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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]

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]

This retrospective cohort study used Taussig Cancer Center's Myeloma Patient Registry to identify adults with multiple myeloma diagnosed between January 2017-December 2021. Electronic health records data captured time from diagnosis to initial prescription fill for oral antimyeloma medications and initiation of facility administered or oral antimyeloma treatment. We identified 720 patients with a mean age at diagnosis of 67 years ±11; 55% were male, 77% White, 22% Black, 1% other races, covered by private insurance (36%), traditional Medicare (29%), Medicare Advantage (25%), and Medicaid (8.3%). Over a third of patients (37%) resided in an area in the most disadvantaged area deprivation index (ADI) quartile. The median available follow-up was 765 days. Seventy-five percent of the cohort filled an oral antimyeloma medication prescription (excluding corticosteroids), with a median time to fill of 28 days (IQR, 15–61). In the multivariable Cox regression model, Black race (vs. White, adjusted hazard ratio [aHR], 0.61, 95% CI, 0.42–0.87), older age at diagnosis (aHR per 1 year, 0.97, 95% CI, 0.95–0.98), diagnosis during an inpatient admission (aHR, 0.63, 95% CI, 0.43–0.92), and estimated glomerular filtration rate ≤29 ml/min/1.73 m2 (vs. ≥60, aHR, 0.46, 95% CI, 0.29–0.73) were negatively associated with prescription fill for oral antimyeloma medication at 30 days, while insurance type and ADI were not significant predictors. [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]

Current treatment guidelines of myeloma cast nephropathy (MCN) recommend the institution of plasma cell‐directed therapy and consideration of therapeutic plasma exchange (TPE), with the goal of rapid reduction of the serum free light chain (sFLC). However, the role of TPE continues to remain a subject of debate. The goal of this retrospective bi‐institutional study was to evaluate the clinical outcomes of TPE in combination with systemic therapy. Eighty patients were included in this analysis, of whom 72.5% had ≥50% drop in their initial involved sFLC. At 3 months from TPE initiation, the overall hematologic response rate (ORR) was 67.5% with a very good partial response or better (≥VGPR) rate of 40%. At 6 months, ORR was 57.5%, with ≥VGPR rate of 49%. The renal response rate at 3 and 6 months was 47.5% and 43.75%, respectively; the overall renal response rate was 48.75%. On multivariable analysis, every one unit increase in baseline creatinine (odds ratio [OR] 0.76, p = 0.006), and achievement of ≥VGPR (OR 21.7 p < 0.0001) were significantly associated with renal response. Also, a ≥50% drop in sFLC was favorably associated with renal response (OR 3.39, p = 0.09). With a median follow‐up of 36.4 months, the median overall survival (OS) was 11 months. On multivariable analysis, achievement of renal response (hazard ratio [HR] 0.3, p < 0.0001) and newly diagnosed disease (NDMM; HR 0.43, p = 0.0055) were associated with improved OS. Among NDMM patients, those treated with daratumumab‐based regimens had a trend for better OS (p = 0.15), compared to other regimens, but the difference was not significant. At the end of follow‐up, an estimated 40.4% of patients who were on dialysis were able to become dialysis independent. In conclusion, our study highlights the poor survival of patients with MCN. Achievement of early renal response is crucial for prolonged OS, with daratumumab‐based therapies showing promise. [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]

The presence of extramedullary disease (EMD) has been associated with poor outcomes in patients with relapsed-refractory multiple myeloma (RRMM). Herein, we report the outcomes of RRMM patients who were treated with standard-of-care (SOC) chimeric antigen receptor (CAR) T-cell therapy and had active extraosseous EMD before the infusion. Data were retrospectively collected from patients at three US institutions with the intent to receive SOC CAR T. Responses were assessed per the International Myeloma Working Group criteria. A total of 152 patients proceeded with infusion, of whom 47 (31%) had EMD (EMD group) and 105 (69%) did not (non-EMD group). Baseline patient characteristics were comparable between the two groups. The EMD group had a higher incidence of high-grade CRS, steroid and anakinra use, and thrombocytopenia on day +30 compared to the non-EMD group. In addition, the EMD group had an inferior overall response rate (58% vs 96%, p < 0.00001), median progression-free survival (PFS) (5.1 vs 12.4 months; p < 0.0001), and overall survival (OS) (12.2 vs 27.5 months; p = 0.00058) compared to the non-EMD group. We further subdivided the non-EMD patients into those with paramedullary disease (PMD-only group, n = 26 [17%]) and those with neither EMD nor PMD (bone marrow-contained group or BM-only group, n = 79 [52%]). Patients with PMD-only had similar median PFS (11.2 vs 13.6 months, p = 0.3798) and OS (not reached [NR] vs 27.5 months, p = 0.6446) compared to patients with BM-only disease. However, patients with EMD exhibited inferior median PFS (5.1 vs 13.6 months, p < 0.0001) and OS (12.2 vs 27.5, p = 0.0008) compared to patients in the BM-only group. Treatment with SOC CAR T yielded meaningful clinical outcomes in real-world RRMM patients with extraosseous EMD, though responses and survival outcomes were suboptimal compared to patients without EMD. The presence of only EMD but not PMD was associated with significantly worse survival outcomes following the CAR T infusion. [ABSTRACT FROM AUTHOR]

PURPOSE Little is known about the role of social determinants of health (SDOH) in the utilization of novel treatments among patients with newly diagnosed multiple myeloma (NDMM). METHODS This retrospective cohort study used Taussig Cancer Center's Myeloma Patient Registry to identify adults with NDMM between January 1, 2017, and December 31, 2021. Electronic health records data captured treatment with (1) triplet or quadruplet regimen and (2) lenalidomide during the first year after NDMM, and (3) stem-cell transplant (SCT) through December 31, 2022. Multivariable logistic regression models examined associations of demographic/clinical characteristics and SDOH with care patterns. RESULTS We identified 569 patients with median age at diagnosis of 66 years (IQR, 59-73); 55% were male, 76% White, 23% Black, 1.1% other races, insured by Medicare (51%), private payer (38%), Medicaid (8.3%), and self-pay/other (1.8%). In the multivariable models, self-pay/other payers (adjusted odds ratio [AOR], 0.15 [95% CI, 0.03 to 0.54]) was associated with lower odds of triplet or quadruplet regimen, compared with Medicare. Private insurance (AOR, 0.48 [95% CI, 0.27 to 0.86]) and self-pay/other payers (AOR, 0.16 [95% CI, 0.04 to 0.74]) had lower odds of lenalidomide. Black patients (v White; AOR, 0.47 [95% CI, 0.26 to 0.85]) and patients treated at regional hospitals (v Taussig Cancer Center; AOR, 0.27 [95% CI, 0.12 to 0.57]) had lower odds of SCT. The odds of receiving triplet or quadruplet regimen, lenalidomide, and SCT also varied by the year of NDMM. CONCLUSION Care for NDMM varied based on race, insurance type, year of diagnosis, and treatment facility. It may be useful to examine the impact of insurance-related characteristics and recent policy initiatives on care disparities. [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]

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]

This study explored the efficacy of intravenous immunoglobulin (IVIG) prophylaxis in reducing infection‐related hospitalizations (IRHs) in MM patients. This was a retrospective study of MM patients who received IVIG at Taussig Cancer Center between July 2009 and July 2021. The primary endpoint was rate of IRHs per patient‐year on‐IVIG versus off‐IVIG. 108 patients were included. There was a significant difference in the primary endpoint of rate of IRHs per patient‐year on‐IVIG versus off‐IVIG in the overall study population (0.81 vs. 1.08; Mean Difference [MD], −0.27; 95% Confidence Interval [CI], −0.57 to 0.03; p value [P] = 0.04). The subgroup of patients with a 1‐year period of continuous IVIG (49, 45.3%), the subgroup with standard‐risk cytogenetics (54, 50.0%) and the subgroup with 2 or more IRHs (67, 62.0%) all showed a significant reduction in IRHs while on‐IVIG versus off‐IVIG (0.48 vs. 0.78; MD, −0.30; 95% CI, −0.59 to 0.002; p = 0.03) and (0.65 vs. 1.01; MD, −0.36; 95% CI, −0.71 to −0.01; p = 0.02) and (1.04 vs. 1.43; MD, −0.39; 95% CI, −0.82 to 0.05; p = 0.04) respectively. IVIG showed significant benefit in reducing IRHs in the overall population and in multiple subgroups. [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]

Background: Significant advances have been made in the treatment of chronic lymphocytic leukemia (CLL) since the turn of the new millennium. However, most clinical trials were done in developed countries where minority ethnicities were underrepresented. Materials and Methods: To gauge the quality of research in CLL being done in Pakistan, we conducted a comprehensive literature search using PubMed, Clinicaltrials.gov, and Google Scholar on 14 January 2022 following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. Results: A total of 16 studies met the inclusion criteria. The most common study design was cross-sectional. Eight studies evaluated the clinicohematological profile of CLL patients and the effect of various cytogenic abnormalities through fluorescence in situ hybridization (FISH) technique on disease progression and prognosis. Five studies discussed the prevalence of abnormalities such as autoimmune cytopenias and other serum chemistry derangements. Only two studies evaluated treatment outcomes, among which one study reported a 2-year overall survival of 65% among patients with 17p deletion. None of the studies had patients on novel targeted agents. No pharmaceutical sponsored or funded clinical trials were found. Conclusions: Our review suggests that although small clinical studies continue to be performed across the country, multiple financial and logistical barriers need to be addressed for larger, more impactful clinical trials to be conducted that will help answer demographic-specific questions and decrease reliance on foreign studies. [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]

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]

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]

Minimal residual disease (MRD) assessment through blood component sampling by liquid biopsies (LBs) is increasingly being investigated in myeloid malignancies. Blood components then undergo molecular analysis by flow cytometry or sequencing techniques and can be used as a powerful tool for prognostic and predictive purposes in myeloid malignancies. There is evidence and more is evolving about the quantification and identification of cell-based and genebased biomarkers in myeloid malignancies to monitor treatment response. MRD based acute myeloid leukemia protocol and clinical trials are currently incorporating LB testing and preliminary results are encouraging for potential widespread use in clinic in the near future. MRD monitoring using LBs are not standard in myelodysplastic syndrome (MDS) but this is an area of active investigation. In the future, LBs can replace more invasive techniques such as bone marrow biopsies. However, the routine clinical application of these markers continues to be an issue due to lack of standardization and limited number of studies investigating their specificities. Integrating artificial intelligence (AI) could help simplify the complex interpretation of molecular testing and reduce errors related to operator dependency. Though the field is rapidly evolving, the applicability of MRD testing using LB is mostly limited to research setting at this time due to the need for validation, regulatory approval, payer coverage, and cost issues. This review focuses on the types of biomarkers, most recent research exploring MRD and LB in myeloid malignancies, ongoing clinical trials, and the future of LB in the setting of AI. [ABSTRACT FROM AUTHOR]

Despite significant progress and improving outcomes in the management of plasma cell disorders, AL amyloidosis remains diagnostically and therapeutically challenging for clinicians across practice settings. There is, however, a reason for optimism with the advent of new combination therapy approaches and novel targets offering the promise of improvement in end organ function, survival, and quality of life. This review offers a clinically applicable overview of an approach to diagnosis, risk stratification, and clinical management of AL amyloidosis in an era of rapid therapeutic innovation. [ABSTRACT FROM AUTHOR]

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]

Engraftment syndrome (ES) is a non-infectious complication seen both in autologous and allogeneic hematopoietic stem cell transplants and is characterized by the presence of non-infectious fever, diarrhea, skin rash, pulmonary infiltration, pulmonary edema, and deranged renal and liver function tests This review will be delineating the incidence of ES, important differential diagnoses to be considered and management options. The literature search was done through various databases like PubMed, Google scholar, Cochrane library, and EMBASE. The incidence of engraftment syndrome was ranging from 8 to 50% in patients undergoing Autologous stem cell transplantation while the incidence was 10-77% in patients undergoing Allogeneic stem cell transplantation. Fever was the most commonly observed symptom of ES in both Autologous and Allogeneic stem cell transplantation while the second most frequently reported symptom was non-infectious diarrhea in patients undergoing autologous stem cell transplantation and Skin rash in patients with Allogeneic stem cell transplantation. Pro-inflammatory cytokines and immune response dysregulation were highlighted as the mechanism behind ES development. The significant difference between ES and aGVHD was observed based on cytokines, with IL-12, IL-1β, IL-6, TNF-α, and IFN-γ levels in plasma being higher in patients with ES as compared to patients with aGVHD. Intravenous methylprednisolone was used as the treatment of choice in the majority of the studies. Overall the incidence of ES was high in patients undergoing allogeneic hematopoietic stem cells transplantation. The survival in patients developing ES was less compared to those who did not develop ES. Engraftment syndrome is one of the complications following hematopoietic stem cell transplantation that need early identification, differentiation from infectious complications, and aGVHD and timely initiation of corticosteroids therapy. [ABSTRACT FROM AUTHOR]

Background: Patients with plasma cell dyscrasia are at a higher risk of developing a severe Coronavirus-2019 (COVID-19) infection. Here we present a systematic review of clinical studies focusing on the immune response to the COVID-19 vaccination in patients with plasma cell dyscrasia. Objectives: This study aims to evaluate the immune response to COVID-19 vaccines in patients with plasma cell dyscrasia and to utilize the results to improve day-to-day practice. Design: Systematic Review Methods: Online databases (PubMed, CINAHL, Ovid, and Cochrane) were searched following the preferred reporting items for systematic review and meta-analysis (PRISMA) guidelines. Only articles published in the English language were included. Out of 59 studies, nine articles (seven prospective and two retrospective studies) were included in this systematic review. Abstracts, case reports, and case series were excluded. Results: In all nine studies (N = 1429), seroconversion post-vaccination was the primary endpoint. Patients with plasma cell disorders had a lower seroconversion rate compared to healthy vaccinated individuals and the overall percentage of seroconversion ranged between 23% and 95.5%. Among patients on active therapy, lower seroconversion rates were seen on an anti-CD38 agent, ranging from 6.5 up to 100%. In addition, a significantly lower percentage was recorded in older patients, especially in those aged equal to or greater than 65 years and those who have been treated with multiple therapies previously. Only one study reported a statistically significant better humoral response rate with the mRNA vaccine compared to ADZ1222/Ad26.Cov.S. Conclusion: Variable seropositive rates are seen in patients with plasma cell dyscrasia. Lower rates are reported in patients on active therapy, anti-CD38 therapy, and elderly patients. Hence, we propose patients with plasma cell dyscrasias should receive periodic boosters to maintain clinically significant levels of antibodies against COVID-19. Registration: PROSPERO ID: CRD42023404989 Plain language summary: COVID-19 vaccine immune response in patients with plasma cell dyscrasia- a systematic review Background: Patients with plasma cell disorders are at a higher risk of developing a severe coronavirus-19 infection. Here we present a systematic review of clinical studies focusing on the immune response to the coronavirus-19 vaccination in patients with plasma cell dyscrasia. Objectives: This study aims to evaluate the immune response to COVID-19 vaccines in patients with plasma cell dyscrasia and to transcribe the results to day-to-day practice. Design: Systematic Review Data sources: PubMed, CINAHL, Ovid, and Cochrane. Methods: Online databases were searched following the preferred reporting items for systematic review and meta-analysis (PRISMA) guidelines. Only articles published in the English language were included. Abstracts, case reports, and case series were excluded. Out of 59 studies, nine articles were selected for a systematic review. Results: In all 9 studies (N = 1,429), seroconversion post-vaccination was the primary endpoint that our review assessed. Patients with plasma cell disorders had a lower seroconversion rate compared to healthy vaccinated individuals and the overall percentage of seroconversion ranged between 23 and 95.5%. Amongst patients on active therapy, lower seroconversion rates were seen in patients on an anti-CD38 agent, ranging from 6.5 up to 100%. In addition, a significantly lower percentage was recorded in older patients, especially those aged equal to or greater than 65 years and those who have been treated with multiple therapies previously. Only one study reported a statistically significant better humoral response rate with the mRNA vaccine compared to ADZ1222/Ad26.Cov.S. Conclusion: Variable seropositive rates are seen in patients with plasma cell dyscrasia. Lower rates are reported in patients on active therapy, anti-CD38 therapy, and elderly patients. Hence, we propose patients with plasma cell disorders should receive periodic boosters to maintain clinically significant levels of antibodies against COVID-19. [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]

Venous thromboembolism (VTE) is a serious complication commonly experienced in cancer patients. Incidence of VTE typically brings poor prognosis as it represents the second most common cause of mortality in cancer patients just after the malignancy itself. Studies suggest that multiple myeloma (MM) is among the malignancies with further enhanced risk of VTE, especially in patients undergoing autologous hematopoietic cell transplantation (AHCT). However, risk factors and preventative approaches remain poorly explored. Here, we explore the incidence of VTE in MM patients undergoing AHCT, while also highlighting risk factors and preventions that may aid in preventing VTE in patients who are at higher risk. [ABSTRACT FROM AUTHOR]

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]