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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]

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]

Background. Relapsed Ewing’s sarcoma (RES) is an aggressive malignancy with poor survival. Although high-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) given after conventional chemotherapy (CC) has shown survival benefits, it is not generally used in the United States for RES. We performed a systemic review to evaluate the benefits of HDCT for RES. Methods. Literature search involved Medline, Embase, and Cochrane database. We included studies with RES patients treated with HDCT/ASCT. Results. Twenty-four studies with total of 345 reported RES patients that got HDCT were included in final analysis. Seventeen studies had patients with multiple malignancies including RES, while seven had only RES patients. At 2 and 3–5 years, event-free survival (EFS) in studies with only RES patients ranged 42–47% and 20–61% and overall survival (OS) ranged 50–66% and 33–77%, respectively. In studies with combined patients that reported outcomes of RES separately, the EFS at 1–3 and 4 years was 36–66% and 17–50%, respectively. The OS at 1-2 and 3-4 years was 40–60% and 50–70%. Conclusions. Most studies using HDCT/ASCT as consolidation regimen showed improved survival benefits compared to CC. Randomized controlled studies are needed to determine true clinical benefits of HDCT followed by ASCT in patients with RES. [ABSTRACT FROM AUTHOR]

Background: High-dose chemotherapy with autologous stem cell rescue is commonly used for the treatment of relapsed germ cell tumors. We report the first case of delayed rhabdomyolysis with paclitaxel, ifosfamide, carboplatin, and etoposide regimen.Case Presentation: We report a case of a 21-year-old African-American man diagnosed with relapsed non-seminomatous germ cell tumor who received high-dose chemotherapy with carboplatin and etoposide following TIGER trial arm B off-protocol. His course was complicated by muscle pain and rhabdomyolysis after cycle 4 on day +12 after infusion of autologous stem cells. To the best of our knowledge, this complication has not been reported with this regimen. A differential diagnosis of sepsis and neutropenic fever along with side effects of high-dose chemotherapy were considered, but based on the timing of events, it was concluded that the etiology of rhabdomyolysis is high-dose chemotherapy. Rhabdomyolysis was successfully treated with hydration and did not recur during subsequent cycle 5.Conclusions: Delayed rhabdomyolysis after high-dose chemotherapy with paclitaxel, ifosfamide, carboplatin, and etoposide regimen has not been previously reported and needs to be considered for preventive strategy and prompt diagnosis and treatment to avoid renal complications. Physicians should have a low threshold to check creatine kinase enzymes in patients with unexplained muscle pain or renal insufficiency after high-dose chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Some patients with low-grade lymphoid malignancies develop transformed disease, requiring stem cell transplantation (SCT). SCT outcomes in transformed low-grade lymphoid malignancies may differ from those of nontransformed disease or other aggressive non-Hodgkin lymphomas. We conducted a pooled analysis of the clinical outcomes of allogeneic versus high-dose therapy (HDT) with autologous SCT in adult patients with transformed low-grade lymphoid malignancies. Methods: A PubMed, EMBASE, and Cochrane search yielded 4 comparative studies reporting allogeneic versus HDT with autologous SCT outcomes in adults (age ≥18) with transformed low-grade lymphoid malignancies, including follicular, chronic/small lymphocytic, and marginal zone lymphoma. Risk ratio (RR) and 95% CI were calculated using random-effects models. Results: Rates for overall survival (OS) were 51.0 versus 69.5% (RR = 1.55, 95% CI 1.19-2.02, p = 0.001), rates of relapse were 37.3 versus 35.3% (RR = 1.04, 95% CI 0.70-1.55, p = 0.84), and rates of transplant-related mortality (TRM) were 33.3 versus 7.2% (RR = 4.52, 95% CI 2.75-7.43, p < 0.00001) for allogeneic versus autologous SCT. Previous rituximab treatment, reduced intensity conditioning regimen prior to SCT, or original pathology had no prognostic impact. Conclusion: HDT followed by autologous SCT was associated with lower TRM and a better OS, but there was no difference in relapse versus allogeneic SCT. Autologous SCT may be the better therapeutic option, considering the second chance of allogeneic SCT in the case of relapse. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy for multiple myeloma (MM) has been the focus in recent years due to its myeloma-specific immune responses. We reviewed the literature on non-Food and Drug Administration (FDA) approved monoclonal antibodies (mAbs) to highlight future perspectives. We searched PubMed, EMBASE, Web of Science, Cochrane Library and ClinicalTrials.gov to include phase I/II clinical trials. Data from 39 studies (1906 patients) were included. Of all the agents, Isatuximab (Isa, anti-CD38) and F50067 (anti-CXCR4) were the only mAbs to produce encouraging results as monotherapy with overall response rates (ORRs) of 66.7% and 32% respectively. Isa showed activity when used in combination with lenalidomide (Len) and dexamethasone (Dex), producing a clinical benefit rate (CBR) of 83%. Additionally, Isa used in combination with pomalidomide (Pom) and Dex resulted in a CBR of 73%. Indatuximab Ravtansine (anti-CD138 antibody-drug conjugate) produced an ORR of 78% and 79% when used in combination with Len-Dex and Pom-Dex, respectively. Conclusions: Combination therapy using mAbs such as indatuximab, pembrolizumab, lorvotuzumab, siltuximab or dacetuzumab with chemotherapy agents produced better outcomes as compared to monotherapies. Further clinical trials investigating mAbs targeting CD38 used in combination therapy are warranted. [ABSTRACT FROM AUTHOR]

Standard induction therapy for multiple myeloma is three-drug combination based on following classes of drugs: proteasome inhibitors, immunomodulators and steroids. Despite its notable efficacy, bortezomib has side effects like peripheral neuropathy (PNP) with reported incidence of grade ≥3 PNP between 2%–23% Schlafer et al., 2017. Carfilzomib (CFZ) has high selectivity and minimal off-target adverse effects including lower rates of PNP. CFZ is already approved for treatment of relapsed and refractory multiple myeloma (RRMM) as single agent as well as in combination with lenalidomide and/or dexamethasone. Extensive literature search identified a total of 1839 articles. Twenty-six articles (n = 5980) met the inclusion criteria, 15 in newly diagnosed multiple myeloma (NDMM) and 11 in RRMM group. CFZ demonstrates comparable or even better efficacy to bortezomib with much favorable AE profile. Deep, rapid and sustainable response using KRd with safer toxicity profile supports extension of KRd therapy to frontline therapy for all risk categories of MM. High incidence of grade ≥3 HTN underscores the importance of serial BP monitoring. In RRMM, CFZ has documented efficacy with standard 20–27mg/m2 dose. Further large-scale trials are needed to study benefit-to-risk profile of 20–56 and 20–70 mg/m2 dose of CFZ vs standard 20–27 mg/m2 dose in NDMM and RRMM. [ABSTRACT FROM AUTHOR]

Background CD30 (Ki-1) is a cell membrane protein derived from the tumor necrosis factor (TNF) receptor family. The CD30 antigen has been associated primarily with Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL). Brentuximab vedotin (BV) is an antibody-drug conjugate targeting the CD30 antigen. FDA approval for BV includes relapsed and refractory HL and sALCL. The CD30 antigen also has been identified in many solid tumors, predominantly of germ cell origins and early clinical data is promising. Objective Perform a focus literature review evaluating the prevalence of the CD30 antigen among nonlymphomatous tumors with a potential correlate for CD30 targeted therapy. Eligibility criteria Inclusion criteria: all retrospective reviews and case reports citing CD30 positivity or negativity in non-lymphomatous malignancies in which data were presented based on location. Exclusion criteria: studies with hematopoetic malignancies, cutaneous malignancies, non-human populations, and non-english publications. Included studies A total of 119 articles met these criteria and are summarized in this manuscript. Conclusion The CD30 antigen has shown variable prevalence among non-hematopoetic tumors, most notably among germ cell tumors and mesothelioma. With additional, preclinical and properly powered clinical studies, CD30 targeted therapy such as that of BV, alone or in combination with other agents may prove to be a strong candidate in the treatment of various CD30 + malignancies. [ABSTRACT FROM AUTHOR]