Immunomodulatory Monoclonal Antibodies Research Articles

Immunotherapy in HIV-associated Kaposi Sarcoma: Challenges and Prospects

Abstract: Kaposi Sarcoma [KS] stems from malignant endothelial cells targeting the cutaneous and lymphatic systems. The aetiological agent, human herpesvirus type 8, has been implicated in the induction of KS. Of the four variants of KS that exist, HIV/AIDS associated KS remains one of the leading cancers in people living with HIV in sub-Saharan Africa [SSA]. It is estimated that approximately 80% of KS cases were attributed to HIV in 2020. Although the introduction of anti-retroviral therapy [ART] alleviated the burden in 1981, its prevalence on the continent remains significant in comparison to the rest of the world. Traditional therapeutics such as chemotherapy continue to be the most common form of managing HIV-associated KS; however, the incidence of this global cancer continues to rise, predominantly in SSA. Furthermore, a significant number of HIV/AIDS-associated KS patients had been observed with normal CD4+ count and low viral load levels. This necessitates the development of other therapeutic strategies to collectively manage the continental crisis. Various strategies, such as immunomodulatory agents, monoclonal antibodies and therapeutic cytokines, are being investigated to be used as potential therapeutic strategies. One strategy highlights targeting the signalling pathways and growth factors involved in angiogenesis, which is an important characteristic of KS. The PD-1/PD-L1 immune checkpoint blockades are particularly interesting since cell cycle inhibitors have shown promising results as a potential immunotherapeutic agent. Predictive biomarkers and alternative vaccines will be discussed here while potential barriers which reduce the impact of immunotherapy are discussed throughout the review.

Перспективы применения иммуномодулирующих препаратов и модуляторов цереблон Е3-лигазы в лечении множественной миеломы

In recent decades, the progress in multiple myeloma (MM) treatment has been linked to a clearer insight into the biology of this disease and practical application of new pharmaceutical classes, such as immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies (MABs). Modern IMiDs (lenalidomide and pomalidomide) are thalidomide derivatives which despite the similarity of chemical structure show only a relative cross-resistance. Lenalidomide is a second-generation immunomodulator with high anti-tumor activity and a favorable safety profile. In 2006, the use of lenalidomide combined with dexamethasone (Rd regimen) was approved by FDA (USA) for the treatment of relapsed/refractory MM, and 9 years later, in 2015, for newly diagnosed MM. During 2015–2019, the treatment of relapsed MM applied the newly developed regimens involving Rd combined with bortezomib (VRd), carfilzomib (KRd), ixazomib (IRd), elotuzumab (ERd), and daratumumab (DRd), the so-called triplets. Pomalidomide is a third-generation drug used in lenalidomide-refractory patients. For patients with relapsed/refractory MM who received at least two therapy lines with lenalidomide and bortezomib, regimens with 3 drugs were introduced which include pomalidomide and dexamethasone combined with elotuzumab (EPd), isatuximab (Isa-Pd), and daratumumab (DPd). In 2010, the molecular target of IMiD action was discovered, that is protein cereblon (CRBN), a component of CRBN E3 ligase enzyme complex. The insight into this mechanism provided the basis for developing a new family of thalidomide derivatives which are now called CRBN E3 ligase modulators (CELMoDs). In phase I/II trials, two drugs belonging to this group (iberdomide and mezigdomide) showed promising activity in MM refractory to three classes of antitumor drugs (IMiDs, PIs, and anti-CD38 MABs). The present review is focused on prospective studies of IMiDs and CELMoDs at different stages of MM treatment.

Treatment of multiple myeloma with selinexor: a review.

Over the last 20 years, breakthroughs in accessible therapies for the treatment of multiple myeloma (MM) have been made. Nevertheless, patients with MM resistant to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies have a very poor outcome. Therefore, it is necessary to explore new drugs for the treatment of MM. This review summarizes the mechanism of action of selinexor, relevant primary clinical trials, and recent developments in both patients with relapsed/refractory myeloma and patients with newly diagnosed myeloma. Selinexor may be useful for the treatment of refractory MM.

Real-world outcomes in relapsed refractory multiple myeloma patients exposed to three or more prior treatments: an analysis from the ANZ myeloma and related diseases registry.

There is no currently available standard of care for triple-class exposed, relapsed refractory myeloma (RRMM) patients in Australia. CARTITUDE-1 (CART-1) was a single-arm, phase 1b/2 study of 97 triple-class exposed RRMM patients, who received BCMA-CAR-T cell therapy with ciltacabtagene autocel. Overall response rate (ORR) was 98%. Median progression free survival (PFS) and overall survival (OS) had not been reached at a median follow-up of 28 months. We performed a retrospective analysis on a cohort of CART-1 comparable RRMM patients participating in the Australian and New Zealand Myeloma and Related Diseases Registry (MRDR), to compare outcomes in triple-class exposed MM patients treated with currently available therapies, in a real-world context. The CE-MRDR cohort (n = 28) fulfilled CARTITUDE-1 eligibility (CE) criteria: ≥3 lines of therapy (LOT) including an immunomodulatory agent, proteasome inhibitor and CD38-directed monoclonal antibody (CD38mAb) and Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0-2 at diagnosis. The modified-CE-MRDR (n = 132) received ≥3 LOT but may not have received a CD38mAb with an ECOG PS score of 3 (0-3). Responses to the first subsequent therapy after eligibility were poor - ORR was 23% and 0% with progressive disease (PD) reported in 61% and 36%, CE-MRDR and m-CE-MRDR respectively. Responses to the second subsequent therapy after eligibility were worse, ORR 0% and 31%, CE-MRDR and m-CE-MRDR respectively, with high rates of PD, particularly in CE-MRDR. Median OS was 5.4 versus 9.5 months, CE-MRDR versus m-CE-MRDR. This retrospective analysis confirms uniformly poor outcomes for Australian RRMM patients. There remains a critical need for greater accessibility to novel treatments, such as CAR-T, outside clinical trials.

Allogeneic Stem Cell Transplantation in Multiple Myeloma: Risk Factors and Outcomes in the Era of New Therapeutic Options-A Single-Center Experience.

Despite major treatment advances, multiple myeloma remains incurable. The outcome of patients who are refractory to immunomodulatory agents, proteasome inhibitors, and anti-CD38 monoclonal antibodies is poor, and improved treatment strategies for this difficult-to-treat patient population are an unmet medical need. This retrospective, unicentric analysis included 38 patients with relapsed/refractory multiple myeloma or plasma cell leukemia who underwent allogeneic stem cell transplantation (allo-HSCT) between 2013 and 2022. Survival outcomes, relapse incidence, and non-relapse mortality were calculated according to remission status, date of allo-HSCT, cytogenetic risk status, timing, and number of previous autologous HSCTs. The median PFS was 13.6 months (95% CI, 7.7-30.4) and the median OS was 51.4 months (95% CI, 23.5-NA) in the overall cohort. The cumulative incidence of relapse at 3 years was 57%, and non-relapse mortality was 16%. The median PFS and OS were significantly longer in patients with very good partial remission (VGPR) or better compared to patients with less than VGPR at the time of allo-HSCT (mPFS 29.7 months (95% CI, 13.7-NA) vs. 6.5 months (95% CI, 2.6-17.0); p = 0.009 and mOS not reached vs. 18.6 months (95% CI, 7.0-NA); p = 0.006). For selected patients, allo-HSCT may result in favorable overall survival, in part by providing an appropriate hemato-immunological basis for subsequent therapies.

Vdpace As Salvage Therapy in Triple Class Relapse/Refractory Multiple Myeloma

Background: Patients that have triple-class relapsed/refractory multiple myeloma (RRMM) have relapsed on each of the following classes: an immunomodulatory drugs (IMiDs), proteasome inhibitors (PI), and anti-CD38 monoclonal antibody (MoAb). RRMM poses a significant challenge with poor prognosis due to limited options. We evaluated VDPACE (bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, etoposide) for efficacy and safety as salvage therapy in heavily pre-treated RRMM. Methods: We retrospectively analyzed 54 patients who had triple-class RRMM and received at least 1 cycle of VDPACE between June 2016 - July 2023 at the University of Kansas Health System in collaboration with the U.S Myeloma Innovations Research Collaborative (USMIRC). VDPACE consisted of bortezomib 1 mg/m2 subcutaneous on days 1,4,8 and 11, doxorubicin 10 mg/m2 continuous infusion (CI) x 4 days, cisplatin 10 mg/m2 CI x 4 days, cyclophosphamide 400 mg/m2 CI x 4 days and etoposide 40 mg/m2 CI x 4 days. Descriptive analysis was performed on available data for patient characteristics, disease course, and outcomes differentiating these two groups. Adverse events were graded based on the CTCAE v5.0 criteria. Responses to therapy, including overall response rate (ORR), complete response or better (≥CR), and very good partial response (VGPR) were evaluated using the International Myeloma Working Group (IMWG) criteria. The Kaplan-Meier method was used for progression-free survival (PFS) and overall survival (OS) assessments. Results: Of the 54 patients in this study, the median age was 62 years (41-75), 81% (n=44) were Caucasian, 48% (n=26) were IgG subtype, 42% of the patients (n=23) had Stage-III disease at treatment, 74% (n=40) had high-risk cytogenetics, and extramedullary disease (EMD) was present in 50% (n=27) of patients. These patients had a median of 5 (2-10) prior lines of therapy;67% (n=36) were penta-drug exposed, 59% (n=32) were penta-RRMM and 19% (n=10) were refractory to BCMA-directory therapy. Patient characteristics are summarized in Table 1. The overall response rate (ORR) for the whole cohort was 54%, 7 (13%) patients achieved ≥ VGPR, median PFS was 4.67 months (95% CI, 2.97 to 8.40), while OS was 7.93 months (95% CI, 6.33 to 14.73), see Figure 1. Regarding efficacy on penta-RRMM (n=32) vs non-penta-RRMM subgroups (n=22), the ORR was 44% vs 68% respectively, while the median PFS was 2.67 months (95% CI, 2-7.6) in the penta-RRMM subgroup compared to 9.28 months(95% CI, 4.67-NA) in the non-penta-refractory subgroup. Treatment post salvage therapy of VDPACE included autologous/allogenic stem cell transplant (SCT), BCMA-directed therapies (CAR-T, T-cell engaging bispecific antibodies and antibody-drug conjugates), other chemotherapies, in addition to enrollment to clinical trials reported at 13%, 26%, 39% and 4%, respectively. 11% patients proceeded to hospice due to progression disease. Most patients experienced hematological adverse events (AEs), including grade III/IV lymphopenia (96%), neutropenia (93%), thrombocytopenia (87%) and anemia (76%). 69% (n=37) required a blood transfusion and 67% (n=36) required platelet transfusion. Neutropenic fever (NF) was reported in 33% (n=18), while the most common cause of infection was bacteremia in 24% of patients, followed by pneumonia in 20% of the patients. Following the initial hospitalization to receive treatment, the readmission rate within 60 days was 50% (n=27), that was mostly due to NF (52%, n=14). Treatment related mortality (TRM) in the first 30 days was reported in 6% (n=3), all due to severe sepsis. See Table 1. Conclusions: Based on our retrospective study, VDPACE is an effective salvage treatment in triple RRMM, and can be used as a bridging therapy prior to CAR-T, prior to enrollment in clinical trials or proceeding to SCT, however, due to TRM secondary to severe infections, careful selection of patients for this intensive therapy must be emphasized.

Real-World Clinical Outcomes Among Triple-Class Exposed Multiple Myeloma Patients and Subgroups in the US Oncology Network

Introduction: Despite the development of advanced treatment options, multiple myeloma (MM) remains an incurable disease. Most MM patients ultimately relapse and require further treatments. MM patients who are triple class exposed (TCE) to immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies have particularly poor outcomes and reduced probability to transition to a next therapy option. In the past few years, several novel therapies including Chimeric Antigen Receptor T-cell (CAR-T) therapies and bispecific antibody therapies became available for TCE patients in the later line setting. Using latest data, this study aims to characterize MM patients treated in US Oncology Network, who were TCE with at least 4 prior lines of therapy (4+ prior LOTs), and to describe their characteristics, treatment patterns, and clinical outcomes. Because treatment history such as penta-drug exposure status (at least two PIs, at least two IMiDs, and at least one anti-CD38) and patient characteristics such as race (White and African American) are known to impact disease outcomes, the impact of these subgroups on treatment to discontinuation or death (TTD) and time to next treatment or death (TTNT) were also evaluated. Methods: Patients with MM who were TCE with 4+ prior LOTs were identified retrospectively from the iKnowMed (iKM) oncology EMR database of the US Oncology Network. Those eligible initiated the next line of therapy (index date) from July 3, 2019 (when additional new treatment options became available) through April 3, 2023, and were followed to the earliest of death, last activity, or end of the study period. Clinical outcomes including TTD and TTNT were analyzed and estimated using the Kaplan-Meier method. Results: A total of 561 TCE patients with 4+ prior LOTs were included in the study, including 95 (16.9%) African American, 387 (69.0%) White, and 310 (55.3%) patients who were penta-drug exposed before index. Key demographic and clinical characteristics are listed in Table 1. The mean (SD) number of prior lines of therapy for the overall TCE & 4+ prior LOTs MM patients before index date was 4.6 (1.2). Prior to the index date, most patients were exposed to daratumumab (99.8%), lenalidomide (95.4%), bortezomib (93.2%), pomalidomide (77.7%), and carfilzomib (61.9%). Excluding corticosteroids, the most common index treatments were pomalidomide- (34.4%), daratumumab- (32.2%), and carfilzomib- (29.1%) based regimens. The most frequently used therapy were triplets (55.1%), followed by doublets (29.3%) and quadruplets (11.9%). CAR-T therapies were not captured in the data, and only 3 patients received bispecific antibody therapy. The estimated median (95% CI) TTD and TTNT in months for the overall TCE with 4+ prior LOTs MM patients were 4.2 (3.9, 5.1) and 6.5 (5.5, 7.4), respectively. TTD and TTNT estimates for the three subgroups are listed in Table 2. Conclusions: This study demonstrates there are limited effective treatment options for heavily treated MM patients in the US Oncology Network. Novel therapies have not been widely used. Clinical outcomes in these patients remain poor, as demonstrated by the short TTD and TTNT. More than half of the patients in the study were penta-drug exposed, a subgroup that showed even worse clinical outcomes than the overall patient group. Racial disparity was also observed, with African American patients appearing to have shorter TTD and TTNT than White patients. The findings highlight the continued need for effective treatments for heavily treated MM patients, including those with demonstrated particularly poor outcomes. Studies investigating innovative therapies to improve the outcomes for these patients are in process.

Patient (pt) Experiences of Receiving Idecabtagene Vicleucel (Ide-Cel, bb2121) Versus Standard (Std) Regimens for the Treatment (Tx) of Relapsed/Refractory Multiple Myeloma (RRMM) in the Randomized, Controlled KarMMa-3 Clinical Trial: Analysis of Longitudinal Qualitative Interviews

Introduction: Ide-cel is a first-in-class B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T cell therapy approved by the United States (US) Food and Drug Administration; the European Medicines Agency; and Japan's Ministry of Health, Labour, and Welfare for treating adult pts with RRMM who were triple-class exposed (TCE) to an immunomodulatory (IMiD) agent, proteasome inhibitor (PI), and anti-CD38 monoclonal antibody and who experienced disease progression/relapse after last therapy. The phase 3 multicenter, open-label, randomized controlled KarMMa-3 trial (NCT03651128) enrolled pts with RRMM who were TCE (including an IMiD agent, PI, and daratumumab [DARA]) after 2-4 prior lines of therapy. Pts were randomized 2:1 to receive either ide-cel or 1 of 5 std regimens (DARA, pomalidomide [POM], dexamethasone [DEX]; DARA, bortezomib, DEX; ixazomib, lenalidomide, DEX; carfilzomib and DEX; elotuzumab, POM, DEX). At median follow-up (18.6 mo), median progression-free survival (13.3 vs 4.4 mo) and response rate (71% vs 42%) were significantly higher in the ide-cel versus std regimen arm (Rodriguez-Otero P, et al. N Engl J Med 2023;388:1002-1014). In addition to the standard pt-reported outcomes instruments, trial-embedded interviews provide further insights into the patient Tx experience (Delforge M, et al. J Clin Oncol 2023;41[suppl 16]. Abstract 8032). This study assessed Tx experience, changes in health-related quality of life, and advantages and disadvantages of assigned Tx for pts enrolled in the KarMMa-3 trial. Methods: To obtain pts' experiences and perspectives in their own words while on the assigned Tx arms during the study, qualitative interviews were embedded into the KarMMa-3 trial. Pts were randomized (1:4) to participate in a series of optional qualitative interviews conducted at baseline (BL), and 3 and 6 mo post Tx. Interviews were audio-recorded and transcribed. Non-English interviews were transcribed directly into English. Transcripts were analyzed in MAXQDA qualitative analysis software; inter-coder agreement exercises were completed to ensure reliability. Analytic approaches included thematic analysis and longitudinal analysis across aspects of health and well-being. Results: In total, 64 pts (n = 43 ide-cel, n = 21 std regimen) across 9 countries in Europe and in the USA participated in ≥ 1 interview. Across both arms, 60, 48, and 38 pts completed interviews at BL, and 3 and 6 mo post Tx, respectively. The mean (median) age of interviewed pts at time of consent in the trial was 60.5 (60) years, and 33% were female. When describing their overall well-being during the previous 4 weeks at 3 mo, 53% of ide-cel pts described their well-being as mostly improved versus 19% in the std regimen arm. In the ide-cel arm, 59% and 56% of pts reported improvements in physical health versus 19% and 10% of pts in the std arm at 3 and 6 mo from BL, respectively; 25% and 28% of pts in the ide-cel arm reported worsening physical health at 3 and 6 mo from BL versus 63% and 80% of pts in the std arm (Table 1). In the ide-cel arm, 47% and 48% of ide-cel pts described improvements in physical functioning at 3 and 6 mo from BL versus 19% and 20% of std regimen pts, respectively; 22% and 16% of pts in the ide-cel arm versus 50% and 60% of pts in the std arm reported worse physical functioning at 3 and 6 mo from BL. Regarding Tx advantages, ide-cel pts reported efficacy (n = 25, 58%), minimal side effects (n = 21, 49%), avoidance of other therapies (n= 16, 37%), and having a 1-time Tx (n = 12, 28%). Std regimen pts also described efficacy (n = 10, 48%) and minimal side effects (n = 8, 38%) as Tx advantages. Disadvantages discussed by pts treated with ide-cel included lack of efficacy (n = 10, 23%), side effects after infusion (n = 9, 21%), or none (n = 9, 21%). Greater proportions of std regimen pts described side effects (n = 9, 43%) and lack of efficacy (n = 7, 33%). Additional well-being results for both arms are presented in Table 1. Conclusions: This study provides unique insight into key pt perceptions of ide-cel Tx compared to std regimens. Overall, pts receiving ide-cel reported more positive changes 6 mo post Tx than pts receiving std regimens, specifically in physical health and functioning. Fewer pts treated with ide-cel described side effects than pts receiving std regimens. These data show that ide-cel as a 1-time infusion can alleviate the burden of managing complex medication regimens in TCE early-line relapse pts.

Teclistamab-cqyv in multiple myeloma.

Multiple myeloma (MM) is an incurable neoplasm characterized by significant morbidity and mortality. Despite advances in treatment, MM patients eventually experienced a relapse of the disease. Penta-drug refractory patients continue to be the hard core of relapsed/refractory (RR) settings. Teclistamab-cqyv is a humanized IgG4 antibody and a bispecific BCMA-director CD3 T-cell engager. It recruits endogenous T cells, by targeting CD3 receptors expressed on their surface, resulting in their activation against BCMA, an antigen expressed by plasma cells. US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved Teclistamab-cqyv in monotherapy for the treatment of RRMM patients who have received at least three prior therapies, including immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (MoAbs) and have demonstrated disease progression during the last therapy. Its effectiveness was demonstrated in a pivotal clinical trial where the overall response rate (ORR) reached 60%. Other clinical studies are currently ongoing to investigate the association of the bispecific antibody with novel drugs with encouraging preliminary results, especially in the setting of heavily pretreated patients. In this review, the authors will provide a comprehensive overview of the drug, including its mechanism of action, major clinical trials, and future perspectives.

Effectiveness of anti-B-cell maturation antigen (BCMA)-targeting therapy after selinexor treatment.

e20034 Background: Multiple myeloma (MM) remains incurable, with the disease typically becoming refractory to three main classes of standard therapies: immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs) and anti-CD38 monoclonal antibodies (αCD38 mAbs). Treatments with novel mechanisms of action, including the XPO1 inhibitor selinexor and T-cell engaging anti-B-cell maturation antigen (αBCMA)-agents (antibody drug conjugates [ADC], bi-specific antibodies [BiS]), are increasingly used for treatment of relapsed and/or refractory MM (RRMM) after standard therapies have failed. Emerging data suggests a deleterious impact on T cell function with certain MM treatments, including alkylators and PIs, leading to inferior clinical outcomes. The influence of selinexor-based treatment on T cell function, which may alter the efficacy of αBCMA agents following selinexor treatment, is unknown. Methods: We analyzed the effectiveness of non-cellular αBCMA (NCA) therapies in pts with MM treated in 4 clinical studies (STORM [NCT02336815]; STOMP [NCT02343042]; BOSTON [NCT03110562], XPORT-MM-028 [NCT04414475]) with selinexor + dexamethasone (Xd), with or without PIs, IMiDs, or αCD38 mAbs, followed by therapy with NCA. After end of treatment with selinexor, survival follow-up data was collected every 3 months for 1 (STORM, STOMP, XPORT-MM-028) to 5 years (BOSTON). Results: Across the 4 clinical studies, 724 pts received selinexor, 404 of which had therapy post-selinexor documented. Thirty-seven pts (median age: 68, range: 40-87) received NCA therapy at any time following a selinexor regimen (Xd, n = 12; Xd + bortezomib, n = 9; Xd + pomalidomide, n = 6; Xd + daratumumab, n = 3; Xd + carfilzomib, n = 5; Xd + ixazomib, n = 2). NCAs included the ADC belantamab mafodotin (n = 28), the BiS teclistamab (n = 2), SEA-BCMA (n = 2), AMG 701 (n = 1), elranatamab (n = 1), MEDI2228 (n = 1), and investigational (n = 3; 2 had αBCMA bispecific antibodies and 1 had αBCMA BITE) (1 pt received 2 NCAs, belantamab and teclistamab). For the selinexor-based regimens, the median number of previous lines of therapy was 5 (range: 2-11) and 21 (56.8%) pts had triple-class refractory MM including 8 (21.6%) with penta-refractory MM. Median time from last dose of selinexor to NCA was 8 weeks (range: 2-117). Median time to treatment discontinuation with NCA was 4.4 months (95% CI: 2.1, NE). The median overall survival from initiation of NCA was 12.0 months (95% CI: 9.4, NE) with a median follow-up of 7.8 months. Conclusions: In this cohort of heavily-pretreated pts with MM who received a selinexor regimen prior to NCA, overall survival was in the range of 1 year, akin to historical results seen with ADCs. The 8-week median time between administration of selinexor and NCAs suggests that selinexor, with various partner agents, did not negatively impact overall survival with subsequent NCA therapy.

Belantamab Mafodotin: From Clinical Trials Data to Real-Life Experiences.

Despite the recent approval of novel immunotherapies, such as immunomodulatory drugs, proteasome inhibitors and anti-CD38 monoclonal antibodies, Multiple Myeloma (MM) remains incurable, and the acquisition of triple-refractoriness leads to really dismal outcomes in even earlier lines of therapy. More recently, innovative therapeutic strategies targeting B cell maturation antigen (BCMA), highly expressed on the plasma cell surface, are drawing different future landscapes in terms of effectiveness and outcomes. Belantamab Mafodotin, a first-in-class anti-BCMA antibody-drug conjugate, demonstrated good efficacy and safety profile in triple-refractory patients in the phase 2 DREAMM-2 trial, and it was approved for the treatment of MM triple-exposed patients with >4 prior lines of therapy. Here, starting from Belantamab Mafodotin clinical trials and also exploring combination studies and different schedules in order to improve its efficacy and toxicity, we focused on real-life experiences all over the world, which have confirmed clinical trial data and encourage further Belantamab Mafodotin investigations.

Adverse Effects of Immune-Checkpoint Inhibitors: A Comprehensive Imaging-Oriented Review

Immune-checkpoint inhibitors (ICIs) are immunomodulatory monoclonal antibodies, which increase antitumor immunity of the host and facilitate T-cell-mediated actions against tumors. These medications have been used in recent years as a weapon against advanced stage malignancies, such as melanoma, renal cell carcinoma, lymphoma, small or non-small cell lung cancer, and colorectal cancer. Unfortunately, they are not free from possible adverse effects (immune-related adverse events-irAEs) that mainly affect skin, gastrointestinal, hepatic, and endocrine systems. Early diagnosis of irAEs is essential to correctly and rapidly manage patients, with ICIs suspension and therapies administration. Deep knowledge of the imaging and clinical patterns of irAEs is the key to promptly rule out other diagnoses. Here, we performed a review of the radiological signs and differential diagnosis, based on the organ involved. The aim of this review is to provide guidance to recognize the most significant radiological findings of the main irAEs, based on incidence, severity, and the role of imaging.

Mutation of the TGN1412 anti-CD28 monoclonal antibody lower hinge confers specific FcγRIIb binding and retention of super-agonist activity.

The agonistic action of several immunomodulatory monoclonal antibodies (mAbs) requires both target antigen binding and clustering of this mAb:target complex by the Fcs interacting with Fcγ receptors (FcγRs), in particular FcγRIIb, on neighboring bystander cells. Fc mutations were made in the immunoglobulin G4 (IgG4)-based TGN1412 anti-CD28 mAb to define the role of FcγR interactions in its "super-agonist" activity. The dual mutation, IgG4-ED269,270 AA, ablated interaction with all human FcγRs and agonistic action was consequentially lost, confirming the FcγR dependence on the action of TGN1412. The IgG4 lower hinge region (F234 L235 G236 G237 ) was modified by L235 E mutation (F234 E235 G236 G237 ), a mutation commonly used to ablate FcγR binding, including in approved therapeutic mAbs. However, rather than ablating all FcγR binding, IgG4-L235 E conferred specific binding to FcγRIIb, the inhibitory Fc receptor. Furthermore, in combination with the core hinge-stabilizing mutation (IgG4-S228 P, L235 E), this mutation increased affinity for FcγRIIb compared with wild-type IgG4. In addition to having FcγRIIb specificity, these engineered TGN1412 antibodies retained their super-agonistic ability, demonstrating that CD28- and FcγRIIb-specific binding are together sufficient for agonistic function. The FcγRIIb-specific nature of IgG4-L235 E has utility for mAb-mediated immune agonism therapies that are dependent on FcγRIIb interaction and of anti-inflammatory mAbs in allergy and autoimmunity that harness FcγRIIb inhibitory signaling.

Humoral and cellular immune response to second and third severe acute respiratory syndrome coronavirus 2 mRNA vaccine in patients with plasma cell dyscrasia.

The recently developed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine has a short history of use and further information is needed regarding its efficacy, especially in immunocompromised conditions, such as plasma cell dyscrasia (PCD). We retrospectively measured serum SARS-CoV-2 antibodies against the spike protein (S-IgG) after the second and third mRNA vaccine doses (doses 2 and 3, respectively) in 109 patients with PCD. We evaluated the proportion of patients with an adequate humoral response (defined as S-IgG titers ≥300 antibody units/mL). Although active anti-myeloma treatments prior to vaccination had a significantly negative impact on adequate humoral response, specific drug subclasses including immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies were not negatively associated, except for B-cell maturation antigen-targeted therapy. Dose 3 (booster vaccination) led to significantly higher S-IgG titers and more patients acquired an adequate humoral response. Furthermore, evaluation of vaccine-induced cellular immune response in patients using T-spot Discovery SARS-CoV-2 kit, revealed an enhanced cellular immune response after Dose 3. This study highlighted the significance of booster SARS-CoV-2 mRNA vaccination in patients with PCD with respect to humoral and cellular immunity. Moreover, this study highlighted the potential impact of certain drug subclasses on vaccine-induced humoral immune response.

Evaluating process utilities for the treatment burden of chemotherapy in multiple myeloma in Japan: a time trade-off valuation study

AimsThis study estimated the “process utilities” of treatment options for patients with relapsed/refractory multiple myeloma (RRMM) in Japan using the time trade-off (TTO) method. Chimeric antigen receptor (CAR) T cell immunotherapy is available for patients with RRMM who are triple-class exposed (TCE) after treatment with immunomodulatory agents, proteasome inhibitors, and anti-CD38 monoclonal antibodies. However, the impact of available treatment options on health state utilities has not been well characterized, particularly in relation to process utilities.MethodsEight vignettes of health states and daily activity restrictions related to each of the following RRMM therapies were prepared: no treatment, CAR T cell therapy with idecabtagene vicleucel (ide-cel), regular intravenous infusion, and oral administration. A face-to-face survey of healthy Japanese adults who were representative of the general population was conducted. The TTO method was used to evaluate each vignette and to generate utility scores for each treatment regimen.ResultsThree hundred and nineteen respondents participated in the survey (mean age: 44 years [range: 20–64]; female: 50%). Utility scores for no treatment, ide-cel, oral pomalidomide, and dexamethasone (Pd) therapy ranged from ∼0.7 to 0.8. Utility scores for regular intravenous infusion regimens ranged from 0.50 to 0.56. There was a difference of ∼0.2 between the utility scores for no treatment/ide-cel/oral administration and regular intravenous infusions.ConclusionsDifferences in treatment administration across RRMM therapies showed a substantial impact on health state utilities. When quantifying the value of treatments, process utility gains should be considered as an independent factor in health technology assessments.

Relapsed/Refractory Multiple Myeloma: A Review of Available Therapies and Clinical Scenarios Encountered in Myeloma Relapse.

Multiple myeloma remains an incurable disease with the usual disease course requiring induction therapy, autologous stem cell transplantation for eligible patients, and long-term maintenance. Risk stratification tools and cytogenetic alterations help inform individualized therapeutic choices for patients in hopes of achieving long-term remissions with preserved quality of life. Unfortunately, relapses occur at different stages of the course of the disease owing to the biological heterogeneity of the disease. Addressing relapse can be complex and challenging as there are both therapy- and patient-related factors to consider. In this broad scoping review of available therapies in relapsed/refractory multiple myeloma (RRMM), we cover the pharmacologic mechanisms underlying active therapies such as immunomodulatory agents (IMiDs), proteasome inhibitors (PIs), monoclonal antibodies (mAbs), traditional chemotherapy, and Venetoclax. We then review the clinical data supporting the use of these therapies, organized based on drug resistance/refractoriness, and the role of autologous stem cell transplant (ASCT). Approaches to special situations during relapse such as renal impairment and extramedullary disease are also covered. Lastly, we look towards the future by briefly reviewing the clinical data supporting the use of chimeric antigen receptor (CAR-T) therapy, bispecific T cell engagers (BITE), and Cereblon E3 Ligase Modulators (CELMoDs).

Cyclophosphamide etoposide dexamethasone as salvage and bridging therapy in relapsed refractory and extramedullary multiple myeloma.

Patients with relapsed refractory multiple myeloma (RRMM) that are triple-exposed to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies have a poor prognosis. Standard treatment for these patients has not been established. Patients with extramedullary disease or secondary plasma cell leukemia often display high tumor cell proliferation and might therefore be susceptible to chemotherapy. While current regimens are often platinum-based, we present single-center data on 70 patients with RRMM who were treated with cyclophosphamide, etoposide, and dexamethasone (CED) after a median of four lines of therapy. An overall response rate of 52% was achieved after 1-6 cycles, with 23% of patients having a very good partial response. Comparable response rates and survival were observed in patients with extramedullary disease and high-risk cytogenetics. Treatment resulted in non-hematological °III-IV adverse events in 31% of patients. No treatment-related deaths occurred. The median progression-free and overall survival were 6.2 and 10.9months, respectively. 23% of patients were bridged to autologous stem cell transplantation (ASCT) or chimeric antigen receptor (CAR) T cell therapy. In summary, CED is an effective treatment regimen for RRMM cases with a tolerable safety profile and suitable as bridging therapy to CAR T cell treatment and ASCT.

Chimeric antigen receptor T-cell therapy in multiple myeloma: A comprehensive review of current data and implications for clinical practice.

Multiple myeloma (MM) is a hematologic malignancy defined by the clonal proliferation of transformed plasma cells. Despite tremendous advances in the treatment paradigm of MM, a cure remains elusive for most patients. Although long-term disease control can be achieved in a very large number of patients, the acquisition of tumor resistance leads to disease relapse, especially in patients with triple-class refractory MM (defined as resistance to immunomodulatory agents, proteosome inhibitors, and monoclonal antibodies). There is an unmet need for effective treatment options in these patients. Chimeric antigen receptor (CAR) T-cell therapy is a novel approach that has demonstrated promising efficacy in the treatment of relapsed, refractory MM (RRMM). These genetically modified cellular therapies have demonstrated deep and durable remissions in other B-cell malignancies, and current efforts aim to achieve similar results in patients with RRMM. Early studies have demonstrated remarkable response rates with CAR T-cell therapy in RRMM; however, durable responses with CAR T-cell therapies in myeloma have yet to be realized. In this comprehensive review, the authors describe the development of CAR T-cell therapies in myeloma, the outcomes of notable clinical trials, the toxicities and limitations of CAR T-cell therapies, and the strategies to overcome therapeutic challenges of CAR T cells in the hope of achieving a cure for multiple myeloma.

Monoclonal Gammopathies and the Bone Marrow Microenvironment: From Bench to Bedside and Then Back Again.

Multiple myeloma (MM) is an incurable hematologic malignancy characterized by a multistep evolutionary pathway, with an initial phase called monoclonal gammopathy of undetermined significance (MGUS), potentially evolving into the symptomatic disease, often preceded by an intermediate phase called "smoldering" MM (sMM). From a biological point of view, genomic alterations (translocations/deletions/mutations) are already present at the MGUS phase, thus rendering their role in disease evolution questionable. On the other hand, we currently know that changes in the bone marrow microenvironment (TME) could play a key role in MM evolution through a progressive shift towards a pro-inflammatory and immunosuppressive shape, which may drive cancer progression as well as clonal plasma cells migration, proliferation, survival, and drug resistance. Along this line, the major advancement in MM patients' survival has been achieved by the introduction of microenvironment-oriented drugs (including immunomodulatory drugs and monoclonal antibodies). In this review, we summarized the role of the different components of the TME in MM evolution from MGUS as well as potential novel therapeutic targets/opportunities.

High or low? Assessing disease risk in multiple myeloma

Based upon the development of highly effective therapies such as immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies that target plasma cell biology, a dramatic improvement in overall survival has been observed for most patients with multiple myeloma (MM) over the past 2 decades. Although it is now commonplace for many patients with myeloma to live in excess of 10 years after diagnosis, unfortunately a large subset of patients continues to experience an aggressive disease course marked by substantial morbidity and early mortality. Many clinical biomarkers and staging systems in use today can help with prognostication, but accurate risk assessment can be difficult due to the presence of many different biomarkers with variable prognostic value. Furthermore, with the implementation of novel therapies and unprecedented rates of deep and durable responses, it is becoming apparent that risk assessment is best envisioned as a dynamic process that requires ongoing reevaluation. As risk and response-adapted approaches are becoming more commonplace, it is essential that clinicians understand the biological and prognostic implications of clinical, genomic, and response-based biomarkers in order to promote management strategies that will help improve both survival and quality of life for patients across the risk spectrum.