dose therapy (HDT) consolidation on overall survival (OS) or progression‐free survival (PFS) in patients who have high‐risk cytogenetics. The authors performed a meta‐analysis of randomized controlled trials (RCTs) to assess the heterogeneity of HDT efficacy according to cytogenetic risk. Methods: All RCTs in patients who had newly diagnosed myeloma from 2000 to 2021 that compared upfront HDT versus standard‐dose therapy (SDT) consolidation were included. The primary objective was to assess the difference in HDT efficacy between standard‐risk and high‐risk cytogenetics in terms of the OS or PFS log(hazard ratio) (HR). The pooled OS and PFS HR was calculated according to cytogenetic‐risk subgroup using a random‐effects model, and heterogeneity (I2) (the percentage of total observed variability explained by between‐study differences) was assessed using an interaction test. Results: After screening 3307 citations, 6 RCTs were included for PFS analysis, and 4 were included for OS analysis. The median follow‐up ranged from 3.1 to 7.8 years. The pooled OS HR for HDT versus SDT consolidation in patients with standard‐risk and high‐risk cytogenetics was 0.90 (95% confidence interval [CI], 0.70‐1.17; I2 = 0%) and 0.66 (95% CI, 0.45‐0.97; I2 = 0%), respectively. The difference in HDT efficacy in terms of OS between standard‐risk and high‐risk patients was statistically significant in favor of the high‐risk group (P for interaction =.03). The pooled PFS HR for HDT versus SDT was 0.65 (95% CI 0.56‐0.76; I2 = 0%) versus 0.52 (95% CI, 0.33‐0.83; I2 = 55%), respectively. The difference in HDT efficacy in terms of PFS between standard‐risk and high‐risk patients was not significant (P for interaction =.25). Conclusions: The magnitude of OS benefit with upfront HDT is cytogenetics‐dependent. Patients with high‐risk cytogenetics should preferably receive upfront rather than delayed HDT consolidation. Lay Summary: Upfront autologous stem cell transplantation improves overall survival in patients with newly diagnosed myeloma harboring high‐risk cytogenetics. The progression‐free survival benefit of upfront autotransplantation in patients with myeloma was similar irrespective of cytogenetic‐risk subgroup. The overall survival benefit of upfront autotransplantation in myeloma was predominantly derived by patients who had high‐risk cytogenetics. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is characterized by malignant proliferation of malignant plasma cells; it is the second most common hematological malignancy associated with significant morbidity. Genetic intricacy, instability, and diverse clinical presentations remain a barrier to cure. The treatment of MM is modernized with the introduction of newer therapeutics agents, i.e., target-specific monoclonal antibodies. The currently available literature lacks the benefits of newer targeted therapy being developed with an aim to reduce side effects and increase effectiveness, compared to conventional chemotherapy regimens. This article aims to review literature about the current available monoclonal antibodies, antibody-drug conjugates, and bispecific antibodies for the treatment of MM. [ABSTRACT FROM AUTHOR]

A case study of a 47-year-old woman underwent evaluation of episodic epigastric pain and iron deficiency anemia (IDA), and Esophagogastroduodenoscopy (EGD) revealed a 3.0-cm yellowish patch on the anterior wall of the lesser curve of the stomach. Topics include amyloidogenic component was immunoglobulin light chains, with no predominance of kappa or lambda chains on mass spectrometry; and localized amyloid deposit was causing chronic bleeding and endoscopic submucosal dissection of the lesion.

aimoona Khan,2 Hamid Ehsan,3 Ahsan Wahab,4 Abdul Rafae,5 Ali Y Khan,6 Abdur Jamil,7 Muhammad Khawar Sana,8 Abdullah Jamal,1 Taimoor Jaffar Ali,1 Iqraa Ansar,2 Muzammil M Khan,9 Jack Khouri,10 Faiz Anwer101Department of Internal Medicine, King Edward Medical University, Lahore, Punjab, Pakistan; 2Department of Medicine, Shifa College of Medicine, Islamabad, Pakistan; 3Department of Hematology/Oncology, Levine Cancer Institute, Atrium Health, Charlotte, NC, USA; 4Hospital Medicine/Internal Medicine, Baptist Medical Center South, Montgomery, AL, USA; 5Department of Internal Medicine, McLaren Regional Medical Center, Flint, MI, USA; 6Department of Internal Medicine, St. Joseph Mercy Oakland Hospital, Pontiac, MI, USA; 7Department of Internal Medicine, Central Michigan University, Saginaw, MI, USA; 8Department of Internal Medicine, John H. Stroger Jr. Hospital of Cook County, Chicago, IL, USA; 9Department of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA, USA; 10Hematology, Oncology, Stem Cell Transplantation, Multiple Myeloma Program, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, 44195, USACorrespondence: Muhammad Khawar SanaDepartment of Internal Medicine, John H. Stroger Jr. Hospital of Cook County, Chicago, IL, USAEmail [email protected] Carfilzomib (CFZ) is a proteasome inhibitor currently approved for the treatment of relapsed and refractory multiple myeloma (RRMM). Multiple trials are ongoing to evaluate its efficacy and safety in newly diagnosed multiple myeloma (NDMM). The use of CFZ-based two- or three-drug combination regimens as induction for the management of NDMM is an emerging approach. CFZ-based regimens include combinations of immunomodulators, alkylating agents, and monoclonal antibodies along with dexamethasone. In this review, we assess the efficacy and toxicity of CFZ-based regimens in NDMM. We reviewed a total of 27 studies (n=4538 patients) with overall response rates (ORR) ranging between 80% and 100%. Studies evaluating the combination of CFZ with daratumumab reported an ORR of approximately 100%. Achievement of minimal residual disease (MRD) negativity, measured by multi-parameter flow cytometry (MPFC), ranged between 60% and 95% in 4 (n=251) out of 6 studies that measured MRD-negativity. The interim results of the ENDURANCE trial failed to show superior efficacy and progression-free survival (PFS) of carfilzomib-lenalidomide when compared to bortezomib–lenalidomide combination, albeit with a lower incidence of neuropathy. Hematological toxicity was the most common adverse event observed with these regimens, and the most common non-hematological adverse events were related to cardiovascular and electrolyte disturbances. We need to further evaluate the role of CFZ in NDMM by conducting more Phase III trials with different combinations. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) remains an incurable disease with the majority of patients experiencing disease relapse despite response to initial therapy. Antibody-drug conjugates (ADCs) and bispecific T-cell engagers are innovative immunotherapeutic approaches currently in development for the treatment of MM. This systematic review summarizes the efficacy and safety of ADCs and bispecific T-cell engagers in relapsed refractory (RR) MM patients from 2010 to date. Comprehensive literature search was conducted on PubMed, EMBASE, Wiley Cochrane Library, Web of Science, and Clinicaltrials.gov . A total of 13 studies (n = 529) met inclusion eligibility. All studies were prospective in nature investigating ADCs or bispecific T-cell engagers in RR MM; 10 trials were phase 1 and 3 were phase 2. The median age of patients ranged from 24 to 82 years. Among trials with ADC regimens, the overall response (OR) ranged from 34 to 60% and complete response (CR) ranged from 3 to 6%. The most common non-hematologic adverse event (AE) of ADCs was keratopathy, while anemia and thrombocytopenia were the most common hematological AEs. With bispecific T-cell engagers , ORR ranged from 31 to 83%, CR ranged from 7 to 22%, and partial response (PR) ranged from 5 to 16%. The most common non-hematologic AE of bispecific T-cell engagers was cytokine release syndrome (CRS) while the most common hematological AE was neutropenia. Initial data appears to show good clinical activity and tolerable safety profiles, making ADCs and bispecific T-cell engagers promising agents for RRMM. Future studies with newer combinations and a longer follow-up are needed to determine the precise role of these novel therapies in the evolving paradigm of MM treatment. [ABSTRACT FROM AUTHOR]

Treatment options are limited for multiple myeloma patients who have developed four/five drug-refractory disease. Selinexor (Sel) and belantamab mafodotin (belamaf) were recently approved by the US FDA for treatment of RRMM. The toxicity profile of these drugs is a concern since these agents are used in patients who have already undergone multiple lines of treatment. In this review, we discuss the toxicity profile and strategies for the management of toxicities of Sel and belamaf for the treatment of RRMM. We conducted a comprehensive literature search on PubMed, Embase, Cochrane, and Clinicaltrials.gov using the terms "selinexor", "belantamab", "belamaf", and "multiple myeloma" without applying any limitations based on the date of the study, language, or country of origin. The most common hematological toxicity associated with these two drugs is thrombocytopenia. Cytopenias, constitutional symptoms, gastrointestinal effects, and hyponatremia are the major toxicities of Sel. Keratopathy and anemia are the major toxicities of belamaf. Treatment modifications and dose interruption are usually needed when side effects are more than grade II. As these are newer drugs with limited data, continuous surveillance and monitoring are warranted during the treatment course with early mitigation strategies. [ABSTRACT FROM AUTHOR]

Background: Patients with multiple myeloma (MM) remain at an increased risk of infection due to the disease process, as well as the ensuing treatments.Methods: We performed a systematic review to evaluate the monthly risk of grade III/IV infection, pneumonia, and neutropenia in patients with myeloma enrolled in randomized clinical trials (RCTs).Results: The risk of grade III or higher infection, pneumonia, and neutropenia persists among all phases of treatment. There was no statistical difference in grade III or higher infection, pneumonia, and neutropenia between frontline and relapsed/refractory setting. In the maintenance setting, the complications of infection, pneumonia, and neutropenia were low, but not negligible. Three-drug regimens were no more likely than two-drug regimens to have an increased risk of Grade III or higher infection.Conclusions: This is the first study to quantify the monthly risk of grade III or higher infection, pneumonia, and neutropenia across different treatment regimens in the frontline, maintenance, and relapsed/refractory settings. The results of our systematic review demonstrate a significant risk for severe infection, pneumonia, and neutropenia in patients with MM. Further studies are needed to determine the value of antibiotic prophylaxis in a broader myeloma patient population, as well as other approaches that will further mitigate the morbidity and mortality related to infection in this vulnerable patient population. [ABSTRACT FROM AUTHOR]

Summary: The IMPEDE VTE score has recently emerged as a novel risk prediction tool for venous thromboembolism (VTE) in multiple myeloma (MM). We retrospectively reviewed 839 patients with newly diagnosed MM between 2010 and 2015 at Cleveland Clinic and included 575 patients in final analysis to validate this score. The c‐statistic of the IMPEDE VTE score to predict VTE within 6 months of treatment start was 0·68 (95% CI: 0·61–0·75). The 6‐month cumulative incidence of VTE was 5·0% (95% CI: 2·1–7·9) in the low risk group, compared to 12·6% (95% CI: 8·9–16·4%) and 24·1% (95% CI: 12·2–36·1) in the intermediate and high risk groups (P < 0·001 for both). In addition, a higher proportion of patients in the VTE cohort had ECOG performance status of ≥2 as compared to the no VTE cohort (33% vs. 16%, P = 0·001). Other MM characteristics such as stage, immunoglobulin subtype, and cytogenetics were not predictors of VTE. In summary, we have validated the IMPEDE VTE score in our patient cohort and our findings suggest that it can be utilized as a VTE risk stratification tool in prospective studies looking into investigating VTE prophylaxis strategies in MM patients. [ABSTRACT FROM AUTHOR]

Data on real-world outcomes of axicabtagene ciloleucel (axi-cel) therapy for relapsed/refractory large B-cell lymphoma (R/R LBCL) are limited. In this intent to treat (ITT) analysis, we reviewed records of 38 consecutive patients with R/R LBCL for whom axi-cel was intended. Twenty-seven (71%) patients received axi-cel and 11 (29%) did not. Patients in the non-axi-cel group had a higher hematopoietic cell transplantation comorbidity index (HCT-CI) (median 4 vs. 2, p =.04). Median overall survival for the ITT, axi-cel and non-axi-cel group was 10 (95% CI, 3.7 to 13), 13 (95% CI, 7.7 to N.R.) and 1 (95% CI, 0.4 to 3.7) month(s) respectively. Factors limiting axi-cel use were disease progression, sepsis, manufacturing failure and socioeconomic barrier in 6 (55%), 3 (27%), 1 (9%) and 1 (9%) patient(s) respectively. Additional strategies are needed to ensure all LBCL patients for whom chimeric antigen receptor (CAR) T-cell therapy is prescribed can receive this treatment. [ABSTRACT FROM AUTHOR]

Background: Acquired thrombocytopenia (aTP) is associated with a high frequency of bleeding and ischemic complications in patients undergoing percutaneous coronary intervention (PCI). Herein, we report a meta-analysis evaluating the adverse effects of aTP on cardiovascular outcomes and mortality post-PCI.Methods: A literature search was performed using PubMed, Embase, Cochrane and, clinicaltrials.gov from the inception of these databases through October 2019. Patients were divided into two groups: 1) No Thrombocytopenia (nTP) and 2) Acquired Thrombocytopenia (aTP) after PCI. Primary endpoints were in-hospital, 30-day and all-cause mortality rates at the longest follow-up. The main summary estimate was random effects Risk ratio (RR) with 95% confidence intervals (CIs).Results: Seven studies involving 57,247 participants were included. There was significantly increased in-hospital all-cause mortality (HR 10.73 [6.82-16.88]), MACE (HR 2.96 [2.24-3.94]), major bleeding (HR 4.78 [3.54-6.47]), and target vessel revascularization (TVR) (HR 7.53 [2.8-20.2]), in the aTP group compared to the nTP group. Similarly, aTP group had a statistically significant increased incidence of 30-day all-cause mortality (HR 6.08), MACE (HR 2.77), post-PCI MI (HR 1.98), TVR (HR 5.2), and major bleeding (HR 12.73). Outcomes at longest follow-up showed increased incidence of all-cause mortality (HR 3.98 [1.53-10.33]) and MACE (HR 1.24 [0.99-1.54]) in aTP group, while there was no significant difference for post-PCI MI (HR 0.94 [0.37-2.39]) and TVR (HR 0.96 [0.69-1.32]) between both groups.Conclusions: Acquired Thrombocytopenia after PCI is associated with increased morbidity, mortality, adverse bleeding events and the need for in-hospital and 30-day TVR. [ABSTRACT FROM AUTHOR]

A hallmark feature of tumorigenesis is uncontrolled cell division. Autophagy is regulated by more than 30 genes and it is one of several mechanisms by which cells maintain homeostasis. Autophagy promotes cancer progression and drug resistance. Several genes play important roles in autophagy‐induced tumorigenesis and drug resistance including Beclin‐1, MIF, HMGB1, p53, PTEN, p62, RAC3, SRC3, NF‐2, MEG3, LAPTM4B, mTOR, BRAF and c‐MYC. These genes alter cell growth, cellular microenvironment and cell division. Mechanisms involved in tumorigenesis and drug resistance include microdeletions, genetic mutations, loss of heterozygosity, hypermethylation, microsatellite instability and translational modifications at a molecular level. Disrupted or altered autophagy has been reported in hematological malignancies like lymphoma, leukemia and myeloma as well as multiple solid organ tumors like colorectal, hepatocellular, gall bladder, pancreatic, gastric and cholangiocarcinoma among many other malignancies. In addition, defects in autophagy also play a role in drug resistance in cancers like osteosarcoma, ovarian and lung carcinomas following treatment with drugs such as doxorubicin, paclitaxel, cisplatin, gemcitabine and etoposide. Therapeutic approaches that modulate autophagy are a novel future direction for cancer drug development that may help to prevent issues with disease progression and overcome drug resistance. [ABSTRACT FROM AUTHOR]

Primary plasma cell leukemia (PCL) is a rare and aggressive variant of multiple myeloma (MM). PCL is characterized by peripheral blood involvement by malignant plasma cells and an aggressive clinical course leading to poor survival. There is considerable overlap between MM and PCL with respect to clinical, immunophenotypic, and cytogenetic features, but circulating plasma cell count exceeding 20% of peripheral blood leukocytes or an absolute plasma cell count of >2000/mm3 distinguishes it from MM. After initial stabilization and diagnosis confirmation, treatment of PCL in a fit patient typically includes induction combination chemotherapy containing novel agents typically, with proteasome inhibitors (such as bortezomib) and immunomodulatory drugs (eg, lenalidomide), followed by autologous hematopoietic stem cell transplant (HSCT) and multidrug maintenance therapy using novel agents post-HSCT. Long-term outcomes have improved employing this strategy but the prognosis for non-HSCT candidates remains poor and new approaches are needed for such PCL patients not eligible for HSCT. Here, we report a case of primary PCL, and a comprehensive and up to date review of the literature for diagnosis and management of PCL. We also present the findings of Positron Emission Tomography (PET) scan. Since PCL is often associated with extra-medulary disease, including PET scan at the time of staging and restaging may be a novel approach particularly to evaluate the extra-medullary disease sites. [ABSTRACT FROM AUTHOR]

Primary plasma cell leukemia (PCL) is a rare and aggressive variant of multiple myeloma (MM). PCL is characterized by peripheral blood involvement by malignant plasma cells and an aggressive clinical course leading to poor survival. There is considerable overlap between MM and PCL with respect to clinical, immunophenotypic, and cytogenetic features, but circulating plasma cell count exceeding 20% of peripheral blood leukocytes or an absolute plasma cell count of >2000/mm3 distinguishes it from MM. After initial stabilization and diagnosis confirmation, treatment of PCL in a fit patient typically includes induction combination chemotherapy containing novel agents typically, with proteasome inhibitors (such as bortezomib) and immunomodulatory drugs (eg, lenalidomide), followed by autologous hematopoietic stem cell transplant (HSCT) and multidrug maintenance therapy using novel agents post-HSCT. Long-term outcomes have improved employing this strategy but the prognosis for non-HSCT candidates remains poor and new approaches are needed for such PCL patients not eligible for HSCT. Here, we report a case of primary PCL, and a comprehensive and up to date review of the literature for diagnosis and management of PCL. We also present the findings of Positron Emission Tomography (PET) scan. Since PCL is often associated with extra-medulary disease, including PET scan at the time of staging and restaging may be a novel approach particularly to evaluate the extra-medullary disease sites. [ABSTRACT FROM AUTHOR]

Introduction: Since the approval of transcatheter aortic valve replacement (TAVR), nonagenarian group patients are being increasingly considered for TAVR. Therefore, we compared the clinical outcomes of surgical aortic valve replacement (SAVR) vs TAVR in nonagenarians with severe aortic stenosis. Methods: A literature search was performed using MEDLINE, Embase, Web of Science, Cochrane, and Clinicaltrials.gov for studies reporting the comparative outcomes of TAVR versus SAVR in nonagenarians. The primary endpoint was short-term mortality. Secondary endpoints were post-operative incidences of stroke or transient ischemic attack (TIA), vascular complications, acute kidney injury (AKI), transfusion requirement, and length of hospital stay. Results: Four retrospective studies qualified for inclusion with a total of 8,389 patients (TAVR = 3,112, SAVR = 5,277). Short-term mortality was similar between the two groups [RR = 0.91 (95% CI: 0.76–1.10), p = 0.318]. The average length of hospital stay was shorter by 3 days in the TAVR group (p = 0.037). TAVR was associated with a significantly lower risk of AKI [RR = 0.72 (95% CI: 0.62–0.83), p < 0.001] and a lower risk of transfusion [RR = 0.71 (95% CI: 0.62–0.81), p < 0.001]. There was no difference in risk of stroke/TIA[RR = 1.01 (95% CI: 0.70–1.45), p = 0.957]. The risk of vascular complications was significantly higher in the TAVR group [RR = 3.39 (95% CI: 2.65–4.333), p < 0.001]. Conclusion: In this high-risk population, TAVR compared to SAVR has similar short-term mortality benefit but has lower risks of perioperative complications and a higher number of patients being discharged to home. [ABSTRACT FROM AUTHOR]

• Graft-versus-host disease (GVHD) often leads to post-transplant morbidity and mortality and can severely compromise quality of life. • Cyclosporine combined with short-course methotrexate is considered standard-of-care GVHD prophylaxis for patients with severe aplastic anemia who undergo transplantation using cyclophosphamide (Cy) plus anti-thymocyte globulin (ATG) conditioning. • Single-agent cyclosporine is a feasible option for GVHD prophylaxis in matched related donor hematopoietic stem cell transplantation using fludarabine-Cy-ATG conditioning and is associated with very low rates of acute and chronic GVHD. Cyclosporine (CsA) combined with short-course methotrexate is considered standard-of-care graft-versus-host disease (GVHD) prophylaxis for patients with severe aplastic anemia (AA) who undergo transplantation using cyclophosphamide (Cy) plus anti-thymocyte globulin (ATG) conditioning. However, there is no consensus on optimal post-transplant GVHD prophylaxis for patients undergoing matched related donor (MRD) transplantation using fludarabine (Flu)-based conditioning. We conducted a single-center retrospective analysis of patients with acquired AA (n = 106) undergoing MRD transplantation from July 2007 through January 2019. All patients received Flu-Cy-ATG conditioning and single-agent CsA as GVHD prophylaxis. Median age of the study cohort was 20 years (range, 3 to 52) and male to female ratio was 3.8:1. Median time from diagnosis to transplant was 11.5 months (range, 2.8 to 62). Graft source was bone marrow harvest in 71 (68%), combined bone marrow and peripheral blood stem cells in 34 (31%), and peripheral blood alone in 1 (1%) patient. Cumulative incidence of neutrophil engraftment at day 28 was 93.4% (95% confidence interval [CI], 87.3% to 97.1%) while that of platelet engraftment at day 100 was 90.5% (95% CI, 84% to 96%). Cumulative incidence of primary graft failure at day 28 was 6.6% (95% CI, 4% to 8%) while secondary graft failure occurred at a median of 190 days (range, 90 to 415) at a cumulative incidence of 3.7% (95% CI, 2% to 5%). Cumulative incidence of grade II to IV acute GVHD at day 100 was 3.8% (95% CI, 1.4% to 9.9%), while a 1-year probability of chronic GVHD was calculated as 7.5% (95% CI, 2.6% to 15%). Median follow-up post-transplant was 61 months (range, 6 to 144). Overall survival was 84.9%, disease-free survival was 80.2%, and GVHD-free relapse-free survival was 76.3%. This study indicates that single-agent cyclosporine is a feasible option for GVHD prophylaxis in MRD hematopoietic stem cell transplantation using Flu-Cy-ATG conditioning and is associated with very low rates of acute and chronic GVHD. [ABSTRACT FROM AUTHOR]

The blood transfusion (BT) system in Pakistan is fragmented, demand-driven and depends on weakly regulated transfusion practices. There is a considerable possibility that transfusion-transmissible infections (TTIs) are contributing to the current epidemic of hepatitis B virus (HBV) and hepatitis C virus (HCV) (affecting 7.4% of the general population) in the country. To study this issue, we conducted a systematic review to identify articles related to TTIs and transfusion safety in Pakistan from January 1, 2010 to January 31, 2020. A review of 33 articles met the final criteria for qualitative synthesis. Analysis of these studies showed a cumulative frequency of HBV 2.04%, HCV 2.44%, HIV 0.038%, syphilis 1.1% and malaria 0.11%. The frequency of coinfections among blood donors varied from 0.0099% to 0.35%. The highest number of coinfections were HCV and syphilis, followed by HCV and HBV infections. Syphilis and malaria were tested in only 38% and 46% of all the blood donations in one study. The rate of voluntary non-remunerated donations (VNRDs) was less than 13%, and male donors were 95% to 100% in these studies. There was a significant difference in the frequency of HBV and HCV in VNRDs (0.48%) as compared to replacement donors (RDs) (4.15%). In short, this review shows a high frequency of TTIs, especially HBV, HCV and syphilis in the blood donor population in Pakistan. There is a high dependency on RDs, minimal use of healthy voluntary blood donation practices, inadequate screening of high-risk donors, repeated collections of the blood from RDs, poor quality of screening methods and limited knowledge of donor health. Without standardized safe transfusion practices, there will be an ongoing increase in transmission of TTIs, especially HBV, HCV, syphilis, and HIV leading to a significant adverse public health impact. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a hematological malignancy characterized by an abnormal clone of plasma cells in the bone marrow. MM and its therapy increase the risk of complications like anemia, osteolytic lesions, pain, infections, and renal abnormalities in MM patients. Supportive care for MM patients improves the quality of life. Treatment with bisphosphonates decreases skeletal-related events. Vertebroplasty and kyphoplasty are done in cases of vertebral compression fractures. Prophylactic antibiotics and antivirals can decrease infections related to morbidity. Plasmapheresis in patients with renal dysfunctions decreases dialysis dependency and improve quality of life. [ABSTRACT FROM AUTHOR]

Summary: Characterisation and prognostic impact of immunoparesis in relapsed multiple myeloma (MM) is lacking in the current literature. We evaluated 258 patients with relapsed MM, diagnosed from 2008 to 2015, to investigate the prognostic impact of deep immunoparesis on post‐relapse survival. On qualitative immunoparesis assessment, no, partial and full immunoparesis was present in 9%, 30% and 61% of patients, respectively. Quantitative immunoparesis was assessed by computing the average relative difference (ARD) between polyclonal immunoglobulin(s) and corresponding lower normal limit(s), with greater negative values indicating deeper immunoparesis. The median ARD was −39%, with an optimal cut‐off of −50% for overall survival (OS) by recursive partitioning analysis. Deep immunoparesis (ARD ≤–50%) was associated with a higher tumour burden at first relapse compared to none/shallow [ARD >−50%] immunoparesis. The OS (P = 0·007) and progression‐free survival (PFS; P < 0·001) differed significantly between the deep and none/shallow immunoparesis groups. Kaplan–Meier estimates for 3‐year OS were 36% and 46%, and for 2‐year PFS were 17% and 27%, respectively. On multivariable analysis (MVA) for PFS, both qualitative and quantitative immunoparesis retained negative prognostic impact independently. However, only quantitative immunoparesis was independently prognostic for OS on MVA. Depth of immunoparesis in relapsed MM is an important prognostic factor for post‐relapse survival in the era of novel agents and continuous therapy. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA) is an established risk factor for poor cardiovascular outcomes and coronary artery disease, but its influence on the development of peripheral artery disease (PAD) is not well established. The aim of our study was to understand the mutual prevalence of OSA and PAD and any reported statistical association between the two conditions. PubMed, Ovid Embase, Web of Science, Cochrane library and clinicaltrials.gov databases were systematically searched up to 29 November 2018. A total of 844 articles were identified and 744 articles were screened for relevance. Eleven prospective cohorts qualified for inclusion with N = 63,642 (M = 28,062, F = 35,494). All studies evaluated OSA severity primarily with apnea–hypopnea index (AHI) values. The overall prevalence of PAD was 20.5% (N = 13,068). Except for two studies, all studies reported an increased prevalence of OSA in patients with PAD. OSA severity was not found to have an association with poor ankle brachial index values or increasing daytime sleepiness as measured by Epworth sleepiness scale. Further prospective clinical trials are required to further delineate this finding. [ABSTRACT FROM AUTHOR]

Background: Thromboprophylaxis is routinely used with lenalidomide-based regimens in multiple myeloma because of a substantial risk of venous thromboembolism (VTE). However, little is known about the incidence of VTE with contemporary lenalidomide-based regimens. The objective of the current study was to estimate the incidence of VTE despite thromboprophylaxis with currently used lenalidomide-based regimens in patients with myeloma.Methods: The Ovid MEDLINE, Embase, and Cochrane databases were queried from study inception to January 2019 for keywords to cover the following concepts: "lenalidomide," "venous thromboembolism," and "multiple myeloma." Phase 1, 2, and 3 clinical trials evaluating lenalidomide-based regimens with thromboprophylaxis were included. The pooled incidence rate of VTE was estimated using a random-effects model.Results: The search generated 1372 citations, with 51 clinical trials and 9069 patients included for analysis. The most common thromboprophylaxis agents were aspirin, low-molecular-weight heparin or warfarin, administered either per risk-stratification or at investigators' discretion. The pooled incidence of VTE in trials of patients who had newly diagnosed and relapsed/refractory myeloma was 6.2% (95% CI, 5.4%-7.1%) over median treatment durations ranging from 2 to 34 cycles, which translated into 1.2 VTE events per 100 patient-cycles (95% CI, 0.9-1.7 VTE events per 100 patient-cycles). Among contemporary regimens, the risk of VTE was low with combined lenalidomide and low-dose dexamethasone (0.2 [95% CI, 0.1-0.6] events/100 patient-cycles) and lenalidomide maintenance (0.0 [95% CI, 0.0-0.7] events per 100 patient-cycles). VTE risk was higher with combined lenalidomide and low-dose dexamethasone plus proteasome inhibitors (1.3 [95% CI, 0.7-2.3] events per 100 patient-cycles).Conclusions: Despite adequate thromboprophylaxis, lenalidomide-based regimens have a substantial risk of VTE in controlled clinical trial settings. Further studies are needed on new thromboprophylaxis strategies with regimens that have a high VTE risk. [ABSTRACT FROM AUTHOR]

Relapse after stem cell transplantation for Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) remains a significant challenge. In this systematic review, we compare survival outcomes of second-generation tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib with first-generation TKI imatinib when these agents are used after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in Ph+ ALL. In addition, we review the literature on TKI use to prevent relapse in patients who proceed to allo-HSCT beyond first complete response (>CR1). We performed database searches (inception to January 2018) using PubMed, Cochrane Library, and Embase. After exclusions, 17 articles were included in this analysis. Imatinib was used post-transplant either prophylactically or preemptively in 12 studies, 7 prospective studies and 5 retrospective studies. Overall survival (OS) for most prospective studies at 1.5 to 3 and 5 years ranged between 62% to 92% and 74.5% to 86.7%. Disease-free survival at 1.5 to 5 years was 60.4% to 92%. Additionally, imatinib failed to show survival benefit in patients who were >CR1 at the time of allo-HSCT. The cumulative OS for most retrospective studies using imatinib at 1 to 2 and 3 to 5 years was 42% to 100% and 33% to 40% respectively. Event-free survival at 1 to 2 and 3 to 5 years was 33.3% to 67% and 20% to 31% respectively. Dasatinib was used as maintenance treatment in 3 retrospective studies (n = 34). The OS for patients with Ph+ ALL using dasatinib as maintenance regimen after allo-HSCT at 1.4 to 3 years was 87% to 100% and disease-free survival at 1.4 to 3 years was 89% to 100%. Ninety-three percent of patients with minimal residual disease (MRD) positive status after allo-HSCT became MRD negative. Three prospective studies used nilotinib. In 2 studies where investigators studied patients with advanced chronic myeloid leukemia and Ph+ ALL, the cumulative OS and event-free survival at 7.5 months to 2 years were 69% to 84% and 56% to 84%, respectively. In the third study (n = 5) in patients with Ph+ ALL, nilotinib use resulted in OS at 5 years of 60%. Our review showed that use of TKIs (all generations) after allo-HSCT for patients in CR1 improved OS when given as a prophylactic or preemptive regimen. Limited data suggest that second-generation TKIs (ie, dasatinib) have a better OS, especially in patients with MRD-positive status. Imatinib did not improve OS in patients who were >CR1 at the time of allo-HSCT; for this population, no data were available with newer generation TKIs. The evaluation of survival benefit with newer generation TKIs and their efficacy in patients in >CR1 needs further study in large randomized clinical trials. [ABSTRACT FROM AUTHOR]

• Transplant donors and recipients should be current on their vaccination schedule. • Post-transplant vaccination is crucial to prevent infections. • Transplant recipients should be vaccinated again endemic diseases before travel. • Live vaccines should be avoided in those in close contact with transplant patients. Vaccination is an effective strategy to prevent infections in immunocompromised hematopoietic stem cell transplant recipients. Pretransplant vaccination of influenza, pneumococcus, Haemophilus influenza type b, diphtheria, tetanus, and hepatitis B, both in donors and transplant recipients, produces high antibody titers in patients compared with recipient vaccination only. Because transplant recipients are immunocompromised, live vaccines should be avoided with few exceptions. Transplant recipients should get inactive vaccinations when possible to prevent infection. This includes vaccination against influenza, pneumococcus, H. influenza type b, diphtheria, tetanus, pertussis, meningococcus, measles, mumps, rubella, polio, hepatitis A, human papillomavirus, and hepatitis B. Close contacts of transplant recipients can safely get vaccinations (inactive and few live vaccines) as per their need and schedule. Transplant recipients who wish to travel may need to get vaccinated against endemic diseases that are prevalent in such areas. There is paucity of data on the role of vaccinations for patients receiving novel immunotherapy such as bispecific antibodies and chimeric antigen receptor T cells despite data on prolonged B cell depletion and higher risk of opportunistic infections. [ABSTRACT FROM AUTHOR]

• High-risk aplastic anemia (AA) is associated with inferior overall survival (OS) and disease-free survival (DFS) when conventional cyclophosphamide-based conditioning is used. • Fludarabine-based conditioning is well tolerated, with lower rates of rejection and excellent long-term survival in these high-risk aplastic anemia patients. • High-risk factors identified in our study were prior hematopoietic stem cell transplant (HSCT), age ≥ 20 years, disease duration > 3 months, RBC transfusions > 20, and random platelet transfusions > 50. • Cyclosporine alone as GVHD prophylaxis and marrow source stem cells as graft source are preferable options. • A randomized trial of fludarabine-based versus conventional cyclophosphamide-containing conditioning would be helpful in establishing a standard of care conditioning regimen in high-risk AA patients. Despite excellent transplant outcomes of aplastic anemia (AA) in developed countries, management in developing countries is challenging because of delay in the diagnosis, use of family donors for transfusions, and higher infection risk pretransplant. These factors can lead to allo-immunization, increased risk of graft failure, graft-versus-host disease (GVHD), and transplant-related mortality, leading to unfavorable outcomes. Conventional cyclophosphamide (Cy) and antithymocyte globulin (ATG) are associated with inferior overall survival in such high-risk patients. We conducted single-center retrospective analysis of high-risk AA patients (N = 147) enrolled consecutively and undergoing matched related donor transplant from March 2002 through October 2018. We included high-risk AA patients receiving fludarabine (Flu)-based conditioning. Median patient age was 20 years (range, 3 to 52). The median time from diagnosis to transplant was 11 months (range, 3 to 63). High-risk features included age ≥ 20 years in 55.8% of patients (n = 82), disease duration more than 3 months in 95 % (n = 140), RBC concentrates transfusions > 20 in 79.6% (n = 117), random donor platelet transfusion > 50 in 64.6% of patients (n = 95), and second hematopoietic stem cell transplant (HSCT) in 7.4% (11). We divided patients into 2 groups based on different conditioning regimens. Flu group 1 (Flu1) received Flu 120 to 150 mg/m2, Cy 120 to 200 mg/kg, and ATG 20 mg/kg, and Flu group 2 (Flu2) was given Flu 150 mg/m2, Cy 300 mg/m2, and ATG 20 mg/kg. Bone marrow stem cells were used as graft source in 97% of patients (n = 144) (alone in 52% and with peripheral blood stem cells in 45%). Cyclosporine alone was used for GVHD prophylaxis in 75% (n = 110) and cyclosporine plus methotrexate in 25% (n = 37). Median total nucleated cell dose was 5 × 108/kg. Median days for neutrophil engraftment was 13 (range, 10 to 20) and platelet engraftment 20 (range, 14 to 43). Day 100 mortality was 7.5% (n = 11). Sustained successful engraftment was achieved in 87.8% of patients (n = 129). Most graft failures (40%) occurred in Flu2 conditioning (P =.000) and in patients with >2 risk factors (P =.000). Overall incidence of acute and chronic GVHD was 11.6% (n = 17) and 12.9% (n = 19), respectively, in Flu1 and Flu2 groups. Overall survival (OS), disease-free survival (DFS), and GVHD-free relapse-free survival (GRFS) was 83.7%, 78.2%, and 70.7%, respectively. A trend toward improved OS was observed in patients receiving Flu1 conditioning but was statistically nonsignificant (P =.256), whereas DFS and GRFS were significantly better in Flu1 versus Flu2 (P =.004 and.001, respectively). When stratified per number of risk factors (age > 20, RBC concentrate > 20 or platelet > 50 random, duration > 3 months, previous HSCT), OS and DFS decreased significantly with increasing number of risk factors (P =.000 and.001, respectively). Patients are able to tolerate Flu-based conditioning well with lower rates of rejection and excellent long-term survival in high-risk AA patients. Cyclosporine alone as GVHD prophylaxis and marrow source stem cells as graft source are preferable options. Use of Flu plus low-dose Cy conditioning is associated with inferior survival outcomes. A randomized trial of Flu-based versus conventional Cy-containing conditioning would be helpful in establishing a standard of care conditioning regimen in high-risk AA patients. [ABSTRACT FROM AUTHOR]

Background Conditional survival (CS) is defined as the probability of surviving an additional x years given a patient has already survived y years since diagnosis or a time-point of interest. Although there are readily available overall survival (OS) estimates in multiple myeloma (MM) from the time of diagnosis or autologous stem cell transplantation (ASCT), data on CS in those who had already survived a landmark time since ASCT are lacking. Our objective was to investigate 5-year CS rate and standardized mortality ratio (SMR) in 1-, 3- and 5-year survivors after front-line ASCT in MM. Method We reviewed the institutional transplant database at Cleveland Clinic to identify 340 patients who underwent frontline ASCT (≤18 months from diagnosis) for MM between 1996 and 2013. OS was estimated by the Kaplan-Meier method. Relapse mortality (RM) and non-relapse mortality (NRM) were estimated with cumulative incidence. SMR was defined as the ratio of number of deaths in the study patients to that in an age, sex and race-matched healthy population. Estimates of outcomes and SMR are presented with 95% confidence intervals (CI). Results We identified 309 survivors at 1 year, 246 at 3 years, and 178 at 5 years from ASCT. The median age at ASCT was 56 years (range, 22-76) in all 3 cohorts. The median time from diagnosis to ASCT was 7.9 months in 1- and 3-year and 8.2 months in 5-year survivors. Approximately 40%, 35%, and 25% of patients had ISS stage I, II and III disease respectively at diagnosis in all cohorts. Median follow-up from ASCT in surviving patients was 88 months, 90 months and 100 months in 1-, 3- and 5-year survivors respectively. Estimated 5-year CS was 59% (53-64) in 1-year survivors, 60% (53-67) in 3-year survivors and 62% (53-70) in 5-year survivors. The respective cumulative incidence of 5-year conditional RM was 34% (28-39), 29% (23-35) and 25% (18-33) and that of NRM was 7% (5-11), 11% (7-16) and 13% (8-19). The SMR of 1-year, 3-year and 5-year survivors was 6.9 (5.8-8.2), 6.1 (5.0-7.5) and 5.6 (4.3-7.3) respectively, indicating significantly worse survival compared to demographically-matched healthy population irrespective of the duration of survival after ASCT. Survival curves for the 3 cohorts are shown in Figure I. Conclusion The probability of surviving an additional 5 years in patients with MM undergoing front-line ASCT does not improve with time, as shown in 1-, 3- and 5-year survivors, with estimated 5-year CS staying constant at around 60%. However, a decrease in the magnitude of SMR was observed with increase in the number of years already survived after ASCT. Information on CS and SMR is a pragmatic resource for long-term survivorship and beneficial at an individual level for counselling patients. [ABSTRACT FROM AUTHOR]

Highlights • Myeloma patients need personalized therapy according to their comorbidities and age. • Age, performance status and frailty guide the selection of treatment in elderly. • Bortezomib regimens are the mainstay of therapy in patients with renal impairment. • Denosumab should be used for bone disease in patients with CrCl < 30 ml/min. • Doses of bortezomib and thalidomide should be reduced to manage neuropathy. Abstract Multiple Myeloma (MM) is primarily a disease of old age with a median age of sixty-nine years at diagnosis. The development of novel therapies for induction and use of autologous stem cell transplantation has resulted in improved clinical outcomes and better quality of life for MM patients. Elderly patients, comprising the majority of MM population, have a higher incidence of age-related comorbidities, frailty and organ dysfunction which complicates the coordination of treatment and limits the selection of therapies. Even in the era of multiple chemotherapeutic options, the clinical heterogeneity of the myeloma patients' demands personalized treatments which often require dose-adjustments or dose delays. The use of reduced-dose regimens and various comorbidity indices has improved clinical outcome and regimen tolerability in MM patients with renal, neurological and bone abnormalities. We focus on advancements in the treatment of multiple myeloma with the goal to guide clinicians towards patient-specific management. [ABSTRACT FROM AUTHOR]