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Plain language summaryWhat is this summary about? This plain language summary describes the results of a Phase 3 study called KarMMa-3. In this ongoing study, researchers looked at a relatively new treatment for people with multiple myeloma, a type of blood cancer, whose cancer got worse despite treatment (refractory) or had cancer that at first improved with treatment, but eventually stopped responding (relapsed). How was this study conducted? In the KarMMa-3 study, people with relapsed or refractory multiple myeloma received either a one-time infusion of a new treatment, named ide-cel, or one of the standard of care regimens currently available for patients with this cancer. People were treated with the standard of care regimens in weekly or monthly cycles until the cancer got worse, there were unacceptable side effects, or the person withdrew from the study. What were the results? The results of this study showed that people receiving the one-time infusion of ide-cel lived longer without the cancer getting worse and had a greater reduction in cancer cells than patients receiving the standard of care regimen. A higher percentage of patients receiving ide-cel responded to treatment than patients receiving the standard of care regimen, and the response to treatment was better with idecel. These results show that ide-cel is a promising treatment for this challenging disease. Clinical Trial Registration:NCT03651128 (KarMMa-3 study) [ABSTRACT FROM AUTHOR]

This document provides a summary of a study on proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID), a kidney disease characterized by the presence of a monoclonal immunoglobulin. The study analyzed 15 patients with PGNMID in Belgium and The Netherlands and provided detailed information on patient demographics, kidney function, biopsy findings, and treatment regimens. The study found that patients who received clone-directed therapy had a better renal response compared to those who did not. Recurrence of PGNMID after kidney transplantation was common, and the study calls for further research to improve diagnostic and therapeutic strategies for this disease. [Extracted from the article]

Introduction: Teclistamab is the first approved B cell maturation antigen × CD3 bispecific antibody with precision dosing for the treatment of triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM). We compared the effectiveness of teclistamab in MajesTEC-1 versus real-world physician's choice of therapy (RWPC) in patients from the prospective, non-interventional LocoMMotion and MoMMent studies. Methods: Patients treated with teclistamab from MajesTEC-1 (N = 165) were compared with an external control arm from LocoMMotion (N = 248) or LocoMMotion + MoMMent pooled (N = 302). Inverse probability of treatment weighting adjusted for imbalances in prognostic baseline characteristics. The relative effect of teclistamab versus RWPC for overall response rate (ORR), very good partial response or better (≥ VGPR) rate, and complete response or better (≥ CR) rate was estimated with an odds ratio using weighted logistic regression transformed into a response-rate ratio (RR) and 95% confidence interval (CI). Weighted proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: Baseline characteristics were well balanced between treatment cohorts after reweighting. Patients treated with teclistamab had significantly improved outcomes versus RWPC in LocoMMotion: ORR (RR [95% CI], 2.44 [1.79–3.33]; p < 0.0001), ≥ VGPR (RR 5.78 [3.74–8.93]; p < 0.0001), ≥ CR (RR 113.73 [15.68–825.13]; p < 0.0001), DOR (HR 0.39 [0.24–0.64]; p = 0.0002), PFS (HR 0.48 [0.35–0.64]; p < 0.0001), and OS (HR 0.64 [0.46–0.88]; p = 0.0055). Teclistamab versus RWPC in LocoMMotion + MoMMent also had significantly improved outcomes: ORR (RR 2.41 [1.80–3.23]; p < 0.0001), ≥ VGPR (RR 5.91 [3.93–8.88]; p < 0.0001), ≥ CR (RR 132.32 [19.06–918.47]; p < 0.0001), DOR (HR 0.43 [0.26–0.71]; p = 0.0011), PFS (HR 0.49 [0.37–0.66]; p < 0.0001), and OS (HR 0.69 [0.50–0.95]; p = 0.0247). Conclusion: Teclistamab demonstrated significantly improved effectiveness over RWPC in LocoMMotion ± MoMMent, emphasizing its clinical benefit as a highly effective treatment for patients with TCE RRMM. Trial Registration: MajesTEC-1, ClinicalTrials.gov NCT03145181 (phase 1) and NCT04557098 (phase 2); LocoMMotion, ClinicalTrials.gov NCT04035226; MoMMent, ClinicalTrials.gov NCT05160584. [ABSTRACT FROM AUTHOR]

This document presents the findings of a study comparing two treatments for patients with relapsed/refractory multiple myeloma (RRMM) who have been exposed to multiple classes of drugs. The study analyzed data from the KarMMa trial and the DREAMM-2 trial to compare the efficacy and health-related quality of life (HRQoL) outcomes of idecabtagene vicleucel (ide-cel) and belantamab mafodotin (bela-maf). The analysis showed that ide-cel had better overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and HRQoL outcomes compared to bela-maf in patients with RRMM. The results were consistent across different populations and sensitivity analyses. The study suggests that ide-cel may provide clinically relevant improvements in both clinical efficacy and HRQoL outcomes for patients with RRMM. [Extracted from the article]

Simple Summary: The emergence of new therapeutic agents for multiple myeloma (MM) over the last 2 decades has resulted in a significant improvement in overall survival (OS). However, this improvement might be associated with the increased incidence of second primary malignancies (SPMs). Most studies in the field reviewed patients that participated in phase 2–3 clinical studies, focusing on the incidence of SPMs. The current study evaluated the characteristics, management, and outcomes of MM patients diagnosed with SPMs outside clinical studies. In our study, we present real-world data of 165 MM patients that were diagnosed with SPM during the course of their disease; we offer detailed data on SPM characteristics and management, as well as valuable insights into the management of MM post-SPM detection and the actual prognosis of MM patients following SPM diagnosis. Background: There is an increased risk of second primary malignancies (SMPs) in patients with multiple myeloma (MM). This multinational 'real-world' retrospective study analyzed the characteristics and outcomes of MM patients that developed SPMs. Results: 165 patients were analyzed: 62.4% males; 8.5% with a prior cancer; 113 with solid SPMs, mainly ≥stage 2; and 52 with hematological SPM (hemato-SPM), mainly MDS/AML. Patients with hemato-SPM were younger (p = 0.05) and more frequently had a prior AutoHCT (p = 0.012). The time to SPM was shorter in the older (>65 years) and more heavily pretreated patients. One hundred patients were actively treated at the time of SPM detection. Treatment was discontinued in 52, substituted with another anti-MM therapy in 15, and continued in 33 patients. Treatment discontinuation was predominant in the patients diagnosed with hemato-SPM (76%). The median OS following SPM detection was 8.5 months, and the main cause of death was SPM. A poor ECOG status predicted a shorter OS (PS 3 vs. 0, HR = 5.74, 2.32–14.21, p < 0.001), whereas a normal hemoglobin level (HR = 0.43, 0.19–0.95, p = 0.037) predicted longer OS. Conclusions: With the continuing improvement in OS, a higher proportion of MM patients might develop SPM. The OS following SPM diagnosis is poor; hence, frequent surveillance and early detection are imperative to improve outcomes. [ABSTRACT FROM AUTHOR]

Background: No adequate data exist on the impact of multiple myeloma (MM) with extramedullary disease (EMD) after autograft and maintenance therapy. Methods: We identified 808 patients with newly diagnosed MM who received first autograft, of whom 107 had EMD (83 paraskeletal and 24 organ involvement), and who had been reported to the EBMT registry December 2018. Distribution according to type of involvement was similar between the treatment groups (p =.69). For EMD, 46 (40%) received thalidomide, 59 (51%) lenalidomide, and 11 (10%) bortezomib. Results: The median follow‐up from maintenance start was 44 months. Three‐year progression‐free survival (PFS) was 52% (48%–57%) for no EMD, 56% (44%–69%) for paraskeletal involvement, and 45% (22%–68%) for organ involvement (p =.146). Early PFS (within first year) appeared to be significantly worse for organ involvement (hazard ratio, 3.40), while no significant influence was found after first year from maintenance start. Three‐year overall survival (OS) was 81% (77%–84%), 88% (80%–96%), and 68% (47%–89%; p =.064), respectively. With thalidomide as reference, lenalidomide was significantly associated with better PFS and OS, whereas bortezomib appeared to improve outcome specifically in EMD. Conclusion: Lenalidomide maintenance is standard of care for MM without EMD, whereas extramedullary organ involvement remains a significant risk factor for worse outcome, especially for early events after maintenance start. [ABSTRACT FROM AUTHOR]

Introduction: Patients with triple-class-exposed relapsed/refractory multiple myeloma (TCE-RRMM) have a poor prognosis and limited treatment options. Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, was studied in patients with TCE-RRMM in the single-arm MajesTEC-1 study. To assess the relative effectiveness of teclistamab versus real-world physician's choice of therapy (RWPC), adjusted comparisons were performed using individual patient data from MajesTEC-1 and LocoMMotion, a prospective study of patients with TCE-RRMM. Methods: An external control arm for MajesTEC-1 was created from patients in LocoMMotion (n = 248; clinical cut-off: November 2, 2021) and compared with treated patients (n = 165) from MajesTEC-1 (teclistamab 1.5 mg/kg weekly; clinical cut-off: March 16, 2022). Inverse probability weighting was used to adjust for imbalances in baseline covariates. For binary endpoints [overall response rate (ORR), very good partial response or better (≥ VGPR) rate, complete response or better (≥ CR)], relative effect of teclistamab versus RWPC was estimated with an odds ratio and relative response rate and 95% confidence interval (CI), derived from weighted logistic regression. Weighted Cox proportional hazards model was used to estimate hazard ratios (HR) and 95% CIs for time-to-event endpoints [duration of response (DOR), progression-free survival (PFS), and overall survival (OS)]. Results: After weighting, baseline characteristics were balanced across cohorts. In adjusted comparisons, teclistamab-treated patients were 2.3-fold, 5.2-fold and 148.3-fold, more likely to reach ORR [response-rate ratio (RR) = 2.31, 95% CI 1.77–2.85, p < 0.0001], ≥ VGPR (RR = 5.19, 95% CI 3.26–7.12, p < 0.0001) and ≥ CR (RR = 148.25, 95% CI 20.63–1065.40, p < 0.0001), respectively, versus patients receiving RWPC. Following adjustment, DOR (HR 0.32, 95% CI 0.19–0.54, p < 0.0001) and PFS (HR 0.48, 95% CI 0.35–0.65, p < 0.0001) were significantly longer with teclistamab versus RWPC. OS was numerically better with teclistamab versus RWPC [HR 0.77 (0.55–1.09), p = 0.1419]. Conclusion: Teclistamab demonstrated improved effectiveness versus RWPC, highlighting its clinical benefit as a novel and effective treatment for patients with TCE-RRMM. Trial Registration: Majest TEC-1, ClinicalTrials.gov NCT04557098; LocoMMotion, ClinicalTrials.gov NCT04035226. [ABSTRACT FROM AUTHOR]

Introduction: Given the rapid increase in novel treatments for patients with multiple myeloma (MM), this patient preference study aimed to establish which treatment attributes matter most to MM patients and evaluate discrete choice experiment (DCE) and swing weighting (SW) as two elicitation methods for quantifying patients’ preferences. Methods: A survey incorporating DCE and SW was disseminated among European MM patients. The survey included attributes and levels informed by a previous qualitative study with 24 MM patients. Latent class and mixed logit models were used to estimate the DCE attribute weights and descriptive analyses were performed to derive SW weights. MM patients and patient organisations provided extensive feedback during survey development. Results: 393 MM patients across 21 countries completed the survey (Myears since diagnosis=6; Mprevious therapies=3). Significant differences (p<.01) between participants’ attribute weights were revealed depending on participants’ prior therapy experience, and their experience with side-effects and symptoms. Multivariate analyses showed that participants across the three MM patient classes identified via the latent class model differed regarding their past number of therapies (F=4.772, p=.009). Patients with the most treatments (class 1) and those with the least treatments (class 3) attached more value to life expectancy versus quality of life-related attributes such as pain, mobility and thinking problems. Conversely, patients with intermediary treatment experience (class 2) attached more value to quality of life-related attributes versus life expectancy. Participants highlighted the difficulty of trading-off between life expectancy and quality of life and between physical and mental health. Participants expressed a need for greater psychological support to cope with their symptoms, treatment side-effects, and uncertainties. With respect to patients’ preferences for the DCE or SW questions, 42% had no preference, 32% preferred DCE, and 25% preferred SW. Conclusions: Quality of life-related attributes affecting MM patients’ physical, mental and psychological health such as pain, mobility and thinking problems were considered very important to MM patients, next to life expectancy. This underscores a need to include such attributes in decision-making by healthcare stakeholders involved in MM drug development, evidence generation, evaluation, and clinical practice. This study highlights DCE as the preferred methodology for understanding relative attribute weights from a patient’s perspective. [ABSTRACT FROM AUTHOR]

Background Drug-induced myocarditis is a rare complication of certain cancer treatments, characterized by the development of myocardial inflammation shortly after initiation of treatment, potentially leading to heart failure and/or malignant arrhythmias. The development of eosinophilic myocarditis after administration of lenalidomide has been described and bortezomib has been associated with the development of cardiomyopathies and atherosclerosis. Case summary A 69-year-old woman, recently diagnosed with multiple myeloma underwent local radiotherapy for a pathological fracture of the 4th lumbar vertebra and was treated with bortezomib–lenalidomide–dexamethasone. Within 19 days after therapy initiation, she presented with gastrointestinal symptoms, an erythematous pruritic rash, and general fatigue. Surprisingly, routine electrocardiogram (ECG) showed upwardly concave ST-elevation in I and aVL and ST-depressions in II, III, and aVF. Troponin levels were markedly elevated to 5470 ng/L. Complete blood count revealed eosinophilia. Based on further cardiac work-up, including echocardiography, coronary angiography, and cardiac magnetic resonance imaging (MRI) showing positive T2 imaging and patchy subepicardial late gadolinium enhancement, she was diagnosed with hypersensitivity myocarditis. Additional endomyocardial heart biopsy did not reveal any abnormalities, probably due to sampling error. After discontinuation of chemotherapy and prompt treatment with high doses of corticosteroids, the patient recovered. Discussion Diagnosis of drug-induced myocarditis can be challenging and even long known widely used (chemo)therapy should be considered a potential trigger. Early diagnosis and treatment are crucial, warranting alertness for suggestive symptoms. Cardiac biomarkers, ECG monitoring, and cardiac MRI are key to confirm the diagnosis. In patients with preserved left ventricular systolic function, two-dimensional speckle tracking echocardiography can provide additional diagnostic information. Every patient presenting with eosinophilia and/or acute onset of auto-immune symptoms after initiation of therapy with lenalidomide/bortezomib deserves prompt cardiac screening. The gold standard remains an endomyocardial biopsy, although sampling error may occur. [ABSTRACT FROM AUTHOR]

Purpose: Multiple myeloma (MM) patients with triple- and penta-refractory disease have a poor survival and limited treatment options. Selinexor, in combination with bortezomib and dexamethasone, demonstrated clinical activity in the STOMP study as well as in the BOSTON study in previously treated patients with disease refractory to a proteasome inhibitor (PI). Patients and Methods: Here, we report a real-world case series of 7 heavily pretreated MM patients who had been extensively pretreated with bortezomib and had disease refractory to PIs, including carfilzomib; who were administered a starting dose of 100 mg of selinexor, 20– 40 mg dexamethasone and 1.3 mg/m2 of bortezomib, each once weekly. The majority of these patients (6 patients, 86.0%) had penta-refractory disease, with 5 patients (71.4%) having disease refractory to bortezomib and carfilzomib, and all 7 patients having pomalidomide refractory disease. The median number of prior lines of therapy was 8 (range 4– 12). Results: The seven patients in this case series received selinexor for a median of 5 cycles (range 1– 10). Four patients (57.1%) had a dose reduction of selinexor. Five patients (71.4%) had a response, of which 2 (29.0%) had a very good partial response (VGPR) and 3 (43.0%) had a partial response (PR). One patient (14.3%) had stable disease (SD) and 1 (14.3%) had progressive disease (PD). There were no new safety signals. Conclusion: The selinexor, bortezomib, and dexamethasone triplet combination demonstrates activity in PI-resistant MM and patients with heavily pretreated MM with refractory disease and after multiple lines of therapy. [ABSTRACT FROM AUTHOR]

Background Light-chain amyloidosis has always been described as a sporadic disease caused by plasma cell dyscrasia. Cardiac amyloidosis refers to cardiac involvement with infiltration of amyloid fibrils in the myocardium. The degree of cardiac involvement is the greatest predictor of prognosis. To our knowledge, AL cardiac amyloidosis has only been reported once before in first-degree relatives. Case summary In this report, we describe the unusual cases of two sisters with light-chain cardiac amyloidosis. The first patient underwent autologous stem cell transplantation and remained in remission for 10 years until the disease relapsed and she died of end-stage heart failure. The second patient was promptly started on a chemotherapy regimen but died shortly after her initial diagnosis due to rapid progression of cardiac dysfunction. Conclusion Cardiac amyloidosis is a severe life-threatening condition which requires a multidisciplinary diagnostic and therapeutic approach. Based on this case report, a genetic cause for AL amyloidosis might be suspected or is this a purely coincidental finding? Counselling, screening, and follow-up of other family members are very challenging. As is often the case with rare diseases, many unsolved questions remain, representing important challenges for clinicians. [ABSTRACT FROM AUTHOR]

Idecabtagene vicleucel (ide-cel, bb2121), a chimeric antigen receptor (CAR) T cell therapy, has been investigated in patients with relapsed and refractory multiple myeloma (RRMM) who have received an immunomodulatory drug, proteasome inhibitor, and anti-CD38 antibody in the single-arm phase 2 KarMMa clinical trial. Two therapies with distinct mechanisms of action – selinexor plus dexamethasone (Sd) and belantamab mafodotin (BM) – are currently approved in the United States for heavily pretreated patients, including those who are triple-class refractory. To compare ide-cel versus Sd and ide-cel versus BM, matching-adjusted indirect comparisons were performed. Ide-cel extended progression-free survival (PFS) and overall survival (OS) versus both Sd and BM (hazard ratio (HR); 95% confidence interval (CI)). PFS: ide-cel versus Sd, 0.46; 0.28–0.75; ide-cel versus BM, 0.45; 0.27–0.77. OS: ide-cel versus Sd, 0.23; 0.13–0.42; ide-cel versus BM, 0.35; 0.14–0.87. These results suggest ide-cel offers clinically meaningful improvements over currently approved regimens for patients with heavily pretreated RRMM. [ABSTRACT FROM AUTHOR]

Objectives and design A novel risk stratification algorithm estimating risk of death in patients with relapsed multiple myeloma starting second-line treatment was recently developed using multivariable Cox regression of data from a Czech registry. It uses 16 parameters routinely collected in medical practice to stratify patients into four distinct risk groups in terms of survival expectation. To provide insight into generalisability of the risk stratification algorithm, the study aimed to validate the risk stratification algorithm using real-world data from specifically designed retrospective chart audits from three European countries. Participants and setting Physicians collected data from 998 patients (France, 386; Germany, 344; UK, 268) and applied the risk stratification algorithm. Methods The performance of the Cox regression model for predicting risk of death was assessed by Nagelkerke’s R2, goodness of fit and the C-index. The risk stratification algorithm’s ability to discriminate overall survival across four risk groups was evaluated using Kaplan-Meier curves and HRs. Results Consistent with the Czech registry, the stratification performance of the risk stratification algorithm demonstrated clear differentiation in risk of death between the four groups. As risk groups increased, risk of death doubled. The C-index was 0.715 (95% CI 0.690 to 0.734). Conclusions Validation of the novel risk stratification algorithm in an independent ‘real-world’ dataset demonstrated that it stratifies patients in four subgroups according to survival expectation. [ABSTRACT FROM AUTHOR]

Summary: Multiple myeloma (MM) is a malignancy with varying survival outcomes and drivers of disease progression. Existing MM staging tools were developed using data from newly diagnosed patients. As patient characteristics and disease‐related factors change between diagnosis and the initiation of second‐line (2L) treatment, an unmet need exists for a tool that can evaluate risk of death at first relapse. We have developed a risk stratification algorithm (RSA) using data from patients with MM who were at 2L. Hazard ratios for independent predictors of overall survival (OS) were derived from a Cox models, and individual patient scores were calculated for total risk. K‐adaptive partitioning for survival was used to stratify patients into groups based on their scores. Relative risk doubled with ascending risk group; median OSs for patients in group 1 (lowest risk)–4 (highest risk) were 61·6, 29·6, 14·2 and 5·9 months, respectively. Differences in OS between risk groups were significant. Similar stratification was observed when the RSA was applied to an external validation data set. In conclusion, we have developed a validated RSA that can quantify total risk, frailty risk and disease aggressiveness risk, and stratify patients with MM at 2L into groups with profoundly different survival expectations. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The efficacy and safety of bortezomib‐based therapy for relapsed/refractory multiple myeloma (RRMM) in clinical trials may differ from the oncology practice experience. The electronic VELCADE® OBservational Study was designed to prospectively evaluate bortezomib for multiple myeloma (MM) in real‐world medical practice. Method: Patients scheduled to receive intravenous bortezomib for MM were eligible. The primary objective was to evaluate clinical outcomes, including response, time to response, time to next therapy, treatment‐free interval, progression‐free survival (PFS), and overall survival (OS). Secondary objectives included safety and healthcare resource utilization. Results: In total, 873 patients with a median of two therapy lines prior to initiating bortezomib were included. The overall response rate (≥partial response) was 69%, including 37% complete response/near‐complete response. Median time to response was 1.8 months, median time to next therapy was 9.7 months, and median treatment‐free interval was 7.9 months. After 22.6 months’ median follow‐up, median PFS was 12.0 months and median OS was 36.1 months. The most common adverse events (AEs) were neuropathy not otherwise specified (19%), diarrhea NOS, and thrombocytopenia (each 17%); 230 (26%) patients discontinued bortezomib due to AEs. Of 689 (79%) patients without baseline peripheral neuropathy (PN), the rate of new‐onset any‐grade PN increased to 51% (12% grade 3/4) by cycle 8. Overall, 244 (28%) patients were hospitalized, 372 (43%) attended an outpatient visit, and 341 (39%) underwent a diagnostic/therapeutic procedure during bortezomib treatment. Conclusion: These prospective real‐world data demonstrate the effectiveness and safety of bortezomib‐based therapy for RRMM and confirm high response rates and long OS for this population. [ABSTRACT FROM AUTHOR]

To the Editor, Free light chains (FLCs) are valuable laboratory markers to support the diagnosis, prognosis and follow-up of patients with monoclonal gammopathies. / ratio by N-Latex and Freelite in MGUS and MM: The / ratio was determined in 525 samples from 255 MGUS patients (described in [[8]]) and the results were classified as normal or abnormal. When the minimum and maximum / ratio determined in the 282 controls in this study was used, then 39.4% of the samples from MGUS patients in this study had an abnormal / ratio with both assays, 9% with only Freelite, and 7.6% with only N-Latex. [Extracted from the article]

To the Editor: The worldwide COVID-19 pandemic is expected to be a devastating infection in patients with chronic hematological disorders. So far, no data have been reported in multiple myeloma (MM), a disease characterized by a severe humoral and cellular immune deficiency that exposes patients to infectious complications. In order to assess the impact of COVID-19 in the Belgian MM community, we collected data on the disease by sending questionnaires to 30 different cancer centers. [Extracted from the article]

The article presents a study on antigen excess detection by automated assays for free light chains. Topics discussed include role of free light chains (FLCs) in diagnosis, prognosis and follow-up of patients with monoclonal gammopathy; information on antigen excess detection system; and the issues relating to the multiple myeloma, a cancer that forms in a type of white blood cell.

We report a multicentre retrospective study that analysed clinical characteristics and outcomes in 117 patients with primary plasma cell leukaemia (pPCL) treated at the participating institutions between January 2006 and December 2016. The median age at the time of pPCL diagnosis was 61 years. Ninety-eight patients were treated with novel agents, with an overall response rate of 78%. Fifty-five patients (64%) patients underwent upfront autologous stem cell transplantation (ASCT). The median followup time was 50 months (95% confidence interval [CI] 33; 76), with a median overall survival (OS) for the entire group of 23 months (95% CI 15; 34). The median OS time in patients who underwent upfront ASCT was 35 months (95% CI 24·3; 46) as compared to 13 months (95% CI 6&3183;3; 35·8) in patients who did not receive ASCT (P = 0&3183;001). Multivariate analyses identified age ≥60 years, platelet count ≤100 9 109/l and peripheral blood plasma cell count ≥20 9 109/l as independent predictors of worse survival. The median OS in patients with 0, 1 or 2–3 of these risk factors was 46, 27 and 12 months, respectively (P < 0·001). Our findings support the use of novel agents and ASCT as frontline treatment in patients with pPCL. The constructed prognostic score should be independently validated. [ABSTRACT FROM AUTHOR]

Although immunomodulatory drugs, alkylating agents, corticosteroids, protease inhibitors, and therapeutic monoclonal antibodies improve multiple myeloma outcomes, treatment burden is still an issue. Neutropenia is a known complication of cytotoxic cancer therapy and is often associated with infections; it is an important consideration in myeloma given the fact that patients often have a weakened immune system. The risk of febrile neutropenia increases with severe and persisting neutropenia. Recombinant granulocyte colony-stimulating factors (G-CSFs) are commonly used to reduce the incidence, duration, and severity of febrile neutropenia. Here, we review the risk and management of neutropenia associated with new and commonly used anti-myeloma agents. Few papers report the use of G-CSF in patients with multiple myeloma receiving anti-cancer treatments, and fewer describe whether G-CSF was beneficial. None of the identified studies reported G-CSF primary prophylaxis. Further studies are warranted to evaluate the need for G-CSF prophylaxis in multiple myeloma. Prophylaxis may be particularly useful in patients at high risk of prolonged severe neutropenia. [ABSTRACT FROM AUTHOR]

Unraveling the mechanism of action and molecular target of small molecules remains a major challenge in drug discovery. While many cancer drugs target genetic vulnerabilities, loss-of-function screens fail to identify essential genes in drug mechanism of action. Here, we report CRISPRres, a CRISPR-Cas-based genetic screening approach to rapidly derive and identify drug resistance mutations in essential genes. It exploits the local genetic variation created by CRISPR-Cas-induced non-homologous end-joining (NHEJ) repair to generate a wide variety of functional in-frame mutations. Using large sgRNA tiling libraries and known drug–target pairs, we validate it as a target identification approach. We apply CRISPRres to the anticancer agent KPT-9274 and identify nicotinamide phosphoribosyltransferase (NAMPT) as its main target. These results present a powerful and simple genetic approach to create many protein variants that, in combination with positive selection, can be applied to reveal the cellular target of small-molecule inhibitors. [ABSTRACT FROM AUTHOR]

The FIRST trial demonstrated that continuous therapy with lenalidomide and dexamethasone (Rd) prolongs overall survival (OS) and improves health-related quality of life (HRQoL) during the first 18 months of therapy in newly diagnosed multiple myeloma (NDMM) patients. However, patient-reported HRQoL data were not collected after 18 months. We therefore estimated HRQoL scores based on time-varying data collected during progression-free follow-up after 18 months. During the initial 18 months of Rd, observed changes from baseline were within the 95% confidence interval of the predictive models at 33 of 35 time points across 7 HRQoL scores. Predicted scores after 18 months of therapy showed that observed HRQoL improvements during therapy were maintained or improved. Therefore, the survival gain observed with Rd does not come at a cost of declining HRQoL during continuous therapy beyond 18 months, supporting long-term Rd as a standard of care for initial myeloma therapy. [ABSTRACT FROM AUTHOR]

This is a summary of a phase 1–2 clinical trial called MajesTEC-1. This trial tested the cancer drug teclistamab in people with relapsed or refractory multiple myeloma, a cancer that forms in a certain type of white blood cells known as plasma cells. Most participants who took part in the study had at least 3 prior treatments for multiple myeloma before their cancer came back. A total of 165 participants from 9 countries were included in this study. All participants were given teclistamab once per week and monitored for side effects. Once participants started taking teclistamab, they were checked regularly to monitor if their cancer had no change, improved (responded to treatment), or worsened or spread (known as disease progression). After approximately 14.1 months of follow-up (from 2020 to 2021), 63% of participants who were given teclistamab had a decrease in myeloma burden, meaning that they responded to treatment with teclistamab. Participants who responded to teclistamab lived without their myeloma coming back for approximately 18.4 months. The most common side effects were infections, cytokine release syndrome, abnormally low white and red blood cell counts (neutropenia, lymphopenia, and anemia), and low platelet cell counts (thrombocytopenia). Approximately 65% of participants experienced serious side effects. Overall, more than half of the participants (63%) in the MajesTEC-1 study responded to treatment with teclistamab despite previous myeloma treatment failures. Clinical Trial Registration: NCT03145181, NCT04557098 (ClinicalTrials.gov) [ABSTRACT FROM AUTHOR]

Objectives Heavily pretreated patients with relapsed and refractory multiple myeloma are susceptible to treatment-related adverse events (AEs). Managing AEs are important to ensure patients continue therapy long enough to receive the best clinical benefit. Data from the MM-002, MM-003, and MM-010 trials were pooled to further characterize the safety profile of pomalidomide plus low-dose dexamethasone and AE management. Methods This analysis included 1088 patients who received ≥ 2 prior therapies, including lenalidomide and bortezomib, and progressed ≤ 60 days of last therapy. Patients received 28-day cycles of pomalidomide 4 mg/day on days 1-21 and low-dose dexamethasone 40 mg (20 mg if aged > 75 years) weekly until disease progression or unacceptable toxicity. Thromboprophylaxis was required. Results The most common grade 3/4 AEs were neutropenia (56.2%), anemia (32.3%), and thrombocytopenia (25.8%), which occurred within the first few cycles of treatment. Grade 3/4 infections occurred in 33.7% patients, of whom 13.9% had pneumonia, and 40.3% had neutropenia. Pomalidomide dose reductions or interruptions were reported in 24.2% and 66.0% of patients, respectively. AEs were managed by dose modifications and/or supportive care. Conclusions Pomalidomide plus low-dose dexamethasone showed an acceptable safety profile, and AEs were well managed according to study protocols and established guidelines. [ABSTRACT FROM AUTHOR]

Delanzomib (CEP-18770), a reversible P2 threonine boronic acid proteasome (β5/β1 subunits) inhibitor that showed promising anti-myeloma effects in preclinical studies, was investigated in a single-agent multicenter phase I/II study in patients with relapsed/refractory myeloma. Sixty-one patients (17 during dose escalation; 44 in the expansion cohort) received delanzomib on days 1, 8, and 15 in 28-d cycles; 47 received the maximum tolerated dose (MTD), 2.1 mg/m2. Dose-limiting toxicities (DLTs) at 2.4 mg/m2 were rash and thrombocytopenia. At the MTD, the most prominent adverse events were nausea, vomiting, anorexia, fatigue, and pyrexia; grade 3/4 thrombocytopenia and neutropenia occurred in 53 and 23% of patients, respectively. Peripheral neuropathy (21%) was limited to grades 1/2. At the MTD, 26 patients (55%) had stable disease and four (9%) had a partial response (PR). Median time to progression (TTP) was 2.5 months across the cohort. Based upon the efficacy results, development of delanzomib for myeloma was discontinued. [ABSTRACT FROM AUTHOR]

Renal impairment (RI) is a major comorbidity in patients with multiple myeloma (MM). Here we present the pooled safety and efficacy analysis of three clinical trials (MM-002, MM-003, and MM-010) of pomalidomide + low-dose dexamethasone (POM + LoDEX) in patients with moderate RI (creatinine clearance [CrCl] ≥ 30 to <60 mL/min) and without RI (≥ 60 mL/min). Trial protocols were approved by the institutional review board of each site involved. Patients with RI were older than patients without RI, although other baseline characteristics were similar. The dosing and safety profile of POM + LoDEX was similar across RI subgroups. Median overall response rate, progression-free survival, time to progression, and duration of response were not significantly different between RI subgroups. However, patients with vs. without RI had significantly shorter median overall survival (10.5 vs. 14.0 months, respectively;p = .004). This analysis demonstrates that POM + LoDEX is a safe and effective treatment for patients with moderate RI. The trials were registered at ClinicalTrials.gov as NCT00833833 (MM-002), NCT01311687 (MM-003), and NCT01712789 (MM-010) and at EudraCT as 2010-019820-30 (MM-003) and 2012-001888-78 (MM-010). [ABSTRACT FROM AUTHOR]

With increasing number of therapies available for the treatment of multiple myeloma, it is timely to examine the course of patients' journeys. We investigated patient characteristics, treatment durations and outcomes, and symptom burden across the treatment pathway in Belgium, France, Germany, Italy, Spain, Switzerland and the UK. In total, 435 physicians retrospectively reviewed 4997 patient charts. Profiles of patients diagnosed with multiple myeloma during the last 12 months were similar across countries; bone pain was the most common presentation. Median duration of first-line therapy was 6 months, followed by a median treatment-free interval of 10 months; both these decreased with increasing lines of therapy, as did time to progression. Depth of response, as assessed by the treating physician, also decreased with each additional line of therapy: 74% of patients achieved at least a very good partial response at first line, compared with only 11% at fifth line. Deeper responses were associated with longer time to progression, although these were physician-judged. Toxicities and co-morbidities increased with later treatment lines, and were more likely to have led to discontinuation of treatment. These real-world data provide an insight into patient outcomes and treatment decisions being made in clinical practice. [ABSTRACT FROM AUTHOR]

Real-world data describing management of patients with multiple myeloma are limited. A European (Belgium, France, Germany, Italy, Spain, Switzerland, UK) observational chart review was conducted to address this. Physicians completed questionnaires for every patient seen during a 2-4-week observation period, regardless of treatment status. A total of 435 physicians completed 7635 cross-sectional chart reviews. Overall, 47% of patients were undergoing anti-tumour drug treatment, 42% had previously received ≥1 line of treatment and 12% had never received anti-tumour drug treatment. Of the patients treated by oncologists, onco-haematologists or internists, 95% received, or were expected to receive, at least one line of anti-tumour drug treatment, 61% received ≥2 lines of therapy and 38% received ≥3 lines. Except in the UK, the most commonly used induction therapies contained bortezomib (48%); lenalidomide was the most commonly used first-line maintenance therapy (45%) and second- and third-line agent overall (60% and 52% of patients at those lines, respectively). Bortezomib retreatment was used in 47% of patients who received it first line. Treatment patterns became more diverse with subsequent treatment lines. This study provides insight into real-world treatment patterns in Europe. While treatment practices are broadly similar across countries, some notable differences in the agents used exist. [ABSTRACT FROM AUTHOR]

Skin infiltration in multiple myeloma (skin MM) is a rare clinical problem. Only a few cases of skin involvement have been reported, primarily in single case reports. We analyzed and present the clinical outcomes, immunohistochemistry and cytogenetic features, and relevant laboratory data on 53 biopsy-proven skin MM cases. The median time from MM diagnosis to skin involvement was 2 years. There appears to be an overrepresentation of immunoglobulin class A (IgA) and light chain disease in skin MM. We found no correlation between CD56 negative MM and skin infiltration. We found that skin MM patients presented in all MM stages (i.e. ISS stages I to III), and there was no preferential cytogenetic abnormality. Patients with skin MM carry a very poor prognosis with a median overall survival (OS) of 8.5 months as time from skin involvement. Moreover, patients with IgA disease and plasmablastic morphology appear to have a worse OS. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies (mAbs) are a recent addition to multiple myeloma (MM) therapies and a number of mAbs directed at myeloma cell surface molecules are in development. Daratumumab is a CD38 mAb that has demonstrated substantial activity and good tolerability in four phase I, phase I/II and phase II studies as monotherapy, as well as in combination with current standard treatments in MM. The positive results obtained in the relapsed/refractory setting in patients with advanced-stage disease and in a small number of patients with newly diagnosed disease provide the rationale for the investigation of the agent in a number of ongoing phase III trials. mAbs are generally better tolerated than conventional chemotherapy; however, their use requires other special considerations. Such factors include those common to all mAbs, namely infusion-related reactions, but also factors that are observed with mAbs used in myeloma, such as interference with response assessment, or factors that are related to CD38 mAbs such as daratumumab, for instance blood typing interference. Our review provides an overview of the results from the daratumumab clinical trials conducted to date, as well as practical management considerations for the use of daratumumab based on our experience with the agent. [ABSTRACT FROM AUTHOR]

Bortezomib is a first-generation proteasome inhibitor used in the treatment of multiple myeloma (MM). A few reports have linked bortezomib exposure with the development of thrombotic microangiopathy (TMA). We describe a case of biopsy-proven renal thrombotic microangiopathy associated with the use of bortezomib in a 51-year-old man with IgG lambda MM. To our knowledge, this is the first biopsy-proven case. In addition, reexposure to bortezomib 18 months later was associated with recurrence of TMA. This supports a possible causal role of bortezomib. The exact mechanisms remain to be elucidated. [ABSTRACT FROM AUTHOR]

Heavy chain diseases are rare variants of B-cell lymphomas that produce one of three classes of immunoglobulin heavy chains, without corresponding light chains. We describe two patients with asymptomatic heavy chain monoclonal gammopathy. The first patient is a 51-year-old woman with alpha paraprotein on serum immunofixation. The second case is a 46-year-old woman with gamma paraprotein on urine immunofixation. Neither patient had corresponding monoclonal light chains. Workup for multiple myeloma and lymphoma was negative in both patients. These two cases illustrate that heavy chain monoclonal gammopathy can exist in the absence of clinically apparent malignancy. Only a few reports of “heavy chain MGUS” have been described before. In the absence of specialized guidelines, we suggest a similar follow-up as for MGUS, while taking into account the higher probability of progression to lymphoma than to myeloma. [ABSTRACT FROM AUTHOR]

The article reports on lack of clinical benefit of zoledronic acid in myelofibrosis, a results of multi-center phase II trial. It states that bisphosphonates inhibitors of osteoclast mediated bone resorption and an established treatment for hypercalcemia of malignancy, osteoporosis and solid tumors. It mentions that zoledronic acid to provide benefit over treatment with the nitrogen-containing bisphosphonates (N-BPs) and has beneficial effect on blood counts became apparent after infusion.