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Simple Summary: Our research explores the profile and risk factors for infections in multiple myeloma patients undergoing treatment with daratumumab, a key drug in chemotherapy regimens for this disease. The study seeks to identify which patients are at the highest risk of developing severe infections and the factors contributing to this risk, as infections are a major concern for these patients. Analysis of patient data from our facility showed that lower hemoglobin levels and poorer performance status significantly increase the risk of serious infections. Additionally, we developed predictive algorithms to identify individuals at elevated risk of developing pneumonia during treatment. The findings from our study may help healthcare providers identify high-risk patients and implement targeted strategies to prevent infections, ultimately improving patient care. Background: Daratumumab (Dara) is the first monoclonal antibody introduced into clinical practice to treat multiple myeloma (MM). It currently forms the backbone of therapy regimens in both newly diagnosed (ND) and relapsed/refractory (RR) patients. However, previous reports indicated an increased risk of infectious complications (ICs) during Dara-based treatment. In this study, we aimed to determine the profile of ICs in MM patients treated with Dara-based regimens and establish predictors of their occurrence. Methods: This retrospective, real-life study included MM patients treated with Dara-based regimens between July 2019 and March 2024 at our institution. Infectious events were evaluated using the Terminology Criteria for Adverse Events (CTCAE) version 5.0. Results: The study group consisted of a total of 139 patients, including 49 NDMM and 90 RRMM. In the RR setting, the majority (60.0%) of patients received the Dara, bortezomib, and dexamethasone (DVd) regimen, whereas ND patients were predominantly (98%) treated with the Dara, bortezomib, thalidomide, and dexamethasone (DVTd) regimen. Overall, 55 patients (39.6%) experienced ICs. The most common IC was pneumonia (37.5%), followed by upper respiratory tract infections (26.8%). Finally, twenty-five patients had severe ICs (grade ≥ 3) and required hospitalization, and eight patients died due to ICs. In the final multivariable model adjusted for setting (ND/RR) and age, hemoglobin level (OR 0.77, 95% CI: 0.61–0.96, p = 0.0037), and Eastern Cooperative Oncology Group (ECOG) >1 (OR 4.46, 95% CI: 1.63–12.26, p = 0.0037) were significant factors influencing severe IC occurrence. Additionally, we developed predictive models using the J48 decision tree, gradient boosting, and random forest algorithms. After conducting 10-fold cross-validation, these models demonstrated strong performance in predicting the occurrence of pneumonia during treatment with daratumumab-based regimens. Conclusions: Simple clinical and laboratory assessments, including hemoglobin level and ECOG scale, can be valuable in identifying patients vulnerable to infections during Dara-based regimens, facilitating personalized prophylactic strategies. [ABSTRACT FROM AUTHOR]

Real-world evidence on the impact of monoclonal antibodies as first-line treatment in Spain is limited. This observational, retrospective and prospective, multicenter, descriptive study included 117 transplant-ineligible newly diagnosed multiple myeloma (TIE-NDMM) patients divided into Group A, who received no daratumumab standard regimens, and the DVMP group (daratumumab, bortezomib, melphalan, and prednisone treatment). More than 90% of the patients in Group A received bortezomib, lenalidomide, or a combination of them. The median follow-up time for Group A was 38.2 months in comparison to 25.8 months for the DVMP group (p < 0.0001). The rate of DVMP patients that experienced disease progression or death from any cause was 36.8%, compared to 67.3% of Group A patients at 36 months of follow-up. The DVMP group had a higher 36-month progression-free survival (PFS) rate (52.9% vs. 31.7%). During the retrospective period, 73.0% of patients reported adverse drug reactions, while in the prospective period, 40.5% experienced adverse events, with no clinical differences between groups. The study supports the use of daratumumab regimens in frontline therapy based on real-world data. The findings provide valuable insights into the clinical outcomes of daratumumab therapy, which can help physicians make informed decisions regarding the optimal treatment approach for this patient population. [ABSTRACT FROM AUTHOR]

Background/Objectives: Monoclonal antibodies (mAbs) have revolutionized multiple myeloma (MM) treatment. However, post-marketing data on their neuropsychiatric safety are limited. This study aimed to evaluate neuropsychiatric adverse events (AEs) related to mAbs used for MM through a retrospective pharmacovigilance analysis using the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS) database. Methods: Individual case safety reports (ICSRs) from 2015 to 2023 with at least one neuropsychiatric AE and one of the MM-approved mAbs as the suspected drug (i.e., daratumumab, elotuzumab, isatuximab, belantamab mafodotin, teclistamab, elranatamab, and talquentamab) were analyzed using descriptive and disproportionality approaches. Results: Unknown signals of disproportionate reporting (SDR) included the following: cerebral infarction for daratumumab (n = 45; reporting odds ratio (ROR) = 2.39, 95% confidence interval (CI) = 1.79–3.21; information component (IC) = 1.54, IC025–IC075 = 1.05–1.9), elotuzumab (25; 7.61, 5.13–11.28; 3.03, 2.37–3.51), and isatuximab (10; 2.56, 1.38–4.76; 1.67, 0.59–2.4); mental status changes for daratumumab (40; 2.66, 1.95–3.63; 1.67, 1.14–2.04) and belantamab mafodotin (10; 4.23, 2.28–7.88; 2.3, 1.22–3.03); an altered state of consciousness for daratumumab (32; 1.97, 1.39–2.78; 1.32, 0.73–1.74) and belantamab mafodotin (6; 2.35, 1.05–5.23; 1.6, 0.19–2.52); Guillain-Barre syndrome (GBS) for daratumumab (23; 6.42, 4.26–9.69; 2.81, 2.11–3.3), isatuximab (8; 10.72, 5.35–21.48; 3.57, 2.35–4.37), and elotuzumab (3; 4.74, 1.53–14.7; 2.59, 0.52–3.8); and orthostatic intolerance for daratumumab (10; 12.54, 6.71–23.43; 3.75, 2.67–4.48) and elotuzumab (4; 28.31, 10.58–75.73; 5, 3.24–6.08). Conclusions: Our analysis highlighted several previously unacknowledged SDRs for MM-approved mAbs. Given the complex and not entirely understood etiology of some neuropsychiatric AEs, including GBS, further investigations are necessary. [ABSTRACT FROM AUTHOR]

Simple Summary: Daratumumab (DARA) plus bortezomib, thalidomide, and dexamethasone (D-VTd) represent the standard of induction care in Europe for autologous stem cell transplantation (auto-SCT)-eligible, newly diagnosed multiple myeloma (NDMM) patients. This study aimed to investigate the possible impact of D-VTd induction therapy on hematopoietic engraftment after auto-SCT. Our findings indicate that patients treated with D-VTd experienced longer neutrophil and platelet engraftment times than those treated with VTd. Additionally, D-VTd treatment was associated with a higher incidence of febrile neutropenia and grade 2 or higher diarrhea. However, no significant differences were observed in the median number of days to discharge. The conclusion we can draw from our real-life study is that a four-drug induction therapy containing DARA does not impact transplant safety outcomes. Background: This real-life study aimed to investigate the possible impact of D-VTd induction therapy on hematopoietic engraftment after autologous stem cell transplantation (auto-SCT). Methods: Sixty consecutive NDMM patients received four cycles of induction therapy with D-VTd. The conditioning regimen consisted of melphalan 200 mg/m2. These patients were compared with a historical control group of 80 patients who received four cycles of VTd as induction therapy. Results: The median days to reach neutrophil and platelet engraftment significantly differed between patients treated with D-VTd (11 and 13 days, respectively) and VTd (10 and 12 days). Univariate Cox analyses show that patients treated with D-VTd had a hazard ratio of neutrophil engraftment that was 42% significantly lower than those in the VTd arm (HR: 0.58, p = 0.002), and a multivariate model confirmed this result. Patients treated with D-VTd developed FN more frequently. Univariate and multivariate logistic regressions revealed an association between D-VTd and FN. Delayed engraftment did not correlate with more extended hospitalization. No patients died in the first six months after transplantation. Conclusions: Our real-life study showed that a four-drug induction therapy containing DARA does not impact transplant safety outcomes. [ABSTRACT FROM AUTHOR]

Monoclonal antibody (MoAb) therapy has been increasingly used in recent years for hematologic malignancies. The MoAbs anti-CD38 and anti-CD47 are immunoglobulins directed against epitopes that are highly expressed not only on cancer cells, but also on red blood cells (RBCs), as well as platelets. Additionally, producing an off-target effect interferes in pre-transfusion testing, having the potential to unchain hemolytic anemia. Blood banks must assure the availability and safety of blood products for patients in need. Thus, MoAbs have become a challenge for blood banks, since methods to overcome interferences must be adopted. Several strategies have been proposed to mitigate pan-reactivity in pre-transfusion indirect antiglobulin tests, such as the treatment of reagent RBCs with enzymes or reducing agents, allogeneic RBC adsorptions, and drug-specific neutralization assays. All of these have some kind of limitation. This review summarizes the interferences of MoAbs in pre-transfusion testing, focusing on the available strategies to mitigate them in order to provide a safe transfusion. [ABSTRACT FROM AUTHOR]

We previously reported the structure, affinity, and anticancer activity of a bivalent bispecific natural killer cell engager (BiKE) composed of one anti-CD16a VHH and one anti-HER2 VHH fused via a linker. In this study, we explored the engineering of a tetravalent BiKE by fusing two anti-CD16a and two anti-HER2 VHHs in tandem, using bivalent BiKE as a template. The tetravalent BiKE was genetically engineered, and its tertiary structure was predicted using in silico modeling. The antigen binding and affinity of the tetravalent BiKE were assessed using ELISA, flow cytometry, and biolayer interferometry. The ability of the BiKEs to kill cancer cells was evaluated through classical and residual antibody-dependent cellular cytotoxicity (ADCC) assays. Additionally, we investigated the potential for NK cell fratricide via CD16a-CD16a crosslinking. Our results revealed that the tetravalent BiKE exhibited at least 100-fold higher affinity toward its target antigens compared to its bivalent counterpart. The residual ADCC assay indicated that the tetravalent BiKE was more effective in killing cancer cells than the bivalent BiKE, attributable to its lower Koff value, which prolonged its binding to NK cell surfaces. Fratricide assays demonstrated that neither the bivalent nor the tetravalent BiKE mediated fratricide. Notably, our findings showed that daratumumab-induced NK fratricide was restricted to CD38-CD38 crosslinking and was not related to ADCC via CD16a-CD38 crosslinking. This study is the first in the literature to show the successful engineering of a tetravalent immune cell engager composed of tandem VHH units, which achieves high affinity and anticancer activity without mediating fratricide. [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]

Background: The morbidity and mortality from AL amyloidosis has significantly improved with the development of novel treatments. Daratumumab is a highly effective treatment for AL amyloidosis, but end-stage kidney disease is a common complication of this condition. Kidney transplantation is the ideal form of renal replacement therapy but has historically been contraindicated in this group of patients. Methods: Given the improved survival and better treatments of both conditions, we argue that it is time to reconsider transplanting these patients. Results: We report our experience of transplanting four patients with AL amyloidosis who had achieved stable remission through treatment with daratumumab. Conclusions: We highlight the key challenges involved and discuss important clinical issues for patients receiving daratumumab, particularly the difficulties with interpreting the crossmatch in light of daratumumab and immunoglobulin therapy interference. We also discuss the complexities involved in balancing the risks of infection, relapse, rejection, and immunosuppression in such patients. [ABSTRACT FROM AUTHOR]

This systematic review examines the available clinical data on CD34+ cell mobilization, collection, and engraftment in multiple myeloma patients treated with the anti-CD38 monoclonal antibodies daratumumab and isatuximab in clinical trials and in real life. Twenty-six clinical reports were published between 2019 and February 2024. Most studies documented lower circulating CD34+ cells after mobilization compared to controls, leading to higher plerixafor requirements. Although collection yields were significantly lower in approximately half of the studies, the collection target was achieved in similar proportions of daratumumab- and isatuximab-treated and nontreated patients, and access to autologous stem cell transplant (ASCT) was comparable. This could be explained by the retained efficacy of plerixafor in anti-CD38 monoclonal antibody-treated patients, while no chemotherapy-based or sparing mobilization protocol proved superior. Half of the studies reported slower hematopoietic reconstitution after ASCT in daratumumab- and isatuximab-treated patients, without an excess of infectious complications. While no direct effect on stem cells was observed in vitro, emerging evidence suggests possible dysregulation of CD34+ cell adhesion after daratumumab treatment. Overall, anti-CD38 monoclonal antibodies appear to interfere with CD34+ cell mobilization, without consistently leading to significant clinical consequences. Further research is needed to elucidate the underlying mechanisms and define optimal mobilization strategies in this patient population. [ABSTRACT FROM AUTHOR]

Background: New multiple myeloma (MM) medications have revolutionized the treatment landscape, but they are also associated with a range of adverse events (AEs). This study aims to provide a comprehensive overview of AEs reported for four new MM medications: daratumumab, ixazomib, elotuzumab, and panobinostat. Methods: This study uses a descriptive retrospective approach to analyze the FDA Adverse Event Reporting System (FAERS) from 2015 to 2022. It includes variables like medication names, report details, patient demographics, adverse events, and reporter types. The initial dataset consists of over 3700 adverse events, which are categorized into 21 groups for clarity and comparison. Results: The FAERS database revealed 367,756 adverse events (AEs) associated with novel multiple myeloma drugs from 2015–2022. Ixazomib had the highest number of reported AEs with 206,243 reports, followed by daratumumab with 98,872 reports, then elotuzumab with 26,193 AEs. Ixazomib's AE reports increased dramatically over the study period, rising approximately 51-fold from 1183 in 2015 to 60,835 in 2022. Of the medications studied, ixazomib also recorded the highest number of deaths (24,206), followed by daratumumab (11,624), panobinostat (7227), and elotuzumab (3349). The majority of AEs occurred in patients aged 55–64 and 65–74 years. Conclusions: Ixazomib, a new MM medication, had the highest number of AEs reported. Also, it has the highest rate of reported deaths compared to other new MM medications. Clinicians should be aware of the potential AEs associated with this medication and further research is needed to understand the reasons for the high number of AEs and to develop mitigation strategies. More attention should also be paid to the safety of new multiple myeloma medications in younger patients. [ABSTRACT FROM AUTHOR]

Histiocytic sarcoma (HS) is an extremely rare but aggressive hematopoietic malignancy, and the prognosis has been reported to be rather unfavorable with a median overall survival of merely 6 months. We presented a 58-year-old female patient complaining of abdominal pain and fever, who was admitted to our institution in September 2021. Fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography–computed tomography (PET/CT) scan showed enlargement of generalized multiple lymph nodes. Subsequently, laparoscopic retroperitoneal lesion biopsy and bone marrow aspiration were performed. The pathological findings indicated the diagnosis of HS concurrent with follicular lymphoma. The immunohistochemistry (IHC) staining of the tumor lesion revealed a high expression of CD38 and PD-L1 proteins. Furthermore, KRAS gene mutation was identified by means of next-generation sequencing. The patient exhibited poor treatment response to both first- and second-line cytotoxic chemotherapies. Therefore, she underwent six cycles of Daratumumab (anti-CD38 monoclonal antibody), Pazopanib (multi-target receptor tyrosine kinases inhibitor) combined with third-line chemotherapy, followed by involved-site radiotherapy and maintenance therapy with the PD-1 inhibitor Tislelizumab. Long-term partial remission was finally achieved after multi-modality treatment. Duration of remission and overall survival reached 22 and 32 months, respectively. Our case indicated that immuno-targeted treatment coupled with chemotherapy and radiotherapy might constitute a potential therapeutic option for HS. [ABSTRACT FROM AUTHOR]

Simple Summary: Daratumumab is a CD38-targeting antibody that is being increasingly integrated into first-line multiple myeloma (MM) induction treatment, leading to an improved response depth and a longer progression-free survival. Autologous stem cell transplantation (ASCT) is commonly performed as a consolidation strategy following first-line treatment in fit MM patients. However, limited data on the short-term effects of daratumumab on the success and safety of stem cell mobilization and autologous stem cell transplantation are available to date. We analyzed the performance of stem cell mobilization and collection, as well as engraftment kinetics, in MM patients treated with daratumumab-containing induction regimens, compared to daratumumab-free therapy. Daratumumab is being increasingly integrated into first-line multiple myeloma (MM) induction regimens, leading to improved response depth and longer progression-free survival. Autologous stem cell transplantation (ASCT) is commonly performed as a consolidation strategy following first-line induction in fit MM patients. We investigated a cohort of 155 MM patients who received ASCT after first-line induction with or without daratumumab (RVd, n = 110; D-RVd, n = 45), analyzing differences in stem cell mobilization, apheresis, and engraftment. In the D-RVd group, fewer patients successfully completed mobilization at the planned apheresis date (44% vs. 71%, p = 0.0029), and more patients required the use of rescue plerixafor (38% vs. 28%, p = 0.3052). The median count of peripheral CD34+ cells at apheresis was lower (41.37 vs. 52.19 × 106/L, p = 0.0233), and the total number of collected CD34+ cells was inferior (8.27 vs. 10.22 × 106/kg BW, p = 0.0139). The time to recovery of neutrophils and platelets was prolonged (12 vs. 11 days, p = 0.0164; and 16 vs. 14 days, p = 0.0002, respectively), and a higher frequency of erythrocyte transfusions (74% vs. 51%, p = 0.0103) and a higher number of platelet concentrates/patients were required (4 vs. 2; p = 0.001). The use of daratumumab during MM induction might negatively impact stem cell mobilization and engraftment in the context of ASCT. [ABSTRACT FROM AUTHOR]

Multiple myeloma is a malignancy characterized by the accumulation of malignant plasma cells in bone marrow and the production of monoclonal immunoglobulin. A hallmark of cancer is the evasion of immune surveillance. Histone deacetylase inhibitors have been shown to promote the expression of silenced molecules and hold potential to increase the anti-MM efficacy of immunotherapy. The aim of the present work was to assess the potential effect of tinostamustine (EDO-S101), a first-in-class alkylating deacetylase inhibitor, in combination with daratumumab, an anti-CD38 monoclonal antibody (mAb), through different preclinical studies. Tinostamustine increases CD38 expression in myeloma cell lines, an effect that occurs in parallel with an increment in CD38 histone H3 acetylation levels. Also, the expression of MICA and MICB, ligands for the NK cell activating receptor NKG2D, augments after tinostamustine treatment in myeloma cell lines and primary myeloma cells. Pretreatment of myeloma cell lines with tinostamustine increased the sensitivity of these cells to daratumumab through its different cytotoxic mechanisms, and the combination of these two drugs showed a higher anti-myeloma effect than individual treatments in ex vivo cultures of myeloma patients' samples. In vivo data confirmed that tinostamustine pretreatment followed by daratumumab administration significantly delayed tumor growth and improved the survival of mice compared to individual treatments. In summary, our results suggest that tinostamustine could be a potential candidate to improve the efficacy of anti-CD38 mAbs. [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]

Remarkable advancements have been made in the treatment outcomes of multiple myeloma (MM) patients; however, for frail elderly patients, these treatment outcomes are still insufficient. Elderly MM patients are increasing, as are their treatment regimens. There is a heightened demand to assess these patients in order to provide optimized treatments. While continuous treatment is more common for MM patients when compared to fixed-duration treatment, due to the risk of treatment interruption causing reduced survival rates, effectiveness and safety are essential. Treatment goals vary for each patient, but must preserve their quality of life (QOL). When planning treatments for these patients, frailty evaluation is increasingly emphasized as a stratification factor which helps develop accurate screening tools. Daratumumab (DARA) therapy, used globally, is not only effective in frail elderly MM patients, but also has QOL benefits. Proficiency in utilizing DARA regimens is potentially advantageous for patients not included in clinical trials, and innovative usage can further broaden its scope. The development of tools to accurately assess frailty and the establishment of optimal treatments for frail elderly MM patients are imperative. This review is an overview, challenging the frailty assessments for MM patients, re-examining the evidence for DARA regimens in frail elderly MM patients, and discussing potential areas for improvement. [ABSTRACT FROM AUTHOR]

T-cell lymphoblastic lymphoma is an uncommon lymphoid neoplasm in adults, although more frequent in children and teenagers, that often affects the mediastinum and bone marrow, requiring intensive chemotherapy protocols. Its prognosis is poor if a cure is not achieved with first-line treatments. We present a case report of a 19-year-old man diagnosed with this type of lymphoma due to significant respiratory distress and a mediastinal mass. He received treatment according to the hyper-CVAD regimen, with a complete metabolic response. However, seven months later a new mediastinal growth was observed, leading to salvage treatment with a combination of nelarabine and daratumumab. We observed not only refractoriness, but also leukemization, which prompted consideration of hematopoietic stem cell transplantation. Based on this case, we conducted a review of pharmacological treatment options for refractory or relapsed lymphoblastic lymphoma, as well as the role of radiotherapy in managing mediastinal disease. This case report highlights the limited evidence available regarding later-line treatments, with unusual reports regarding employing our combination of daratumumab and nelarabine, and emphasizes the importance of achieving cures in the first line of treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: On rare occasions, a handful of innovative cancer drugs may successfully go through clinical trials and manage to obtain simultaneous regulatory approvals to treat a specific disease, providing hope for improved treatment outcomes. In the past few years, physicians in North America, Europe, and other countries with stronger economies have been able to use several of the recently approved drugs to treat a blood cancer called multiple myeloma, once older therapies have failed. This study looked at the treatment outcomes associated with the wave of newer drugs in patients diagnosed with multiple myeloma in Greece. The results showed that approximately three-quarters of patients who received one of the newer drugs after having progressed on front-line therapies remained in remission a year after initiating treatment. This finding was comparable to the results from previous studies in Greek patients who were diagnosed with relapsed or refractory multiple myeloma and had previously used other therapies. Newer methodologies are needed to assess the real-world comparative effectiveness of a "generation" of pharmaceutical innovation versus the prior standard of care. This chart review study aimed to first evaluate the cumulative clinical benefits of pharmaceutical innovation in everyday relapse/refractory multiple myeloma before analyzing findings in the context of respective real-world outcomes from the bortezomib/lenalidomide era. Study endpoints included the 52-week PFS rate in second and third line of therapy (LOT), mPFS-2 across the first and second LOT, the ORR, reasons for discontinuation, and the treatment duration per therapeutic algorithm. Data from 107 patients were collected. The median follow-up was 2.0 years. Of the subjects who met the selection criteria for the second LOT, 72.2% maintained the PFS at 52 weeks. In the third-line setting, the PFS rate at 52 weeks was 63.5%. The mPFS across the first and second, the second, and the third LOTs were 26, 17, and 15 months, respectively. The ORR was 76.1% in the second and 69.7% in the third LOT. After non-response or progression, the main reason for drug discontinuation was treatment intolerability. The second-line ORR and the 52-week PFS rate were similar to previous real-world findings from the bortezomib/lenalidomide era. The cumulative mPFS across the second and third LOTs was higher than the respective mPFS across the first and second LOTs. Despite its limitations, the methodology and findings from this study may be used in future clinical and economic evaluations across all hematological malignancies. [ABSTRACT FROM AUTHOR]

Background: Over the last decade, many studies have assessed the efficacy of treatments for refractory/relapsed multiple myeloma (R/R MM). While combination therapies show greater efficacy than traditional methods, limited research has targeted elderly patients who might be less resilient to treatments. Our study aimed to evaluate treatment efficacy for these elderly patients. Methods: We carried out a comprehensive review of the literature using a systematic approach. Initially, 4966 citations were retrieved and subsequently narrowed down to 13 eligible randomized controlled trials (RCTs) through our systematic review process from databases like Embase, PubMed, and Cochrane Library from 1 January 2000 to 31 December 2022. Evidence was collated through a frequentist network meta-analysis, using the hazard ratio (HR) for evaluation. Results: Combined therapy of daratumumab, lenalidomide, and dexamethasone (DaraLenDex) was the preferred treatment for R/R MM elderly patients. Its strengths included an HR for progression-free survival (0.15; 95% CI: 0.09–0.25) and a 96% P-score. Conclusions: Our analysis suggests that, pending more comprehensive RCTs, DaraLenDex is the treatment with the highest efficacy for R/R MM in elderly patients. [ABSTRACT FROM AUTHOR]

In multiple myeloma impressive outcomes have improved with the introduction of new therapeutic approaches, mainly those including naked monoclonal antibodies such as daratumumab and isatuximab. However, moving to earlier lines of therapy with effective anti-myeloma drugs led to an increase in the number of patients who developed multi-refractoriness to them early on. Currently, triple- or multi-refractory MM represents an unmet medical need, and their management remains a complicated challenge. The recent approval of new immunotherapeutic approaches such as conjugated monoclonal antibodies, bispecific antibodies, and CAR T cells could be a turning point for these heavily pretreated patients. Nevertheless, several issues regarding their use are unsolved, such as how to select patients for each strategy or how to sequence these therapies within the MM therapeutic landscape. Here we provide an overview of the most recent data about approved conjugated monoclonal antibody belantamab, mafodotin, bispecific antibody teclistamab, and other promising compounds under development, mainly focusing on the ongoing clinical trials with monoclonal antibody combination approaches in advanced and earlier phases of MM treatment. [ABSTRACT FROM AUTHOR]

Multiple myeloma is a chronic hematologic malignancy that obstinately tends to relapse. Basic research has made giant strides in better characterizing the molecular mechanisms of the disease. The results have led to the manufacturing of new, revolutionary drugs which have been widely tested in clinical trials. These drugs have been approved and are now part of the therapeutic armamentarium. As a consequence, it is essential to combine what we know from clinical trials with real-world data in order to improve therapeutic strategies. Starting with this premise, our review aims to describe the currently employed regimens in multiple myeloma and compare clinical trials with real-life experiences. We also intend to put a spotlight on promising therapies such as T-cell engagers and chimeric antigen receptor T-cells (CAR-T) which are proving to be effective in changing the course of advanced-stage disease. [ABSTRACT FROM AUTHOR]

The landscape of therapeutic measures to treat multiple myeloma has undergone a seismic shift since the dawn of the current century. This has been driven largely by the introduction of new classes of small molecules, such as proteasome blockers (e.g., bortezomib) and immunomodulators (e.g., lenalidomide), as well as by immunotherapeutic agents starting with the anti-CD38 monoclonal antibody daratumumab in 2015. Recently, other immunotherapies have been added to the armamentarium of drugs available to fight this malignancy. These include the bispecifics teclistamab, talquetamab, and elranatamab, and the chimeric antigen receptor (CAR) T-cell products idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). While the accumulated benefits of these newer agents have resulted in a more than doubling of the disease's five-year survival rate to nearly 60% and improved quality of life, the disease remains incurable, as patients become refractory to the drugs and experience relapse. This review covers the current scope of antimyeloma immunotherapeutic agents, both those in clinical use and in development. Included in the discussion are additional monoclonal antibodies (mAbs), antibody–drug conjugates (ADCs), bi- and multitargeted mAbs, and CAR T-cells and emerging natural killer (NK) cells, including products intended for "off-the-shelf" (allogeneic) applications. Emphasis is placed on the benefits of each along with the challenges that need to be surmounted if MM is to be cured. [ABSTRACT FROM AUTHOR]

Simple Summary: Impaired kidney function is a common complication of a certain blood cancer called multiple myeloma. Patients with severe kidney problems are usually left out of medical studies, so data on safety and efficacy of treatments are limited for these patients. The academic phase II GMMG-DANTE trial (NCT02977494) investigated a combination of drugs—daratumumab, bortezomib, and dexamethasone—in patients who had already tried other treatments before, and had severe kidney impairment. Even though the study had to end early, the results were promising. About 67% of the patients had their cancer respond to the treatment, and their kidney function improved. The treatment was overall well tolerated. Renal function impairment (RI) is a common complication in multiple myeloma (MM). However, limited data exist on the safety and efficacy of anti-MM regimens in patients with severe RI, as these patients are frequently excluded from clinical trials. This investigator-initiated multicentric phase II GMMG-DANTE trial evaluated daratumumab, bortezomib, and dexamethasone (DVd) in relapsed or refractory (r/r) MM patients with severe RI. r/rMM patients with ≥1 prior treatment line and a GFR <30 mL/min/1.73 m2 or undergoing hemodialysis were eligible and received eight cycles of DVd followed by daratumumab maintenance. The trial closed prematurely after 22/36 planned patients. The primary endpoint was overall response rate (ORR). Median age of patients was 70 (range 55–89) years, with a median GFR of 20.1 mL/min/1.73 m2 (interquartile range, 9.4–27.3 mL/min/1.73 m2), and eight patients under hemodialysis. Median number of prior lines was two (range 1–10). The trial was successful, albeit with premature termination, as it met its primary endpoint, with an ORR of 67% (14/21). The rates of partial response, very good partial response, and complete response were 29%, 29%, and 10%, respectively (n = 6, 6, and 2). Fourteen patients (67%) achieved renal response. After median follow-up of 28 months, median progression-free survival was 10.4 months; median overall survival was not reached. Higher-grade toxicity was mainly hematologic, and non-hematologic toxicities ≥Grade 3 were mostly infections (24%). The prospective GMMG-DANTE trial investigating DVd exclusively in r/rMM patients with severe RI showed efficacy and safety to be comparable to data from patients without RI. [ABSTRACT FROM AUTHOR]

Anti-CD38 monoclonal antibody (MoAB) therapy has significantly improved the prognosis of patients with multiple myeloma. However, not all patients sustain durable responses. We aimed to describe the natural history of patients relapsed or refractory (R/R) to CD38 MoAB therapy. We performed a single-center, retrospective analysis of the clinical characteristics and outcomes of 81 patients with multiple myeloma who progressed after treatment with daratumumab. Our cohort was heavily pretreated, with a median of two lines prior to daratumumab and only 17 patients received daratumumab as a first line. A total of 38.2% had received a previous autologous stem cell transplantation (ASCT), and 61.7% had received both an immunomodulatory drug (IMID) and a proteasome inhibitor (PI). The median overall survival (OS) was 21 months for the global cohort but it decreased to 14 months for triple-class refractory patients and 5 months for penta-refractory patients. Most of the patients (83.9%) received treatment after daratumumab progression, in many cases with second generation IMID or PI, but seven patients were treated with anti-BCMA therapy and three patients received CART therapy within a clinical trial. In conclusion, patients R/R to daratumumab represent an unmet clinical need with poor prognosis and in need of incorporation of new treatments. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a cancerous condition characterized by the proliferation of plasma cells within the hematopoietic marrow, resulting in multiple osteolytic lesions. MM patients typically experience bone pain, kidney damage, fatigue due to anemia, and infections. Historically, MM was an incurable disease with a life expectancy of around three years after diagnosis. However, over the past two decades, the development of novel therapeutics has significantly improved patient outcomes, including response to treatment, remission duration, quality of life, and overall survival. These advancements include thalidomide and its derivatives, lenalidomide and pomalidomide, which exhibit diverse mechanisms of action against the plasma cell clone. Additionally, proteasome inhibitors such as bortezomib, ixazomib, and carfilzomib disrupt protein degradation, proving specifically toxic to cancerous plasma cells. Recent advancements also involve monoclonal antibodies targeting surface antigens, such as elotuzumab (anti-CS1) and daratumumab (anti-CD38), bispecific t-cell engagers such as teclistamab (anti-BCMA/CD3) and Chimeric antigen receptor T (CAR-T)-based strategies, with a growing focus on drugs that exhibit increasingly targeted action against neoplastic plasma cells and relevant effects on the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a currently incurable hematologic cancer. This disease is characterized by immunological alterations of myeloid cells and lymphocytes. The first-line therapy involves the use of classic chemotherapy; however, many patients have a relapsed form that could evolve into a refractory MM. The new therapeutic frontiers involve the use of new monoclonal antibodies (Mab) such as daratumumab, isatuximab, and elotuzumab. In addition to monoclonal antibodies, new immunotherapies based on modern bispecific antibodies and chimeric antigen receptor (CAR) T cell therapy have been investigated. For this reason, immunotherapy represents the greatest hope for the treatment of MM. This review intends to focus the attention on the new approved antibody targets. The most important are: CD38 (daratumumab and isatuximab), SLAM7 (elotuzumab), and BCMA (belantamab mafodotin) for the treatment of MM currently used in clinical practice. Although the disease is still incurable, the future perspective is to find the best therapeutic combination among all available drugs. [ABSTRACT FROM AUTHOR]

Daratumumab (DARA) has improved the outcome of treatment of multiple myeloma (MM). DARA acts via complement-dependent and -independent mechanisms. Resistance to DARA may result from upregulation of the complement inhibitory proteins CD55 and CD59, downregulation of the DARA target CD38 on myeloma cells or altered expression of the checkpoint inhibitor ligand programmed death ligand-1 (PD-L1) or other mechanisms. In this study, EVs were isolated from peripheral blood (PB) and bone marrow (BM) from multiple myeloma (MM) patients treated with DARA and PB of healthy controls. EV size and number and the expression of CD38, CD55, CD59 and PD-L1 as well as the EV markers CD9, CD63, CD81, CD147 were determined by flow cytometry. Results reveal that all patient EV samples express CD38, PD-L1, CD55 and CD59. The level of CD55 and CD59 are elevated on MM PB EVs compared with healthy controls, and the level of PD-L1 on MM PB EVs is higher in patients responding to treatment with DARA. CD147, a marker of various aspects of malignant behaviour of cancer cells and a potential target for therapy, was significantly elevated on MM EVs compared with healthy controls. Furthermore, mass spectrometry data suggests that MM PB EVs bind DARA. This study reveals a MM PB and BM EV protein signature that may have diagnostic and prognostic value. [ABSTRACT FROM AUTHOR]

We report the first case of Daratumumab interference of allogeneic crossmatch tests repeatedly causing aberrant false-positive results, which inadvertently delayed transplant for a waitlisted renal patient with multiple myeloma. Daratumumab is an IgG1κ human monoclonal antibody commonly used to treat multiple myeloma, characterized by cancerous plasma cells and often leads to renal failure requiring kidney transplant, by depleting CD38-expressing plasma cells. In this case study, the patient had end-stage renal disease secondary to multiple myeloma and was continuously receiving Daratumumab infusions. The patient did not have any detectable antibodies to human leukocyte antigens but repeatedly had unexpected positive crossmatch by the flow cytometry-based method with 26 of the 27 potential deceased organ donors, implying donor-recipient immunological incompatibility. However, further review and analysis suggested that the positive crossmatches were likely false-positive as a result of interference from Daratumumab binding to donor cell surface CD38 as opposed to the presence of donor-specific antibodies. The observed intensity of the false-positive crossmatches was also highly variable, potentially due to donor- and/or cell-dependent expression of CD38. The variability of CD38 expression was, therefore, for the first time, characterized on the T and B cells isolated from various tissues and peripheral blood of 78 individuals. Overall, T cells were found to have a lower CD38 expression profile than the B cells, and no significant difference was observed between deceased and living individuals. Finally, we show that a simple cell treatment by dithiothreitol can effectively mitigate Daratumumab interference thus preserving the utility of pre-transplant crossmatch in multiple myeloma patients awaiting kidney transplant. [ABSTRACT FROM AUTHOR]

CD38 was first discovered as a T-cell antigen and has since been found ubiquitously expressed in various hematopoietic cells, including plasma cells, NK cells, B cells, and granulocytes. More importantly, CD38 expression levels on malignant hematopoietic cells are significantly higher than counterpart healthy cells, thus presenting itself as a promising therapeutic target. In fact, for many aggressive hematological cancers, including CLL, DLBCL, T-ALL, and NKTL, CD38 expression is significantly associated with poorer prognosis and a hyperproliferative or metastatic phenotype. Studies have shown that, beyond being a biomarker, CD38 functionally mediates dysregulated survival, adhesion, and migration signaling pathways, as well as promotes an immunosuppressive microenvironment conducive for tumors to thrive. Thus, targeting CD38 is a rational approach to overcoming these malignancies. However, clinical trials have surprisingly shown that daratumumab monotherapy has not been very effective in these other blood malignancies. Furthermore, extensive use of daratumumab in MM is giving rise to a subset of patients now refractory to daratumumab treatment. Thus, it is important to consider factors modulating the determinants of response to CD38 targeting across different blood malignancies, encompassing both the transcriptional and post-transcriptional levels so that we can diversify the strategy to enhance daratumumab therapeutic efficacy, which can ultimately improve patient outcomes. [ABSTRACT FROM AUTHOR]

Plasmablastic lymphoma (PBL) is a rare and aggressive form of large B-cell lymphoma (LBCL) most commonly seen in the setting of chronic immunosuppression or autoimmune disease. The prognosis is poor and CHOP-like regimens often fail to produce durable remission; therefore, there is no established standard of care treatment. However, PBL demonstrates substantial morphologic and immunophenotypic overlap with multiple myeloma (MM), suggesting that MM therapeutics might prove useful in treating PBL. We studied the effects of treatment using the first-in-class monoclonal antibody directed against CD38, daratumumab, in combination with chemotherapy in seven patients with advanced-stage LBCL with plasmablastic features. Treatment was safe and well-tolerated. Among six evaluable patients, six patients had complete response after treatment, and four patients who met strict WHO criteria for PBL had durable response (12–31 months and ongoing). [ABSTRACT FROM AUTHOR]

Multiple myeloma is characterized by a wide clinical heterogeneity due to an intricate network of interactions between bone marrow-resident clonal plasma cells and the microenvironment. Over the last years, dramatic improvement in the understanding of these pathways led to the introduction of novel drugs with immune-mediated mechanisms of action. Some of these compounds, such as the anti-cd38 daratumumab and isatuximab, the anti-slamf-7 elotuzumab, and the antibody-drug conjugate belantamab-mafodotin, have been tested in large clinical trials and have now fully entered the real-life management. The bispecific T-cell engagers are under investigation with promising results, and other satisfactory data is expected from the application of nanotechnologies. The perfect timing to introduce these drugs in the sequence of treatment and their adverse events represent new challenges to be addressed, and further experience is required to improve their use. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple myeloma (MM) is characterized by the presence of deregulated bone metabolism. Restoring bone turnover is essential for patients with MM. We prospectively evaluated the impact of the anti-CD38 monoclonal antibody daratumumab on markers of bone remodeling among patients with relapsed/refractory MM. Overall, daratumumab improved bone turnover by favoring bone formation. Biomarkers of bone turnover in serum are suggestive of bone dynamics during treatment in multiple myeloma (MM). We evaluated the role of daratumumab on bone remodeling among patients with relapsed/refractory MM in the prospective, open-label, phase 2 study REBUILD. Daratumumab was administered according to the approved indication. A total of 33 out of 57 enrolled patients completed 4 months of treatment. The median percent change from baseline to 4 months in C-terminal cross-linking telopeptide of type 1 collagen (CTX) (primary endpoint) was 3.9%, with 13 (39.4%) and 11 (33.3%) patients showing at least 20% and 30% reduction in CTX levels, respectively. The median percent decrease from baseline to 4 months in tartrate resistant acid phosphatase 5b (TRACP-5b) levels (co-primary endpoint) was 2.6%, with 10 (30.3%) and 6 (18.2%) patients showing at least 20% and 30% reduction in TRACP-5b levels, respectively. However, the changes in these markers of bone catabolism were not statistically significant. Furthermore, the levels of osteocalcin, bone-specific alkaline phosphatase and procollagen type-I N-pro-peptide (bone formation markers) increased from baseline to 4 months (secondary endpoints) by 18.4%, 92.6% and 10.2%, respectively. Furthermore, the median levels of dickkopf-1 and C-C motif ligand-3 showed a significant decrease at 4 months by 17.5% and 16.0%, respectively. In conclusion, daratumumab improved bone turnover by inducing bone formation and reducing osteoblast inhibition. [ABSTRACT FROM AUTHOR]

Extranodal natural killer/T(NK/T)-cell lymphoma (ENKTL) is a rare subtype of non-Hodgkin lymphoma that typically presents with an isolated nasal mass, but a sizeable minority present with advanced stage disease and have a significantly poorer prognosis. Those with limited disease are standardly treated with chemotherapy and radiation while those with advanced stage disease are treated with L-asparaginase containing chemotherapy regimens. The addition of modern radiation therapy techniques and the incorporation of L-asparaginase into chemotherapy regimens have significantly improved outcomes in this disease, but relapses and death from relapsed disease remain frequent. Given the high rate of relapse, several novel therapies have been evaluated for the treatment of this disease. In this review, we explore the current standard of care for ENKTL as well as novel therapies that have been evaluated for its treatment and the biologic understanding behind these therapies. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a plasma cell (PC) malignancy whose development flourishes in the bone marrow microenvironment (BMME). The BMME components' immunoediting may foster MM progression by favoring initial immunotolerance and subsequent tumor cell escape from immune surveillance. In this dynamic process, immune effector cells are silenced and become progressively anergic, thus contributing to explaining the mechanisms of drug resistance in unresponsive and relapsed MM patients. Besides traditional treatments, several new strategies seek to re-establish the immunological balance in the BMME, especially in already-treated MM patients, by targeting key components of the immunoediting process. Immune checkpoints, such as CXCR4, T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), PD-1, and CTLA-4, have been identified as common immunotolerance steps for immunotherapy. B-cell maturation antigen (BCMA), expressed on MMPCs, is a target for CAR-T cell therapy, antibody-(Ab) drug conjugates (ADCs), and bispecific mAbs. Approved anti-CD38 (daratumumab, isatuximab), anti-VLA4 (natalizumab), and anti-SLAMF7 (elotuzumab) mAbs interfere with immunoediting pathways. New experimental drugs currently being evaluated (CD137 blockers, MSC-derived microvesicle blockers, CSF-1/CSF-1R system blockers, and Th17/IL-17/IL-17R blockers) or already approved (denosumab and bisphosphonates) may help slow down immune escape and disease progression. Thus, the identification of deregulated mechanisms may identify novel immunotherapeutic approaches to improve MM patients' outcomes. [ABSTRACT FROM AUTHOR]

Systemic amyloidosis arises from monoclonal CD38+ plasma cells that produce misfolded immunoglobulin light chains, which form amyloid fibrils that are deposited into different tissues, leading to organ damage. Daratumumab is a human IgG/k monoclonal antibody that targets CD38, a glycoprotein uniformly expressed on human plasma cells. Daratumumab has been utilized in recent years with unprecedented responses in multiple myeloma. In patients with relapsed or refractory AL amyloidosis, daratumumab has shown promising efficacy in terms of hematologic responses and improvement in organ function. Here, we report real-life treatment with Daratumumab in 33 AL amyloidosis patients treated within the Regional Tuscan Myeloma network at 5 centers with associated MGUS or SMM (n = 15) or symptomatic MM (n = 18). Patients were treated at relapsed/refractory disease stages (n = 29) with a median of one previous line of therapy or at diagnosis (n = 4). Daratumumab showed good efficacy, representing 60% of good hematological responses and 50% of organ responses in a real-life population of patients with an acceptable toxicity profile. [ABSTRACT FROM AUTHOR]

Daratumumab (Dara) is the first-in-class human-specific anti-CD38 mAb approved for the treatment of multiple myeloma (MM). Although recent data have demonstrated very promising results in clinical practice and trials, some patients do not achieve a partial response, and ultimately all patients undergo progression. Dara exerts anti-MM activity via antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), and immunomodulatory effects. Deregulation of these pleiotropic mechanisms may cause development of Dara resistance. Knowledge of this resistance may improve the therapeutic management of MM patients. [ABSTRACT FROM AUTHOR]

Nicotinamide adenine dinucleotide (NAD+) is an essential co-enzyme reported to operate both intra- and extracellularly. In the extracellular space, NAD+ can elicit signals by binding purinergic P2 receptors or it can serve as the substrate for a chain of ectoenzymes. As a substrate, it is converted to adenosine (ADO) and then taken up by the cells, where it is transformed and reincorporated into the intracellular nucleotide pool. Nucleotide-nucleoside conversion is regulated by membrane-bound ectoenzymes. CD38, the main mammalian enzyme that hydrolyzes NAD+, belongs to the ectoenzymatic network generating intracellular Ca2+-active metabolites. Within this general framework, the extracellular conversion of NAD+ can vary significantly according to the tissue environment or pathological conditions. Accumulating evidence suggests that tumor cells exploit such a network for migrating and homing to protected areas and, even more importantly, for evading the immune response. We report on the experience of this lab to exploit human multiple myeloma (MM), a neoplastic expansion of plasma cells, as a model to investigate these issues. MM cells express high levels of surface CD38 and grow in an environment prevalently represented by closed niches hosted in the bone marrow (BM). An original approach of this study derives from the recent use of the clinical availability of therapeutic anti-CD38 monoclonal antibodies (mAbs) in perturbing tumor viability and enzymatic functions in conditions mimicking what happens in vivo. [ABSTRACT FROM AUTHOR]

The introduction of high-dose therapy in the 1990s as well as the development of drugs such as thalidomide, lenalidomide, and bortezomib in the 2000s led to an impressive improvement in outcome of patients with multiple myeloma (MM) eligible for autologous stem cell transplantation (ASCT). Clinical trials conducted in the first ten years of the twenty-first century established as standard therapy for these patients a therapeutic approach including induction, single or double ASCT, consolidation, and maintenance therapy. More recently, incorporating second-generation proteasome inhibitors carfilzomib and monoclonal antibody daratumumab into each phase of treatment significantly improved the efficacy of ASCT in terms of measurable residual disease (MRD) negativity, Progression Free Survival (PFS), and Overall Survival (OS). The availability of techniques such as multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) for MRD assessment allowed the design of MRD-based response-adjusted trials that will define, in particular, the role of consolidation and maintenance therapies. In this review, we will provide an overview of the most recent evidence and the future prospects of ASCT in MM patients. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cell-based therapies have emerged as promising anticancer treatments due to their potency as cytolytic effectors and synergy with concurrent treatments. Multiple myeloma (MM) is an aggressive B-cell malignancy that, despite development of novel therapeutic agents, remains incurable with a high rate of relapse. In MM, the inhospitable tumor microenvironment prevents host NK cells from exerting their cytolytic function. The development of NK cell immunotherapy works to overcome this altered immune landscape and can be classified in two major groups based on the origin of the cell: autologous or allogeneic. In this review, we compare the treatments in each group, such as autologous chimeric antigen receptor (CAR) NKs and allogeneic off-the-shelf NK cell infusions, and their combinatorial effect with existing MM therapies including monoclonal antibodies and proteasome inhibitors. We also discuss their placement in clinical treatment regimens based on the immune profile of each patient. Through this examination, we would like to discover precisely when each NK cell-based treatment will produce the maximum benefit to the MM patient. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a malignant, incurable disease characterized by the expansion of monoclonal terminally differentiated plasma cells in the bone marrow. MM is consistently preceded by an asymptomatic monoclonal gammopathy of undetermined significance, and in the absence of myeloma defining events followed by a stage termed smoldering multiple myeloma (SMM), which finally progresses to active myeloma if signs of organ damage are present. The reciprocal interaction between tumor cells and the tumor microenvironment plays a crucial role in the development of MM and the establishment of a tumor-promoting stroma facilitates tumor growth and myeloma progression. Since myeloma cells depend on signals from the bone marrow microenvironment (BMME) for their survival, therapeutic interventions targeting the BMME are a novel and successful strategy for myeloma care. Here, we describe the complex interplay between myeloma cells and the cellular components of the BMME that is essential for MM development and progression. Finally, we present BMME modifying treatment options such as anti-CD38 based therapies, immunomodulatory drugs (IMiDs), CAR T-cell therapies, bispecific antibodies, and antibody-drug conjugates which have significantly improved the long-term outcome of myeloma patients, and thus represent novel therapeutic standards.

Simple Summary: New treatments in multiple myeloma are embraced by patients and physicians but are also associated with substantial higher costs. To ensure the affordability and accessibility of health care, an evaluation of the outcomes in relation to the costs is increasingly requested. However, an up-to-date summary and assessment of the cost-effectiveness evidence for multiple myeloma treatments is currently lacking. We identified the cost-effectiveness studies currently available and show that novel treatments could improve survival with almost 4 years compared to standard of care. However, additional costs compared to standard of care could increase up to USD 535,530 per patient. The ratio between outcomes and costs is above currently accepted willingness to pay thresholds. Our results show cost-effectiveness ratios should be either improved or less favorable ratios should be accepted to ensure accessibility to promising treatments. Background: Novel therapies for multiple myeloma (MM) promise to improve outcomes but are also associated with substantial increasing costs. Evidence regarding cost-effectiveness of novel treatments is necessary, but a comprehensive up-to-date overview of the cost-effectiveness evidence of novel treatments is currently lacking. Methods: We searched Embase, Medline via Ovid, Web of Science and EconLIT ProQuest to identify all cost-effectiveness evaluations of novel pharmacological treatment of MM reporting cost per quality-adjusted life year (QALY) and cost per life year (LY) gained since 2005. Quality and completeness of reporting was assessed using the Consolidated Health Economic Evaluation Reporting Standards. Results: We identified 13 economic evaluations, comprising 32 comparisons. Our results show that novel agents generate additional LYs (range: 0.311–3.85) and QALYs (range: 0.1–2.85) compared to backbone regimens and 0.02 to 1.10 LYs and 0.01 to 0.91 QALYs for comparisons between regimens containing two novel agents. Lifetime healthcare costs ranged from USD 60,413 to 1,434,937 per patient. The cost-effectiveness ratios per QALY gained ranged from dominating to USD 1,369,062 for novel agents compared with backbone therapies and from dominating to USD 618,018 for comparisons between novel agents. Conclusions: Cost-effectiveness ratios of novel agents were generally above current willingness-to-pay thresholds. To ensure access, cost-effectiveness should be improved or cost-effectiveness ratios above current thresholds should be accepted. [ABSTRACT FROM AUTHOR]

Simple Summary: Targeted radionuclide therapy (TRT) and immunotherapy, an example being chimeric antigen receptor T cells (CAR-Ts), represent two potent means of eradicating systemic cancers. Although each one as a monotherapy might have a limited effect, the potency can be increased with a combination of the two therapies. The complications involved in the dosing and scheduling of these therapies make the mathematical modeling of these therapies a suitable solution for designing combination treatment approaches. Here, we investigate a mathematical model for TRT and CAR-T cell combination therapies. Through an analysis of the mathematical model, we find that the tumor proliferation rate is the most important factor affecting the scheduling of TRT and CAR-T cell treatments with faster proliferating tumors requiring a shorter interval between the two therapies. Targeted radionuclide therapy (TRT) has recently seen a surge in popularity with the use of radionuclides conjugated to small molecules and antibodies. Similarly, immunotherapy also has shown promising results, an example being chimeric antigen receptor T cell (CAR-T) therapy in hematologic malignancies. Moreover, TRT and CAR-T therapies possess unique features that require special consideration when determining how to dose as well as the timing and sequence of combination treatments including the distribution of the TRT dose in the body, the decay rate of the radionuclide, and the proliferation and persistence of the CAR-T cells. These characteristics complicate the additive or synergistic effects of combination therapies and warrant a mathematical treatment that includes these dynamics in relation to the proliferation and clearance rates of the target tumor cells. Here, we combine two previously published mathematical models to explore the effects of dose, timing, and sequencing of TRT and CAR-T cell-based therapies in a multiple myeloma setting. We find that, for a fixed TRT and CAR-T cell dose, the tumor proliferation rate is the most important parameter in determining the best timing of TRT and CAR-T therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: The management of cardiovascular adverse events in patients with relapsed/refractory multiple myeloma undergoing treatment with carfilzomib can be challenging. Herein, we evaluated the potential cardioprotective effect of daratumumab when administered in combination with carfilzomib and dexamethasone (DaraKd). The study included 25 patients receiving either DaraKd (n = 14) or Kd (n = 11) who were evaluated for echocardiographic changes at the sixth cycle of treatment compared with baseline assessment. DaraKd was associated with preserved post-treatment cardiac systolic function compared with Kd. CD38 inhibition by daratumumab might restore metabolic disequilibrium in the cardiac tissue and prevent cardiac injury. A trend for a lower rate of cardiovascular adverse events among patients receiving DaraKd was also evident, although larger studies are needed to determine the association between echocardiographic and/or biomarker changes with cardiovascular adverse events. Carfilzomib has improved survival in patients with relapsed/refractory multiple myeloma (RRMM), but it may exert cardiovascular adverse events (CVAEs). The aim of this study was to assess whether treatment with daratumumab may ameliorate carfilzomib-related toxicity. We prospectively evaluated 25 patients with RRMM who received either daratumumab in combination with carfilzomib and dexamethasone (DaraKd) (n = 14) or Kd (n = 11). Cardiac ultrasound was performed before treatment initiation and C6D16 or at the time of treatment interruption. Patients were followed for a median of 10 months for CVAEs. The mean (± SD) age was 67.8 ± 7.6 years and 60% were men. The two treatment groups did not significantly differ in baseline demographic characteristics (p > 0.1 for all). In the DaraKd group, we did not observe any significant change in markers of ventricular systolic function. However, these markers deteriorated in the Kd group; left ventricular (LV) ejection fraction, LV global longitudinal strain, tricuspid annular plane systolic excursion and RV free wall longitudinal strain significantly decreased from baseline to second visit (p < 0.05). A significant group interaction (p < 0.05) was observed for the abovementioned changes. CVAEs occurred more frequently in the Kd than the DaraKd group (45% vs. 28.6%). DaraKd was associated with preserved post-treatment cardiac systolic function and lower CVAE rate compared with Kd. The clinical significance and the underlying mechanisms merit further investigation. [ABSTRACT FROM AUTHOR]

The prognosis of multiple myeloma (MM) has drastically improved owing to the development of new drugs, such as proteasome inhibitors and immunomodulatory drugs. Nevertheless, MM is an extremely challenging disease, and many patients are still refractory to the existing therapies, thus requiring new treatment alternatives. Venetoclax is a selective, orally bioavailable inhibitor of BCL-2 that shows efficacy in MM not only as a single agent but also in combination therapy, especially for MM patients with translocation t(11;14). However, many patients are refractory to this drug. Here, we treated the MM cell lines KMS12PE and KMS27 with a combination treatment of venetoclax targeting BCL-2 and daratumumab targeting CD38 to evaluate the synergistic cytotoxicity of these drugs in vitro. MM cell lines were co-cultured with natural killer (NK) cells at an effector:target ratio of 0.3:1 in the presence of serial concentrations of daratumumab and venetoclax, and the resulting apoptotic MM cells were detected by flow cytometry using annexin V. These results indicated that the antibody-dependent cell-mediated NK cytotoxicity was enhanced in KMS12PE and KMS27 cells harboring t(11;14) with a high BCL-2 expression, suggesting that the combination treatment of venetoclax and daratumumab should be especially effective in patients with these characteristics. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple Myeloma (MM) is the most common cancer of the bone marrow and remains incurable despite advances in novel therapy. The disease course is typically characterized by an initial response pattern to treatment followed by eventual relapse and treatment refractoriness. Patients who have progressed on several novel therapies, including the CD38-targeting monoclonal antibody Daratumumab, have a dismal outcome with a median overall survival of less than 10 months and are in dire need of therapies with new mechanisms. While emerging novel modalities have shown promising results, the current study explores the use of high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) in heavily pretreated Daratumumab-refractory MM patients. Our results for 69 consecutive patients treated with salvage ASCT indicate that this approach can lead to long-term MM control and should be considered a treatment modality in selected heavily pretreated Daratumumab-refractory patients. Daratumumab, a CD38-targeting monoclonal antibody, has significantly improved survival rates in multiple myeloma (MM), yet patients who progress on Daratumumab have dismal clinical outcomes with an overall median of less than 10 months. While emerging novel modalities have shown promising results, the current study explores the use of high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) in heavily pretreated Daratumumab-refractory MM patients. We retrospectively investigated the outcome of 69 consecutive patients who received upfront ASCT. The median progression-free survival (PFS) for the entire patient cohort was 7.2 months with a median overall survival (OS) of 19.3 months. For patients with ≥very good partial response (VGPR), median PFS and OS improved to 9 months and 34 months, respectively. Achievement of MRD negativity in ≥VGPR did not further improve the outcome. A better performance status, younger age, longer time interval from initial MM diagnosis/initial ASCT to salvage ASCT and low-risk GEP70 were all associated with improved PFS and OS after salvage ASCT. Our results suggest a role for salvage ASCT in selected heavily pretreated and Daratumumab-refractory patients. [ABSTRACT FROM AUTHOR]

Recently, we designed an inventive paradigm in nanomedicine—drug-free macromolecular therapeutics (DFMT). The ability of DFMT to induce apoptosis is based on biorecognition at cell surface, and crosslinking of receptors without the participation of low molecular weight drugs. The system is composed of two nanoconjugates: a bispecific engager, antibody or Fab' fragment—morpholino oligonucleotide (MORF1) conjugate; the second nanoconjugate is a multivalent effector, human serum albumin (HSA) decorated with multiple copies of complementary MORF2. Here, we intend to demonstrate that DFMT is a platform that will be effective on other receptors than previously validated CD20. We appraised the impact of daratumumab (DARA)- and isatuximab (ISA)-based DFMT to crosslink CD38 receptors on CD38+ lymphoma (Raji, Daudi) and multiple myeloma cells (RPMI 8226, ANBL-6). The biological properties of DFMTs were determined by flow cytometry, confocal fluorescence microscopy, reactive oxygen species determination, lysosomal enlargement, homotypic cell adhesion, and the hybridization of nanoconjugates. The data revealed that the level of apoptosis induction correlated with CD38 expression, the nanoconjugates meet at the cell surface, mitochondrial signaling pathway is strongly involved, insertion of a flexible spacer in the structure of the macromolecular effector enhances apoptosis, and simultaneous crosslinking of CD38 and CD20 receptors increases apoptosis. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple myeloma (MM) is a disease that extensively involves bone, and angiogenesis and immunosuppression are important processes in the development of MM. Proteasome inhibitors and immunomodulatory drugs remarkably improve the survival of MM patients. However, MM is still an incurable disease that rapidly becomes resistant to these drugs. There is robust evidence that extracellular vesicles (EVs) contribute to cancer metastasis. Osteoclasts, in addition to immunosuppressive cells in the bone marrow (BM), are key players in osteolysis and immunosuppression. BM stromal cells and MM cells secrete EVs through which they communicate with each other: EVs, in fact, contain proteins, small RNAs, and long non-coding RNAs that mediate this communication and contribute to angiogenesis, osteolysis, and cancer dissemination and drug resistance. Ectoenzymes are expressed in myeloma cells, osteoclasts, and stromal cells and produce immunosuppressive adenosine. Recently, an antibody targeting CD38, an ectoenzyme, has been shown to improve the survival of patients with MM. Thus, understanding the properties of EV and ectoenzymes will help elucidate key processes of MM development. Angiogenesis and immunosuppression promote multiple myeloma (MM) development, and osteolysis is a primary feature of MM. Although immunomodulatory drugs and proteasome inhibitors (PIs) markedly improve the survival of patients with MM, this disease remains incurable. In the bone marrow niche, a chain of ectoenzymes, including CD38, produce immunosuppressive adenosine, inhibiting T cell proliferation as well as immunosuppressive cells. Therefore, anti-CD38 antibodies targeting myeloma cells have the potential to restore T cell responses to myeloma cells. Meanwhile extracellular vesicles (EVs) containing microRNAs, proteins such as cytokines and chemokines, long noncoding RNAs, and PIWI-interacting RNAs have been shown to act as communication tools in myeloma cell/microenvironment interactions. Via EVs, mesenchymal stem cells allow myeloma cell dissemination and confer PI resistance, whereas myeloma cells promote angiogenesis, myeloid-derived suppressor cell proliferation, and osteoclast differentiation and inhibit osteoblast differentiation. In this review, to understand key processes of MM development involving communication between myeloma cells and other cells in the tumor microenvironment, EV cargo and the non-canonical adenosinergic pathway are introduced, and ectoenzymes and EVs are discussed as potential druggable targets for the treatment of MM patients. [ABSTRACT FROM AUTHOR]

Simple Summary: The CD38-targeting antibody daratumumab has marked activity in multiple myeloma through direct anti-tumor effects and immunomodulatory activity. However, eventually most patients will develop daratumumab-refractory disease. We hypothesized that daratumumab-resistance could be reversed by the addition of an inhibitor of the PD-1/PD-L1 signaling pathway, resulting in improved T- and NK-cell mediated anti-tumor immune responses. We therefore performed a phase 2 study to investigate the efficacy and safety of adding the PD-L1 checkpoint inhibitor durvalumab to daratumumab at the time of daratumumab failure. The toxicity profile of the daratumumab/durvalumab combination was acceptable, but none of the 18 enrolled patients achieved a clinical response. Immunomonitoring of bone marrow samples at baseline and during treatment showed a reduction of regulatory T-cell numbers and a decrease in the proportion of T-cells expressing LAG3 and CD8+ T-cells expressing TIM-3, whereas tumor cell characteristics were not affected. These results indicate that co-targeting PD-L1 at the time of daratumumab failure is insufficient to reverse daratumumab-resistance. Daratumumab is active both as a single agent and in combination with other agents in multiple myeloma (MM) patients. However, the majority of patients will develop daratumumab-refractory disease, which carries a poor prognosis. Since daratumumab also has immunomodulatory effects, addition of the PD-L1 blocking antibody durvalumab at the time of progression may reverse daratumumab-resistance. The efficacy and safety of daratumumab and durvalumab in daratumumab-refractory relapsed/refractory MM patients was evaluated in this prospective, single-arm phase 2 study (NCT03000452). None of the 18 enrolled patients achieved PR or better. The frequency of serious adverse events was 38.9%, with one patient experiencing an immune related adverse event (grade 2 hyperthyroidism). No infusion-related reactions were observed. Analysis of tumor- and immune cell characteristics was performed on bone marrow samples obtained at baseline and during treatment. Daratumumab combined with durvalumab reduced the frequency of regulatory T-cells and decreased the proportion of T-cells expressing LAG3 and CD8+ T-cells expressing TIM-3, without altering T- and NK-cell frequencies. Durvalumab did not affect tumor cell characteristics associated with daratumumab resistance. In conclusion, the addition of durvalumab to daratumumab following development of daratumumab-resistance was associated with an acceptable toxicity profile, but was not effective. This indicates that inhibition of the PD-1/PD-L1 signaling pathway at the time of daratumumab-resistance is insufficient to reverse daratumumab-resistance. [ABSTRACT FROM AUTHOR]

Cellular immunotherapy is becoming a new pillar in cancer treatment after recent striking results in different clinical trials with chimeric antigen receptor T cells. However, this innovative therapy is not exempt from challenges such as off-tumor toxicity, tumor recurrence in heterogeneous tumors, and affordability. To surpass these limitations, we exploit the unique anti-tumor characteristics of natural killer (NK) cells. In this study, we aimed to obtain a clinically relevant number of allogeneic NK cells derived from peripheral blood (median of 14,050 million cells from a single donor) to target a broad spectrum of solid and liquid tumor types. To boost their anti-tumor activity, we combined allogeneic NK cells with the approved anti-cluster of differentiation 38 (CD-38) monoclonal antibody Daratumumab to obtain a synergistic therapeutic effect against incurable multiple myeloma. The combination therapy was refined with CD16 polymorphism donor selection and uncomplicated novel in vitro pretreatment to avoid undesired fratricide, increasing the in vitro therapeutic effect against the CD-38 positive multiple myeloma cell line by more than 20%. Time-lapse imaging of mice with established human multiple myeloma xenografts revealed that combination therapy of selected and pretreated NK cells with Daratumumab presented tumor volumes 43-fold smaller than control ones. Combination therapy with an allogeneic source of fully functional NK cells could be beneficial in future clinical settings to circumvent monoclonal antibodies' low therapeutic efficiency due to NK cell dysfunctionality in MM patients. [ABSTRACT FROM AUTHOR]

A search of the scientific literature for Daratumumab and myeloma gives more than 600 results (January 2021), which reflects the interest and activity around this antibody, an interest that was also reflected by the assignment of breakthrough designation for Daratumumab as a treatment for multiple myeloma by FDA in 2013. The high expectations have been supported and met due to a very active clinical development program, and our insight into Daratumumab's modes of action have been expanded by a concomitant, systematic activity of translational research. The scope of this article is to point to some areas where the outcome of treatment with Daratumumab for multiple myeloma may be improved with a focus on areas such as when to initiate treatment with Daratumumab, the use of supportive treatment, duration of therapy and some general thoughts about anti-myeloma treatment as a two-step process involving initial de-bulking followed by reprogramming of the host's immune system and immune-mediated control of myeloma. [ABSTRACT FROM AUTHOR]