INSURE: a pooled analysis of ixazomib-lenalidomide-dexamethasone for relapsed/refractory myeloma in routine practice.

Aim: We pooled data from three observational studies (INSIGHT MM, UVEA-IXA and REMIX) to investigate the real-world effectiveness of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory myeloma. Materials & methods: INSIGHT MM was a prospective study conducted in countries across Europe, Asia and North/Latin America while UVEA-IXA and REMIX were multicenter, retrospective/prospective studies conducted in Europe. Patients who had received IRd as ≥2nd line of therapy were analyzed. Primary outcomes were time-to-next treatment (TTNT) and progression-free survival (PFS). Results: Overall, 564 patients were included (median follow-up: 18.5 months). Median TTNT and PFS were 18.4 and 19.9 months; both outcomes were numerically longer for earlier versus later lines. Median treatment duration was 14.0 months. Overall response rate was 64.6%. No new safety concerns were noted. Conclusion: The effectiveness of IRd in routine practice appears similar to the efficacy observed in TOURMALINE-MM1. IRd benefit in earlier versus later lines was consistent with previous reports.

Real-world multiple myeloma risk factors and outcomes by non-Hispanic Black/African American and non-Hispanic White race/ethnicity in the United States.

Examination of the impact of race and ethnicity on multiple myeloma (MM) outcomes has yielded inconsistent results. This retrospective, real-world (RW) study describes patient, disease, and treatment characteristics (and associations with survival outcomes) among newly diagnosed MM patients of non-Hispanic (NH) Black/African American (AA) and NH White race/ethnicity in the United States. We included patients from the nationwide Flatiron Health electronic health record-derived de-identified database who initiated first line of therapy (LOT) for MM between January 1, 2016 and March 31, 2022. Of 4,614 patients in our study cohort, 23.3% were NH Black/AA. Non-Hispanic Black/AA patients were younger than NH White patients at diagnosis (median 68 vs 71 years) and more likely to be female (53.4% vs 43.5%). Rates of high-risk cytogenetics and 1q21+ were similar between races/ethnicities. The most common primary regimen used was lenalidomide-bortezomib-dexamethasone (50.1% of NH Black/AA and 48.1% of NH White patients). Receipt of stem cell transplantation during first LOT was less common among NH Black/AA (16.5%) than NH White (21.9%) patients. Unadjusted RW progression-free survival (rwPFS) and overall survival (rwOS) were similar between races/ethnicities. After multivariable adjustment, NH Black/AA race/ethnicity was associated with slightly inferior rwPFS (hazard ratio [HR] 1.13; 95% CI 1.01-1.27). The difference in rwOS (HR 1.12; 95% CI 0.98-1.28) was not statistically significant. In general, associations between risk factors for rwPFS and rwOS were consistent between races/ethnicities. Findings from this analysis help to inform clinicians about the impact of race/ethnicity on MM treatment paradigms and outcomes in the United States.

Inflammation of actinic keratosis from chemotherapy in a relapsed multiple myeloma patient.

A man in his 60 s with a history of actinic keratosis (AK) and relapsed IgG kappa multiple myeloma (MM) recently received VD-PACE (bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, etoposide) chemotherapy and presented with numerous haemorrhagic, scaly lesions on his scalp and face. He also had sepsis from methicillin-sensitive Staphylococcus aureus (MSSA) bacteraemia. Since the lesions were only present in the areas of pre-existing AK, a diagnosis of inflammation of AK secondary to chemotherapy was made. Sepsis was treated with appropriate antibiotics, and inflammation of AK was managed with topical steroids, leading to complete recovery.

Birtamimab plus standard of care in light-chain amyloidosis: the phase 3 randomized placebo-controlled VITAL trial.

Amyloid light-chain (AL) amyloidosis is a rare, typically fatal disease characterized by the accumulation of misfolded immunoglobulin light chains (LCs). Birtamimab is an investigational humanized monoclonal antibody designed to neutralize toxic LC aggregates and deplete insoluble organ-deposited amyloid via macrophage-induced phagocytosis. VITAL was a phase 3 randomized, double-blind, placebo-controlled clinical trial assessing the efficacy and safety of birtamimab + standard of care (SOC) in 260 newly diagnosed, treatment-naive patients with AL amyloidosis. Patients received 24 mg/kg IV birtamimab + SOC or placebo + SOC every 28 days. The primary composite end point was the time to all-cause mortality (ACM) or centrally adjudicated cardiac hospitalization ≥91 days after the first study drug infusion. The trial was terminated early after an interim futility analysis; there was no significant difference in the primary composite end point (hazard ratio [HR], 0.826; 95% confidence interval [CI], 0.574-1.189; log-rank P = .303). A post hoc analysis of patients with Mayo stage IV AL amyloidosis, those at the highest risk of early mortality, showed significant improvement in the time to ACM with birtamimab at month 9 (HR, 0.413; 95% CI, 0.191-0.895; log-rank P = .021). At month 9, 74% of patients with Mayo stage IV AL amyloidosis treated with birtamimab and 49% of those given placebo survived. Overall, the rates of treatment-emergent adverse events (TEAEs) and serious TEAEs were generally similar between treatment arms. A confirmatory phase 3 randomized, double-blind, placebo-controlled clinical trial of birtamimab in patients with Mayo stage IV AL amyloidosis (AFFIRM-AL; NCT04973137) is currently enrolling. The VITAL trial was registered at www.clinicaltrials.gov as #NCT02312206.

Phase 1/2 study of carfilzomib, pomalidomide, and dexamethasone with and without daratumumab in relapsed multiple myeloma.

We conducted a phase 1/2 study of carfilzomib, pomalidomide, and dexamethasone (KPd) and KPd with daratumumab (Dara-KPd) in relapsed/refractory multiple myeloma. The primary end points were identification of a maximum tolerated dose (MTD) of KPd for phase 1, and rates of overall response (ORR) and near complete response (nCR) after 4 cycles of KPd and Dara-KPd, respectively, for phase 2. The MTD for KPd was carfilzomib 20/27 mg/m2 on days 1, 2, 8, 9, 15, and 16 (cycles 1-8) and days 1, 2, 15, and 16 for cycles 9 and beyond; oral pomalidomide 4 mg on days 1 to 21; and oral dexamethasone 40 mg weekly in 28-day cycles. Sixty-six patients received KPd, including 34 at the MTD. The ORR after 4 cycles of KPd at the MTD was 27/34 (79%; 95% confidence interval [CI], 62%-91%), meeting the statistical threshold for efficacy. At a median follow-up of 44 months, the median progression-free survival (PFS) was 13 months and overall survival (OS) 44 months. Twenty-eight patients received Dara-KPd. The rate of nCR or better after 4 cycles was 11/28 (39%; 95% CI, 22%-59%), meeting the statistical threshold for efficacy. As the best response to Dara-KPd, the ORR was 25/28 (89%) and the rate of measurable residual disease negativity by flow cytometry (10-5) was 17/26 (65%). At a median follow-up of 26 months, the median PFS and OS for Dara-KPd were not reached. Dara-KPd induced deeper and more durable responses than KPd without compromising safety in a predominantly high-risk, lenalidomide-refractory population, warranting further evaluation of this quadruplet. This trial is registered at www.clinicaltrials.gov as #NCT01665794.

A phase I study of selinexor combined with weekly carfilzomib and dexamethasone in relapsed/refractory multiple myeloma.

We performed a phase I study of weekly selinexor, carfilzomib, and dexamethasone (wSKd) in patients with relapsed/refractory multiple myeloma (MM). The primary objective was to identify the maximum tolerated dose (MTD) of wSKd. Secondary endpoints included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Prior exposure/refractoriness to carfilzomib was permitted. Thirty patients were enrolled; 26 (87%) had triple-class exposed disease and 6 (20%) received chimeric antigen receptor (CAR) T-cell therapy. Dose level 2 (carfilzomib 70 mg/m2 Intravenous [IV] on Days 1, 8, and 15; selinexor 100 mg PO on Days 1, 8, 15, 22; dexamethasone 40 mg on Days 1, 8, 15, 22 of 28-day cycles) was chosen as the MTD, with no DLTs having occurred. The most common hematologic adverse events (AE) were thrombocytopenia (83%), anemia (70%), lymphopenia (50%), and neutropenia (50%). The most common nonhematologic AE were fatigue (70%), nausea (70%), diarrhea (53%), and anorexia (47%). The ORR was 21/30 (70%) overall and 18/23 (78%) at the MTD. At a median follow-up of 12.3 months, the median PFS was 5.3 months and median OS 23.3 months. Responses were similar in carfilzomib naïve and exposed patients. Long-term efficacy of wSKd is modest; wSKd could be employed as a bridging strategy to immunotherapies.

Rates of Influenza and Pneumococcal Vaccination and Correlation With Survival in Multiple Myeloma Patients.

BACKGROUND: Infections are a common reason for hospitalization and death in multiple myeloma (MM). Although pneumococcal vaccination (PV) and influenza vaccination (FV) are recommended for MM patients, data on vaccination status and outcomes are limited in MM. MATERIALS AND METHODS: We utilized data from the global, prospective, observational INSIGHT MM study to analyze FV and PV rates and associated outcomes of patients with MM enrolled 2016-2019. RESULTS: Of the 4307 patients enrolled, 2543 and 2500 had study-entry data on FV and PV status. Overall vaccination rates were low (FV 39.6%, PV 30.2%) and varied by region. On separate multivariable analyses of overall survival (OS) by Cox model, FV in the prior 2 years and PV in the prior 5 years impacted OS (vs. no vaccination; FV: HR, 0.73; 95% CI, 0.60-0.90; P = .003; PV: HR, 0.51; 95% CI, 0.42-0.63; P < .0001) when adjusted for age, region, performance status, disease stage, cytogenetics at diagnosis, MM symptoms, disease status, time since diagnosis, and prior transplant. Proportions of deaths due to infections were lower among vaccinated versus non-vaccinated patients (FV: 9.8% vs. 15.3%, P = .142; PV: 9.9% vs. 18.0%, P = .032). Patients with FV had generally lower health resource utilization (HRU) versus patients without FV; patients with PV had higher or similar HRU versus patients without PV. CONCLUSION: Vaccination is important in MM and should be encouraged. Vaccination status should be recorded in prospective clinical trials as it may affect survival. This trial was registered at www. CLINICALTRIALS: gov as #NCT02761187.

Carfilzomib, lenalidomide, and dexamethasone or lenalidomide alone as maintenance therapy after autologous stem-cell transplantation in patients with multiple myeloma (ATLAS): interim analysis of a randomised, open-label, phase 3 trial.

BACKGROUND: Lenalidomide is a cornerstone of maintenance therapy in patients with newly diagnosed multiple myeloma after autologous stem-cell transplantation. We aimed to compare the efficacy and safety of maintenance therapy with carfilzomib, lenalidomide, and dexamethasone versus lenalidomide alone in this patient population. METHODS: This study is an interim analysis of ATLAS, which is an investigator-initiated, multicentre, open-label, randomised, phase 3 trial in 12 academic and clinical centres in the USA and Poland. Participants were aged 18 years or older with newly diagnosed multiple myeloma, completed any type of induction and had stable disease or better, autologous stem-cell transplantation within 100 days, initiated induction 12 months before enrolment, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) using permuted blocks of sizes 4 and 6 and a web-based system to receive up to 36 cycles of carfilzomib, lenalidomide, and dexamethasone (28-day cycles of carfilzomib 20 mg/m2 administered intravenously in cycle one on days 1 and 2 then 36 mg/m2 on days 1, 2, 8, 9, 15, and 16 in cycles one to four and 36 mg/m2 on days 1, 2, 15, and 16 from cycle five up to 36 [per protocol]; lenalidomide 25 mg administered orally on days 1-21; and dexamethasone 20 mg administered orally on days 1, 8, 15, and 22) or lenalidomide alone (10 mg administered orally for the first three cycles and then at the best tolerated dose [≤15 mg for 28 days in 28-day cycles]) until disease progression or unacceptable toxicity as maintenance therapy. After 36 cycles, patients in both treatment groups received lenalidomide maintenance. Randomisation was stratified by response to previous treatment, cytogenetic risk factors, and country. Investigators and patients were not masked to treatment allocation. Patients in the carfilzomib, lenalidomide, and dexamethasone group with no detectable minimal residual disease after cycle six (as per International Myeloma Working Group criteria) and standard-risk cytogenetics were switched to lenalidomide maintenance as of cycle nine. The primary endpoint was progression-free survival in the intention-to-treat population (defined as all randomly assigned patients). Safety was analysed in all randomly assigned patients who received at least one dose of study treatment. This unplanned interim analysis was triggered by the occurrence of 59 (61%) of the expected 96 events for the primary analysis and the results are considered preliminary. This trial is registered with ClinicalTrials.gov, NCT02659293 (active, not recruiting) and EudraCT, 2015-002380-42. FINDINGS: Between June 10, 2016, and Oct 21, 2020, 180 patients were randomly assigned to receive either carfilzomib, lenalidomide, and dexamethasone (n=93) or lenalidomide alone (n=87; intention-to-treat population). The median age of patients was 59·0 years (IQR 49·0-63·0); 84 (47%) patients were female and 96 (53%) were male. With a median follow-up of 33·8 months (IQR 20·9-42·9), median progression-free survival was 59·1 months (95% CI 54·8-not estimable) in the carfilzomib, lenalidomide, and dexamethasone group versus 41·4 months (33·2-65·4) in the lenalidomide group (hazard ratio 0·51 [95% CI 0·31-0·86]; p=0·012). The most common grade 3 and 4 adverse events were neutropenia (44 [48%] in the carfilzomib, lenalidomide, and dexamethasone group vs 52 [60%] in the lenalidomide group), thrombocytopenia (12 [13%] vs six [7%]), and lower respiratory tract infections (seven [8%] vs one [1%]). Serious adverse events were reported in 28 (30%) patients in the carfilzomib, lenalidomide, and dexamethasone group and 19 (22%) in the lenalidomide group. One treatment-related adverse event led to death (respiratory failure due to severe pneumonia) in the carfilzomib, lenalidomide, and dexamethasone group. INTERPRETATION: This interim analysis provides support for considering carfilzomib, lenalidomide, and dexamethasone therapy in patients with newly diagnosed multiple myeloma who completed any induction regimen followed by autologous stem-cell transplantation, which requires confirmation after longer follow-up of this ongoing phase 3 trial. FUNDING: Amgen and Celgene (Bristol Myers Squibb).

Real-world treatment patterns, costs, and outcomes in patients with AL amyloidosis: analysis of the Optum EHR and commercial claims databases.

BACKGROUND: This study characterised real-world treatment patterns, clinical outcomes, and cost-of-illness in patients with light-chain (AL) amyloidosis. METHODS: Data were extracted from the US-based Optum® EHR and Clinformatics® Data Mart (claims) databases (2008-2019) for patients newly diagnosed with AL amyloidosis and who initiated anti-plasma cell therapies. Healthcare resource utilisation (HCRU) and related costs were compared across lines of therapy (LOT). Incidences of cardiac and renal failure were evaluated using the Kaplan-Meier method. RESULTS: About 1347 patients (EHR, n = 776; claims, n = 571) were included. Median age was 68 years; 56.8% were male. At initial diagnosis, 33.1% and 15.1% of patients had cardiac and renal failure, respectively. Most patients received bortezomib-containing treatment in LOT1 (69%); bortezomib-cyclophosphamide-dexamethasone was most common (26%). HCRU was similar across LOTs. Mean per-patient-per-month and per-patient-per-LOT costs were $19,343 and $105,944 for LOT1, $19,183 and $95,793 for LOT2, and $16,611 and $128,446 for LOT3, respectively. Costs were primarily driven by anti-plasma cell therapies, outpatient visits, and hospitalisations. The 5-year cardiac and renal failure rates following initial diagnosis were 64.5% and 39.0%, respectively. CONCLUSION: AL amyloidosis is associated with substantial costs and suboptimal outcomes, highlighting the need for new therapeutic approaches to prevent organ deterioration, and reduce disease burden.

Immune biomarkers of response to immunotherapy in patients with high-risk smoldering myeloma.

Patients with smoldering multiple myeloma (SMM) are observed until progression, but early treatment may improve outcomes. We conducted a phase II trial of elotuzumab, lenalidomide, and dexamethasone (EloLenDex) in patients with high-risk SMM and performed single-cell RNA and T cell receptor (TCR) sequencing on 149 bone marrow (BM) and peripheral blood (PB) samples from patients and healthy donors (HDs). We find that early treatment with EloLenDex is safe and effective and provide a comprehensive characterization of alterations in immune cell composition and TCR repertoire diversity in patients. We show that the similarity of a patient's immune cell composition to that of HDs may have prognostic relevance at diagnosis and after treatment and that the abundance of granzyme K (GZMK)+ CD8+ effector memory T (TEM) cells may be associated with treatment response. Last, we uncover similarities between immune alterations observed in the BM and PB, suggesting that PB-based immune profiling may have diagnostic and prognostic utility.

Elotuzumab and Weekly Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Without Transplant Intent: A Phase 2 Measurable Residual Disease-Adapted Study.

Importance: Treatment of newly diagnosed multiple myeloma (NDMM) with a quadruplet regimen consisting of a monoclonal antibody, proteasome inhibitor, immunomodulatory imide, and corticosteroid has been associated with improved progression-free survival (PFS) compared with triplet regimens. The optimal quadruplet combination, and whether this obviates the need for frontline autologous stem cell transplant (ASCT), remains unknown. We evaluated elotuzumab and weekly carfilzomib, lenalidomide, and dexamethasone (Elo-KRd) without ASCT in NDMM. Objective: To investigate the efficacy of Elo-KRd using a measurable residual disease (MRD)-adapted design in NDMM regardless of ASCT eligibility. Design, Setting, and Participants: This multicenter, single-arm, phase 2 study enrolled patients between July 2017 and February 2021. Median follow-up was 29 months. Interventions: Twelve to 24 cycles of Elo-KRd; consecutive MRD-negative results at 10-6 by next-generation sequencing (NGS) after cycles 8 (C8) and 12 determined the duration of Elo-KRd. This was followed by Elo-Rd (no carfilzomib) maintenance therapy until disease progression. Main Outcomes and Measures: The primary end point was the rate of stringent complete response (sCR) and/or MRD-negativity (10-5) after C8 Elo-KRd. Secondary end points included safety, rate of response, MRD status, PFS, and overall survival (OS). As an exploratory analysis, MRD was assessed using liquid chromatography mass spectrometry (MS) on peripheral blood samples. Results: Forty-six patients were enrolled (median age 62 years, 11 [24%] aged >70 years). Overall, 32 (70%) were White, 6 (13%) were Black, 3 (6%) were more than 1 race, and 5 (11%) were of unknown race. Thirty-three (72%) were men and 13 (28%) were women. High-risk cytogenetic abnormalities were present in 22 (48%) patients. The rate of sCR and/or MRD-negativity after C8 was 26 of 45 (58%), meeting the predefined statistical threshold for efficacy. Responses deepened over time, with the MRD-negativity (10-5) rate increasing to 70% and MS-negativity rate increasing to 65%; concordance between MRD by NGS and MS increased over time. The most common (>10%) grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively). There was 1 grade 5 myocardial infarction. The estimated 3-year PFS was 72% overall and 92% for patients with MRD-negativity (10-5) at C8. Conclusions and Relevance: An MRD-adapted design using elotuzumab and weekly KRd without ASCT showed a high rate of sCR and/or MRD-negativity and durable responses. This approach provides support for further evaluation of MRD-guided deescalation of therapy to decrease treatment exposure while sustaining deep responses. Trial Registration: ClinicalTrials.gov Identifier: NCT02969837.

Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma.

BACKGROUND: In patients with newly diagnosed multiple myeloma, the effect of adding autologous stem-cell transplantation (ASCT) to triplet therapy (lenalidomide, bortezomib, and dexamethasone [RVD]), followed by lenalidomide maintenance therapy until disease progression, is unknown. METHODS: In this phase 3 trial, adults (18 to 65 years of age) with symptomatic myeloma received one cycle of RVD. We randomly assigned these patients, in a 1:1 ratio, to receive two additional RVD cycles plus stem-cell mobilization, followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Both groups received lenalidomide until disease progression, unacceptable side effects, or both. The primary end point was progression-free survival. RESULTS: Among 357 patients in the RVD-alone group and 365 in the transplantation group, at a median follow-up of 76.0 months, 328 events of disease progression or death occurred; the risk was 53% higher in the RVD-alone group than in the transplantation group (hazard ratio, 1.53; 95% confidence interval [CI], 1.23 to 1.91; P<0.001); median progression-free survival was 46.2 months and 67.5 months. The percentage of patients with a partial response or better was 95.0% in the RVD-alone group and 97.5% in the transplantation group (P = 0.55); 42.0% and 46.8%, respectively, had a complete response or better (P = 0.99). Treatment-related adverse events of grade 3 or higher occurred in 78.2% and 94.2%, respectively; 5-year survival was 79.2% and 80.7% (hazard ratio for death, 1.10; 95% CI, 0.73 to 1.65). CONCLUSIONS: Among adults with multiple myeloma, RVD plus ASCT was associated with longer progression-free survival than RVD alone. No overall survival benefit was observed. (Funded by the National Heart, Lung, and Blood Institute and others; DETERMINATION ClinicalTrials.gov number, NCT01208662.).

Preferences and Priorities for Relapsed Multiple Myeloma Treatments Among Patients and Caregivers in the United States.

Introduction/Background: This study aimed to describe patient and caregiver preferences for treatments of relapsed or refractory multiple myeloma (MM). Materials and Methods: A survey including discrete-choice experiment (DCE) and best-worst scaling (BWS) exercises was conducted among US patients with relapsed or refractory MM and their caregivers. The DCE included six attributes with varying levels including progression-free survival (PFS), toxicity, and mode and frequency of administration. In addition, the impact of treatment cost was assessed using a fixed-choice question. The BWS exercise included 18 items (modes and frequency of administration, additional treatment convenience, and toxicity items). The survey was administered online to patients recruited from the Multiple Myeloma Research Foundation CoMMpass study (NCT01454297). Results: The final samples consisted of 94 patients and 32 caregivers. Avoiding severe nerve damage was most important to patients, followed by longer PFS. Caregivers considered PFS to be the most important attribute. We estimate that a third or more of patients were cost-sensitive, meaning their treatment preference was altered based on cost implications. Caregivers were not cost-sensitive. The three most bothersome treatment features in the BWS exercise were risk of kidney failure, lowering white blood cell counts, and weakening the immune system. Conclusion: Patients with relapsed or refractory MM and their caregivers consider many factors including efficacy, toxicity, mode/frequency of administration, and cost in their decisions regarding treatment options. The study provides a basis for future Research on patient and caregiver treatment preferences, which could be incorporated into shared decision-making with physicians.

Filanesib plus bortezomib and dexamethasone in relapsed/refractory t(11;14) and 1q21 gain multiple myeloma.

Filanesib is a first-in-class kinesin spindle protein inhibitor which demonstrated safety and encouraging activity in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma in a preliminary analysis of dose-escalation phase results. This multicenter study included first a dose-escalation phase to determine maximum tolerated dose of two schedules of filanesib, bortezomib, and dexamethasone and a subsequent dose-expansion phase using the maximum tolerated doses. In the dose-expansion phase, 28 patients were evaluable for safety and efficacy. The most common grade ≥3 adverse events were neutropenia (21%) and anemia (18%), which were noncumulative and reversible, and hypertension (18%). The overall response rate was 43% with median duration of response not yet reached (range, 2.8-23.7+ months) with median follow-up of 6.3 months. A post hoc analysis incorporated 29 dose-escalation phase patients who received therapeutic filanesib doses, with an overall response rate of 39% and median duration of response of 18.0 months among the 57 total patients with median progression-free survival of 8.5 months. Notably, the PFS of high risk patients was comparable at 8.5 months, driven by the patients with 1q21 gain, characterized by increased MCL-1 expression, with a PFS of 9.1 months versus 3.5 months for the remainder of high risk patients. Patients with t(11;14) also had an encouraging PFS of 15.0 months. The combination of filanesib, bortezomib, and dexamethasone continues to show safety and encouraging activity in relapsed/refractory multiple myeloma, particularly in those patients with 1q21 gain and t(11;14).

Circular RNAs in acute myeloid leukemia.

Although mechanistic studies clarifying the molecular underpinnings of AML have facilitated the development of several novel targeted therapeutics, most AML patients still relapse. Thus, overcoming the inherent and acquired resistance to current therapies remains an unsolved clinical problem. While current diagnostic modalities are primarily defined by gross morphology, cytogenetics, and to an extent, by deep targeted gene sequencing, there is an ongoing demand to identify newer diagnostic, therapeutic and prognostic biomarkers for AML. Recent interest in exploring the role of circular RNA (circRNA) in elucidating AML biology and therapy resistance has been promising. This review discerns the circular RNAs' evolving role on the same scientific premise and attempts to identify its potential in managing AML.

Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis.

BACKGROUND: Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease. METHODS: We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response. RESULTS: A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P<0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy. CONCLUSIONS: Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).

Real-world comparative effectiveness of triplets containing bortezomib (B), carfilzomib (C), daratumumab (D), or ixazomib (I) in relapsed/refractory multiple myeloma (RRMM) in the US.

Multiple available combinations of proteasome inhibitors, immunomodulators (IMIDs), and monoclonal antibodies are shifting the relapsed/refractory multiple myeloma (RRMM) treatment landscape. Lack of head-to-head trials of triplet regimens highlights the need for real-world (RW) evidence. We conducted an RW comparative effectiveness analysis of bortezomib (V), carfilzomib (K), ixazomib (I), and daratumumab (D) combined with either lenalidomide or pomalidomide plus dexamethasone (Rd or Pd) in RRMM. A retrospective cohort of patients initiating triplet regimens in line of therapy (LOT) ≥ 2 on/after 1/1/2014 was followed between 1/2007 and 3/2018 in Optum's deidentified US electronic health records database. Time to next treatment (TTNT) was estimated using Kaplan-Meier methods; regimens were compared using covariate-adjusted Cox proportional hazard models. Seven hundred forty-one patients (820 patient LOTs) with an Rd backbone (VRd, n = 349; KRd, n = 218; DRd, n = 99; IRd, n = 154) and 348 patients (392 patient LOTs) with a Pd backbone (VPd, n = 52; KPd, n = 146; DPd, n = 149; IPd, n = 45) in LOTs ≥2 were identified. More patients ≥75 years received IRd (39.6%), IPd (37.8%), and VRd (36.7%) than other triplets. More patients receiving VRd/VPd were in LOT2 vs other triplets. Unadjusted median TTNT in LOT ≥ 2: VRd, 13.9; KRd, 8.7; IRd, 11.4; DRd, not estimable (NE); and VPd, 12.0; KPd, 6.7; IPd, 9.5 months; DPd, NE. In covariate-adjusted analysis, only KRd vs DRd was associated with a significantly higher risk of next LOT initiation/death (HR 1.72; P = 0.0142); no Pd triplet was significantly different vs DPd in LOT ≥ 2. Our data highlight important efficacy/effectiveness gaps between results observed in phase 3 clinical trials and those realized in the RW.

Ixazomib-lenalidomide-dexamethasone in routine clinical practice: effectiveness in relapsed/refractory multiple myeloma.

Aim: To evaluate the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory multiple myeloma in routine clinical practice. Patients & methods: Patient-level data from the global, observational INSIGHT MM and the Czech Registry of Monoclonal Gammopathies were integrated and analyzed. Results: At data cut-off, 263 patients from 13 countries were included. Median time from diagnosis to start of IRd was 35.8 months; median duration of follow-up was 14.8 months. Overall response rate was 73%, median progression-free survival, 21.2 months and time-to-next therapy, 33.0 months. Ixazomib/lenalidomide dose reductions were required in 17%/36% of patients; 32%/30% of patients discontinued ixazomib/lenalidomide due to adverse events. Conclusion: The effectiveness and safety of IRd in routine clinical practice are comparable to those reported in TOURMALINE-MM1. Clinical trial registration: NCT02761187 (ClinicalTrials.gov).

Lay abstract Proteasome inhibitors are drugs used in multiple myeloma (MM), a blood cancer that develops from cells in the bone marrow. Ixazomib is the first oral proteasome inhibitor to be approved for use in MM, when given in combination with two other oral drugs, lenalidomide and dexamethasone, to adult patients who have received one prior therapy. Our study, which was conducted in routine clinical practice, found that the effectiveness and safety of ixazomib + lenalidomide + dexamethasone in previously treated MM patients were similar to those seen in the Phase III clinical trial on which approval was based. These findings are important because they suggest that MM patients in everyday practice can achieve the same benefits from this treatment as patients in clinical trials, despite often being in poorer health.

Selinexor in Combination with R-CHOP for Frontline Treatment of Non-Hodgkin Lymphoma: Results of a Phase I Study.

PURPOSE: The nuclear exporter protein exportin-1 (XPO1) is overexpressed in non-Hodgkin lymphoma (NHL) and correlates with poor prognosis. We evaluated enhancing R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) activity in NHL by targeted inhibition of XPO1 using the selective inhibitor of nuclear export (SINE) compounds. PATIENTS AND METHODS: We evaluated the antitumor activity of SINE compounds in combination with CHO chemotherapy in vitro and in vivo. Newly diagnosed NHL patients in a phase I dose-escalation study received R-CHOP for 6 cycles with weekly selinexor (60, 80, and 100 mg), then selinexor maintenance therapy for one year. RT-PCR, Western blotting, and RNA sequencing were performed on patient blood samples. RESULTS: SINE compounds synergized with CHO in vitro in NHL cell lines and in vivo in our murine xenograft model. In our phase I study, selinexor was dosed at 60 mg (n = 6) and 80 mg (n = 6). The most common adverse events (AE) among 12 patients were fatigue (67%) and nausea (100%). Grade 3-4 AEs were infrequent. Ten evaluable patients had an overall response rate of 100% and complete remission rate of 90% with sustained remissions (median follow-up: 476 days). Maximally tolerated dose was not reached; however, the recommended phase II dose was 60 mg selinexor weekly after evaluating tolerability and discontinuation rates for each dose cohort. Analysis of patient blood samples revealed downregulation of XPO1 and several prosurvival markers. CONCLUSIONS: SINE compounds enhance the activity of CHO in vitro and in vivo. Selinexor in combination with R-CHOP was generally well tolerated and showed encouraging efficacy in NHL (NCT03147885).