Single-cell analysis of the multiple myeloma microenvironment after gamma-secretase inhibition and CAR T-cell therapy.

Chimeric antigen receptor (CAR) T-cells and bispecific antibodies (BsAb) targeting B-cell maturation antigen (BCMA) have significantly advanced the treatment of relapsed and refractory multiple myeloma (MM). Resistance to BCMA-targeting therapies, nonetheless, remains a significant challenge. BCMA shedding by gamma-secretase is a known resistance mechanism, and preclinical studies suggest that inhibition may improve anti-BCMA therapy. Leveraging a phase I clinical trial of the gamma-secretase inhibitor (GSI), crenigacestat, with anti-BCMA CAR T-cells (FCARH143), we utilized single-nuclei RNA sequencing and Assay for Transposase-Accessible Chromatin (ATAC) sequencing to characterize the effects of GSI on the tumor microenvironment. The most significant impacts of GSI involved effects on monocytes, which are known to promote tumor growth. In addition to observing a reduction in the frequency of non-classical monocytes, we also detected significant changes in gene expression, chromatin accessibility, and inferred cell-cell interactions following exposure to GSI. Although many genes with altered expression are associated with gamma-secretase-dependent signaling, such as Notch, other pathways were affected, indicating GSI has far-reaching effects. Finally, we detected monoallelic deletion of the BCMA locus in some patients with prior exposure to anti-BCMA therapy, which significantly correlated with reduced progression-free survival (median PFS 57 days versus 861 days). GSIs are being explored in combination with the full spectrum of BCMA targeting agents, and our results reveal widespread effects of GSI on both tumor and immune cell populations, providing insight into mechanisms for enhancing BCMA-directed therapies.

EVIDENCE meta-analysis: evaluating minimal residual disease as an intermediate clinical end point for multiple myeloma.

ABSTRACT: Estimating progression-free survival (PFS) and overall survival superiority during clinical trials of multiple myeloma (MM) has become increasingly challenging as novel therapeutics have improved patient outcomes. Thus, it is imperative to identify earlier end point surrogates that are predictive of long-term clinical benefit. Minimal residual disease (MRD)-negativity is a common intermediate end point that has shown prognostic value for clinical benefit in MM. This meta-analysis was based on the US Food and Drug Administration guidance for considerations for a meta-analysis of MRD as a clinical end point and evaluates MRD-negativity as an early end point reasonably likely to predict long-term clinical benefit. Eligible studies were phase 2 or 3 randomized controlled clinical trials measuring MRD-negativity as an end point in patients with MM, with follow-up of ≥6 months following an a priori-defined time point of 12 ± 3 months after randomization. Eight newly diagnosed MM studies evaluating 4907 patients were included. Trial-level associations between MRD-negativity and PFS were R2WLSiv, 0.67 (95% confidence interval [CI], 0.43-0.91) and R2copula 0.84 (0.64 to >0.99) at the 12-month time point. The individual-level association between 12-month MRD-negativity and PFS resulted in a global odds ratio (OR) of 4.02 (95% CI, 2.57-5.46). For relapse/refractory MM, there were 4 studies included, and the individual-level association between 12-month MRD-negativity and PFS resulted in a global OR of 7.67 (4.24-11.10). A clinical trial demonstrating a treatment effect on MRD is reasonably likely to eventually demonstrate a treatment effect on PFS, suggesting that MRD may be an early clinical end point reasonably likely to predict clinical benefit in MM, that may be used to support accelerated approval and thereby, expedite the availability of new drugs to patients with MM.

Impact of soluble BCMA and non-T-cell factors on refractoriness to BCMA-targeting T-cell engagers in multiple myeloma.

Adoptive T cell therapy is a promising therapy for multiple myeloma (MM), but its efficacy hinges on understanding relevant biological and predictive markers of response. B cell maturation antigen (BCMA) is a key target antigen in MM, with active development of multiple anti-BCMA T cell engagers (TCE) and chimeric antigen receptor T cell (CAR T) therapies. The regulation of surface BCMA expression by MM cells, resulting in the shedding of soluble BCMA (sBCMA), has triggered debate surrounding the significance of sBCMA as a predictive marker and its potential impact on treatment outcomes. In order to address this, we leveraged whole genome sequencing and in vitro assays to demonstrate that sBCMA may independently predict primary refractoriness to anti-BCMA therapies. In addition to sBCMA, tumor burden and surface BCMA antigen density collectively influence anti-BCMA TCE cytotoxic efficacy. Correlative analyses of 163 patients treated with anti-BCMA TCE teclistamab validated and further underscored the association between elevated baseline sBCMA (>400 ng/mL) and refractoriness. Importantly, increasing TCE dose, the use of TCE against alternative targets (e.g.,GPRC5D), or gamma secretase inhibitors were able to overcome high sBCMA. These findings highlight the importance of accounting for baseline sBCMA levels, disease burden, and TCE dose intensity when administering anti-BCMA TCEs, offering critical insights for optimizing therapeutic strategies to overcome specific high-risk features and primary anti-BCMA TCE refractoriness.

The biological and clinical impact of deletions before and after large chromosomal gains in multiple myeloma.

ABSTRACT: Acquisition of a hyperdiploid (HY) karyotype or immunoglobulin heavy chain (IgH) translocations are considered key initiating events in multiple myeloma (MM). To explore if other genomic events can precede these events, we analyzed whole-genome sequencing data from 1173 MM samples. By integrating molecular time and structural variants within early chromosomal duplications, we indeed identified pregain deletions in 9.4% of patients with an HY karyotype without IgH translocations, challenging acquisition of an HY karyotype as the earliest somatic event. Remarkably, these deletions affected tumor suppressor genes (TSGs) and/or oncogenes in 2.4% of patients with an HY karyotype without IgH translocations, supporting their role in MM pathogenesis. Furthermore, our study points to postgain deletions as novel driver mechanisms in MM. Using multiomics approaches to investigate their biologic impact, we found associations with poor clinical outcome in newly diagnosed patients and profound effects on both the oncogene and TSG activity despite the diploid gene status. Overall, this study provides novel insights into the temporal dynamics of genomic alterations in MM.

GPRC5D-Targeted CAR T Cells for Myeloma.

BACKGROUND: B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapies have generated responses in patients with advanced myeloma, but relapses are common. G protein-coupled receptor, class C, group 5, member D (GPRC5D) has been identified as an immunotherapeutic target in multiple myeloma. Preclinical studies have shown the efficacy of GPRC5D-targeted CAR T cells, including activity in a BCMA antigen escape model. METHODS: In this phase 1 dose-escalation study, we administered a GPRC5D-targeted CAR T-cell therapy (MCARH109) at four dose levels to patients with heavily pretreated multiple myeloma, including patients with relapse after BCMA CAR T-cell therapy. RESULTS: A total of 17 patients were enrolled and received MCARH109 therapy. The maximum tolerated dose was identified at 150×106 CAR T cells. At the 450×106 CAR T-cell dose, 1 patient had grade 4 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), and 2 patients had a grade 3 cerebellar disorder of unclear cause. No cerebellar disorder, ICANS of any grade, or cytokine release syndrome of grade 3 or higher occurred in the 12 patients who received doses of 25×106 to 150×106 cells. A response was reported in 71% of the patients in the entire cohort and in 58% of those who received doses of 25×106 to 150×106 cells. The patients who had a response included those who had received previous BCMA therapies; responses were observed in 7 of 10 such patients in the entire cohort and in 3 of 6 such patients who received 25×106 to 150×106 cells. CONCLUSIONS: The results of this study of a GPRC5D-targeted CAR T-cell therapy (MCARH109) confirm that GPRC5D is an active immunotherapeutic target in multiple myeloma. (Funded by Juno Therapeutics/Bristol Myers Squibb; ClinicalTrials.gov number, NCT04555551.).

Tracking the evolution of therapy-related myeloid neoplasms using chemotherapy signatures.

Patients treated with cytotoxic therapies, including autologous stem cell transplantation, are at risk for developing therapy-related myeloid neoplasms (tMN). Preleukemic clones (ie, clonal hematopoiesis [CH]) are detectable years before the development of these aggressive malignancies, although the genomic events leading to transformation and expansion are not well defined. Here, by leveraging distinctive chemotherapy-associated mutational signatures from whole-genome sequencing data and targeted sequencing of prechemotherapy samples, we reconstructed the evolutionary life-history of 39 therapy-related myeloid malignancies. A dichotomy was revealed, in which neoplasms with evidence of chemotherapy-induced mutagenesis from platinum and melphalan were hypermutated and enriched for complex structural variants (ie, chromothripsis), whereas neoplasms with nonmutagenic chemotherapy exposures were genomically similar to de novo acute myeloid leukemia. Using chemotherapy-associated mutational signatures as temporal barcodes linked to discrete clinical exposure in each patient's life, we estimated that several complex events and genomic drivers were acquired after chemotherapy was administered. For patients with prior multiple myeloma who were treated with high-dose melphalan and autologous stem cell transplantation, we demonstrate that tMN can develop from either a reinfused CH clone that escapes melphalan exposure and is selected after reinfusion, or from TP53-mutant CH that survives direct myeloablative conditioning and acquires melphalan-induced DNA damage. Overall, we revealed a novel mode of tMN progression that is not reliant on direct mutagenesis or even exposure to chemotherapy. Conversely, for tMN that evolve under the influence of chemotherapy-induced mutagenesis, distinct chemotherapies not only select preexisting CH but also promote the acquisition of recurrent genomic drivers.

Association Between Autoimmune Diseases and Monoclonal Gammopathy of Undetermined Significance : An Analysis From a Population-Based Screening Study.

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) is a precursor of multiple myeloma (MM) and related conditions. In previous registry-based, retrospective studies, autoimmune diseases have been associated with MGUS. However, these studies were not based on a screened population and are therefore prone to ascertainment bias. OBJECTIVE: To examine whether MGUS is associated with autoimmune diseases. DESIGN: A cross-sectional study within iStopMM (Iceland Screens, Treats, or Prevents MM), a prospective, population-based screening study of MGUS. SETTING: Icelandic population of adults aged 40 years or older. PATIENTS: 75 422 persons screened for MGUS. MEASUREMENTS: Poisson regression for prevalence ratios (PRs) of MGUS among persons with or without an autoimmune disease, adjusted for age and sex. RESULTS: A total of 10 818 participants had an autoimmune disorder, of whom 599 had MGUS (61 with a prior clinical diagnosis and 538 diagnosed at study screening or evaluation). A diagnosis of an autoimmune disease was not associated with MGUS (PR, 1.05 [95% CI, 0.97 to 1.15]). However, autoimmune disease diagnoses were associated with a prior clinical diagnosis of MGUS (PR, 2.11 [CI, 1.64 to 2.70]). LIMITATION: Registry data were used to gather information on autoimmune diseases, and the homogeneity of the Icelandic population may limit the generalizability of these results. CONCLUSION: The study did not find an association between autoimmune disease and MGUS in a systematically screened population. Previous studies not done in systematically screened populations have likely been subject to ascertainment bias. The findings indicate that recommendations to routinely screen patients with autoimmune disease for MGUS may not be warranted. PRIMARY FUNDING SOURCE: The International Myeloma Foundation and the European Research Council.

Development of a Multivariable Model to Predict the Need for Bone Marrow Sampling in Persons With Monoclonal Gammopathy of Undetermined Significance : A Cohort Study Nested in a Clinical Trial.

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions to multiple myeloma and related disorders. Smoldering multiple myeloma is distinguished from MGUS by 10% or greater bone marrow plasma cells (BMPC) on sampling, has a higher risk for progression, and requires specialist management. OBJECTIVE: To develop a multivariable prediction model that predicts the probability that a person with presumed MGUS has 10% or greater BMPC (SMM or worse by bone marrow criteria) to inform the decision to obtain a bone marrow sample and compare its performance to the Mayo Clinic risk stratification model. DESIGN: iStopMM (Iceland Screens, Treats or Prevents Multiple Myeloma), a prospective population-based screening study of MGUS. (ClinicalTrials.gov: NCT03327597). SETTING: Icelandic population of adults aged 40 years or older. PATIENTS: 1043 persons with IgG, IgA, light-chain, and biclonal MGUS detected by screening and an interpretable bone marrow sample. MEASUREMENTS: Monoclonal gammopathy of undetermined significance isotype; monoclonal protein concentration; free light-chain ratio; and total IgG, IgM, and IgA concentrations were used as predictors. Bone marrow plasma cells were categorized as 0% to 4%, 5% to 9%, 10% to 14%, or 15% or greater. RESULTS: The c-statistic for SMM or worse was 0.85 (95% CI, 0.82 to 0.88), and calibration was excellent (intercept, -0.07; slope, 0.95). At a threshold of 10% predicted risk for SMM or worse, sensitivity was 86%, specificity was 67%, positive predictive value was 32%, and negative predictive value was 96%. Compared with the Mayo Clinic model, the net benefit for the decision to refer for sampling was between 0.13 and 0.30 higher over a range of plausible low-risk thresholds. LIMITATION: The prediction model will require external validation. CONCLUSION: This accurate prediction model for SMM or worse was developed in a population-based cohort of persons with presumed MGUS and may be used to defer bone marrow sampling and referral to hematology. PRIMARY FUNDING SOURCE: International Myeloma Foundation and the European Research Council.

Chromothripsis as a pathogenic driver of multiple myeloma.

Analysis of the genetic basis for multiple myeloma (MM) has informed many of our current concepts of the biology that underlies disease initiation and progression. Studying these events in further detail is predicted to deliver important insights into its pathogenesis, prognosis and treatment. Information from whole genome sequencing of structural variation is revealing the role of these events as drivers of MM. In particular, we discuss how the insights we have gained from studying chromothripsis suggest that it can be used to provide information on disease initiation and that, as a consequence, it can be used for the clinical classification of myeloma precursor diseases allowing for early intervention and prognostic determination. For newly diagnosed MM, the integration of information on the presence of chromothripsis has the potential to significantly enhance current risk prediction strategies and to better characterize patients with high-risk disease biology. In this article we summarize the genetic basis for MM and the role played by chromothripsis as a critical pathogenic factor active at early disease phases.

Early detection of multiple myeloma: A first step towards a screening programme.

Novel therapies for multiple myeloma have substantially improved the prognosis, but before patients are able to benefit from treatment, a diagnosis must have been made. The Myeloma UK laboratory working group has developed a three-part tool box to help primary care physicians to suspect myeloma despite mostly vague symptoms, to do the right tests and to derive the proper conclusions from the results. Commentary on: Drayson et al. Laboratory practice is central to earlier myeloma diagnosis; utilising a primary care diagnostic tool and laboratory guidelines integrated into haematology services. Br J Haematol 2024;204:476-486.

Whole-genome sequencing reveals complex genomic features underlying anti-CD19 CAR T-cell treatment failures in lymphoma.

CD19-directed chimeric antigen receptor (CAR-19) T cells are groundbreaking immunotherapies approved for use against large B-cell lymphomas. Although host inflammatory and tumor microenvironmental markers associate with efficacy and resistance, the tumor-intrinsic alterations underlying these phenomena remain undefined. CD19 mutations associate with resistance but are uncommon, and most patients with relapsed disease retain expression of the wild-type receptor, implicating other genomic mechanisms. We therefore leveraged the comprehensive resolution of whole-genome sequencing to assess 51 tumor samples from 49 patients with CAR-19-treated large B-cell lymphoma. We found that the pretreatment presence of complex structural variants, APOBEC mutational signatures, and genomic damage from reactive oxygen species predict CAR-19 resistance. In addition, the recurrent 3p21.31 chromosomal deletion containing the RHOA tumor suppressor was strongly enriched in patients for whom CAR T-cell therapy failed. Pretreatment reduced expression or monoallelic loss of CD19 did not affect responses, suggesting CAR-19 therapy success and resistance are related to multiple mechanisms. Our study showed that tumor-intrinsic genomic alterations are key among the complex interplay of factors that underlie CAR-19 efficacy and resistance for large B-cell lymphomas.

Evaluating serum free light chain ratio as a biomarker in multiple myeloma.

Not available.

Prior cancer and risk of monoclonal gammopathy of undetermined significance: a population-based study in Iceland and Sweden.

There is some evidence that a prior cancer is a risk factor for the development of multiple myeloma (MM). If this is true, prior cancer should be associated with a higher prevalence or increased progression rate of monoclonal gammopathy of undetermined significance (MGUS), the precursor of MM and related disorders. Those with a history of cancer might therefore constitute a target population for MGUS screening. This two-part study is the first study to evaluate a relationship between MGUS and prior cancers. First, we evaluated whether prior cancers were associated with having MGUS at the time of screening in the Iceland Screens Treats or Prevents Multiple Myeloma (iStopMM) study that includes 75,422 individuals screened for MGUS. Next, we evaluated the association of prior cancer and the progression of MGUS to MM and related disorders in a population-based cohort of 13,790 Swedish individuals with MGUS. A history of prior cancer was associated with a modest increase in the risk of MGUS (odds ratio=1.10; 95% confidence interval: 1.00-1.20). This excess risk was limited to prior cancers in the year preceding MGUS screening. A history of prior cancer was associated with progression of MGUS, except for myeloid malignancies which were associated with a lower risk of progression (hazard ratio=0.37; 95% confidence interval: 0.16-0.89; P=0.028). Our findings indicate that a prior cancer is not a significant etiological factor in plasma cell disorders. The findings do not warrant MGUS screening or different management of MGUS in those with a prior cancer.

Minimal Residual Disease-Adapted Therapy in Multiple Myeloma: Current Evidence and Opinions.

PURPOSE OF REVIEW: Multiple myeloma (MM) is a biologically heterogeneous malignancy with relatively uniform treatment paradigms. This review aims to assess the growing role of Minimal Residual Disease (MRD) assessment in facilitating response-adapted therapeutic decision making to individualize therapy in MM. RECENT FINDINGS: MRD has been repeatedly demonstrated to provide strong prognostic information, superseding traditional IMWG response criteria. The use of MRD to modulate therapy remains controversial. Here, we review the existing landscape of MRD-adapted trial designs in both induction/consolidation and maintenance settings, including recent data from influential studies and retrospective analyses. We navigate existing data, leverage the increased resolution of longitudinal MRD assessments, and comment on trials in progress to explain our current utilization of MRD in the clinic. MRD transcends traditional response assessments by providing a window into disease-treatment interaction over time. As a strong patient-level surrogate, MRD has limited current use in individualizing treatment, but is poised to comprehensively shape treatment strategies at many key points in a patient's MM course.

Disease associations with monoclonal gammopathy of undetermined significance can only be evaluated using screened cohorts: results from the population-based iStopMM study.

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic precursor condition that precedes multiple myeloma and related disorders but has also been associated with other medical conditions. Since systematic screening is not recommended, MGUS is typically diagnosed due to underlying diseases and most cases are not diagnosed. Most previous studies on MGUS disease associations have been based on clinical cohorts, possibly resulting in selection bias. Here we estimate this selection bias by comparing clinically diagnosed and screened individuals with MGUS with regards to demographics, laboratory features, and comorbidities. A total of 75,422 participants in the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study were screened for MGUS by serum protein electrophoresis, immunofixation and free light chain assay (clinicaltrials gov. Identifier: NCT03327597). We identified 3,352 individuals with MGUS, whereof 240 had previously been clinically diagnosed (clinical MGUS), and crosslinked our data with large, nationwide registries for information on comorbidities. Those with clinical MGUS were more likely to have at least one comorbidity (odds ratio=2.24; 95% confidence interval: 1.30-4.19), and on average had more comorbidities than the screened MGUS group (3.23 vs. 2.36, mean difference 0.68; 95% confidence interval: 0.46-0.90). They were also more likely to have rheumatological disease, neurological disease, chronic kidney disease, liver disease, heart failure, or endocrine disorders. These findings indicate that individuals with clinical MGUS have more comorbidities than the general MGUS population and that previous studies have been affected by significant selection bias. Our findings highlight the importance of screening data when studying biological and epidemiological implications of MGUS.

Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): updated outcomes from a randomised, multicentre, open-label, phase 3 study.

BACKGROUND: Despite recent advances in therapeutic options, there remains an unmet need for treating patients with relapsed or refractory multiple myeloma, especially in those previously exposed or refractory to lenalidomide. This updated efficacy and safety analysis from the phase 3 CANDOR study compared carfilzomib, daratumumab, and dexamethasone (KdD) with carfilzomib and dexamethasone (Kd) in patients with relapsed or refractory multiple myeloma. METHODS: In this updated analysis of the randomised, multicentre, open-label, phase 3 CANDOR study, patients (aged ≥18 years) with relapsed or refractory multiple myeloma, at least a partial response to between one and three previous therapies, and Eastern Cooperative Oncology Group performance status of 0-2, were recruited from 102 medical centres globally and randomly assigned (2:1) by interactive voice or web response software to receive KdD or Kd. Participants were stratified by disease stage, previous proteasome inhibitor or anti-CD38 antibody exposure, and number of previous therapies. All patients received intravenous infusions of carfilzomib twice per week at 56 mg/m2 (20 mg/m2 on days 1 and 2 during cycle 1) on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Daratumumab (8 mg/kg) was administered intravenously on days 1 and 2 of cycle 1 and at 16 mg/kg weekly for the remaining doses of the first two cycles, then every 2 weeks for four cycles (cycles 3-6), and every 4 weeks thereafter. Patients received 40 mg dexamethasone weekly (20 mg for patients >75 years old). This analysis was a preplanned interim analysis for overall survival; however, at the time of data cutoff, overall survival data were not mature. The primary endpoint was progression-free survival. Here, we provide updated progression-free survival data, assessed centrally by Onyx Response Computer Algorithm in the intention-to-treat population, with 11 months additional follow-up. Adverse events were assessed in the safety population, which included all participants who received at least one dose of trial treatment. CANDOR is registered with ClinicalTrials.gov, NCT03158688, and is active but not recruiting. FINDINGS: Between June 13, 2017, and June 25, 2018, 466 patients were enrolled, of whom 312 received KdD and 154 received Kd. At data cutoff (June 15, 2020), median follow-up was 27·8 months (IQR 25·6-29·5) for KdD and 27·0 months (13·2-28·6) for Kd. Median progression-free survival was 28·6 months (95% CI 22·7-not estimable [NE]) in the KdD group and 15·2 months (11·1-19·9) in the Kd group (hazard ratio 0·59 [95% CI 0·45-0·78], log-rank p<0·0001). Treatment-emergent adverse events in the safety population were consistent with the primary analysis. Grade 3 or worse treatment-emergent adverse events occurred in 268 (87%) patients in the KdD group and 116 (76%) in the Kd group; most commonly thrombocytopenia (76 [25%] vs 25 [16%], respectively), hypertension (65 [21%] vs 23 [15%]), pneumonia (54 [18%] vs 14 [9%]), and anaemia (53 [17%] vs 23 [15%]). Serious adverse events occurred in 194 (63%) patients with KdD and 76 (50%) with Kd. Adverse events leading to death occurred in 27 (9%) patients in the KdD group and seven (5%) in the Kd group; most commonly septic shock (five [2%] vs one (1%]) and pneumonia (four [1%] vs none). No new treatment-related deaths have occurred since the primary analysis. INTERPRETATION: A clear, maintained progression-free survival benefit of KdD over Kd with longer follow-up was confirmed, making KdD an emerging standard-of-care for patients with relapsed or refractory multiple myeloma. FUNDING: Amgen and Janssen.

Subgroup analysis based on cytogenetic risk in patients with relapsed or refractory multiple myeloma in the CANDOR study.

CANDOR compared the safety/efficacy of carfilzomib with dexamethasone and daratumumab (KdD) to carfilzomib with dexamethasone (Kd) in adults with relapsed/refractory multiple myeloma (RRMM). This CANDOR subgroup analysis evaluated outcomes based on cytogenetic risk. Overall response rates (KdD vs. Kd) were 81% versus 56% in high-risk and 87% versus 79% in standard-risk groups. Median progression-free survival was 11.2 versus 7.4 months in high-risk (hazard ratio, 0.56 [95% CI, 0.34, 0.93]) and not reached versus 16.6 months in standard-risk groups (0.56 [95% CI, 0.39, 0.80]). These data support the efficacy of KdD in RRMM treatment, including in patients with high-risk cytogenetics.

Survival, causes of death, and the prognostic role of comorbidities in chronic lymphocytic leukemia in the pre-ibrutinib era: A population-based study.

OBJECTIVE: To evaluate temporal trends in survival and causes of death in patients with chronic lymphocytic leukemia (CLL) in a nationwide study. METHODS: The cohort consisted of 13,009 Swedish CLL patients diagnosed 1982-2013. Relative survival (RS) and excess mortality rate ratios (EMRR) with 95% confidence intervals (95% CIs) were estimated using flexible parametric survival models. Cause-specific hazard ratios (HRs) were estimated for the linear effect of 10-year increase in year of diagnosis. RESULTS: The excess mortality decreased comparing 2003-2013 to 1982-1992 (EMRR = 0.53, 95% CI 0.48-0.58). The 5-year RS increased between 1982 and 2012 for patients >51 years at diagnosis and improved for patients ≤51 years after 2002. The rate of CLL-specific deaths decreased over time (HR = 0.78, 95% CI 0.75-0.81). Compared to patients with no comorbidity, patients with 1 and 2+ Charlson Comorbidity Index points had HR = 1.35 (95% CI 1.25-1.45) and HR = 1.47 (95% CI 1.37-1.57) for CLL-related mortality, respectively. CONCLUSION: Survival in CLL patients improved in the era of chemoimmunotherapy, and this was largely explained by reduced CLL-related mortality. The increased rate of CLL-related mortality in patients with comorbidities emphasizes the importance of the newer and better tolerated targeted therapy.

Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study.

BACKGROUND: Lenalidomide and bortezomib frontline exposure has raised a growing need for novel treatments for patients with relapsed or refractory multiple myeloma. Carfilzomib in combination with daratumumab has shown substantial efficacy with tolerable safety in relapsed or refractory multiple myeloma in a phase 1 study. In this study, we aimed to compare the efficacy and safety of carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma. METHODS: In this randomised, multicentre, open-label, phase 3 study, 466 patients recruited from 102 sites across North America, Europe, Australia, and Asia with relapsed or refractory multiple myeloma were randomly assigned 2:1 to carfilzomib, dexamethasone, and daratumumab (KdD) or carfilzomib and dexamethasone (Kd). All patients received twice per week carfilzomib at 56 mg/m2 (20 mg/m2; days 1 and 2 during cycle 1). Daratumumab (8 mg/kg) was administered intravenously on days 1 and 2 of cycle 1 and at 16 mg/kg weekly for the remaining doses of the first two cycles, then every 2 weeks for four cycles (cycles 3-6), and every 4 weeks thereafter. Patients received 40 mg dexamethasone weekly (20 mg for patients ≥75 years old starting on the second week). The primary endpoint was progression-free survival assessed by intention to treat. Adverse events were assessed in the safety population. This trial (NCT03158688) is registered with ClinicalTrials.gov, and is active but not recruiting. FINDINGS: Between June 13, 2017, and June 25, 2018, 466 patients of 569 assessed for eligibility were enrolled. After median follow-up of approximately 17 months, median progression-free survival was not reached in the KdD group versus 15·8 months in the Kd group (hazard ratio 0·63; 95% CI 0·46-0·85; p=0·0027). Median treatment duration was longer in the KdD versus the Kd group (70·1 vs 40·3 weeks). Grade 3 or higher adverse events were reported in 253 (82%) patients in the KdD group and 113 (74%) patients in the Kd group. The frequency of adverse events leading to treatment discontinuation was similar in both groups (KdD, 69 [22%]; Kd, 38 [25%]). INTERPRETATION: KdD significantly prolonged progression-free survival versus Kd in patients with relapsed or refractory multiple myeloma and was associated with a favourable benefit-risk profile. FUNDING: Amgen.

Untangling fracture risk in monoclonal gammopathy of undetermined significance: A population-based cohort study.

OBJECTIVE: Monoclonal gammopathy of undetermined significance (MGUS) is the asymptomatic precursor of multiple myeloma (MM). Lytic bone lesions and fractures are hallmarks of MM and although there are no lytic lesions in MGUS, it has also been associated with fractures. The causes of fractures in MGUS are currently unclear but potential causes include inherent MGUS bone disease, undiagnosed MM, and peripheral neuropathy (PN). We therefore conducted a large population-based study including 8395 individuals with MGUS and 30 851 matched controls from Sweden. METHODS: Data on fractures, PN, and confounders were acquired from high-quality registers in Sweden. RESULTS: Monoclonal gammopathy of undetermined significance and PN were independently associated with fractures (hazard ratio [HR]: 1.29; 95% confidence interval [95% CI]: 1.21-1.37; P < .001 and HR: 1.34; 95% CI: 1.16-1.55; P < .001). Imminent MGUS progression increased the risk of fractures (odds ratio: 1.66; 95% CI: 1.27-2.16; P < .001). Fractures were not associated with long-term risk of MGUS progression (HR: 1.08; 95% CI: 0.77-1.53; P = .64). DISCUSSION: Based on these findings, we speculate that MGUS leads to fractures through at least 3 independent mechanisms: undetected MGUS progression to MM, MGUS inherent bone disease, and PN through falls. These findings highlight the need for further study of MGUS inherent bone disease and can inform further research into fracture prevention in MGUS.