Mass Spectrometry-Based Assessment of M-protein in Peripheral Blood During Maintenance Therapy in Multiple Myeloma.

Mass spectrometry (MS) can detect multiple myeloma-derived monoclonal proteins in peripheral blood (PB) with high sensitivity, potentially serving as a PB assay for measurable residual disease (MRD). This study evaluated the significance of PB MS MRD negativity during post-transplant therapy in patients with newly diagnosed multiple myeloma. Serum samples from 138 patients treated in the phase 3 ATLAS trial of post-transplant maintenance with either carfilzomib, lenalidomide, dexamethasone or lenalidomide alone were analyzed using EXENT MS methodology. We established feasibility of measuring MRD by MS in PB in the post-transplant setting, despite unavailability of pre-treatment calibration samples. There was high agreement between MRD by MS in PB and paired BM MRD results at the 10-5 threshold, assessed by either next generation sequencing (NGS) or multiparameter flow cytometry (MFC) (70% and 67%, respectively). Agreement between PB MS and both BM MRD methods was lowest early after transplant and increased with time. MS negativity was associated with improved progression-free survival (PFS), which in landmark analysis reached statistical significance after 18 cycles post-transplant. Combined PB/BM MRD negativity by MFC or NGS was associated with superior PFS compared to MRD negativity by only one modality. Sustained MS negativity carried similar prognostic performance to sustained BM MRD negativity at the 10-5 threshold. Overall, post-transplant MS assessment was feasible and provided additional prognostic information to BM MRD negativity. Further studies are needed to confirm the role and optimal timing of MS in disease evaluation algorithms. The ATLAS trial is registered at www.clinicaltrials.gov as #NCT02659293.

International Myeloma Working Group immunotherapy committee consensus guidelines and recommendations for optimal use of T-cell-engaging bispecific antibodies in multiple myeloma.

Multiple myeloma remains an incurable disease, despite the development of numerous drug classes and combinations that have contributed to improved overall survival. Immunotherapies directed against cancer cell-surface antigens, such as chimeric antigen receptor (CAR) T-cell therapy and T-cell-redirecting bispecific antibodies, have recently received regulatory approvals and shown unprecedented efficacy. However, these immunotherapies have unique mechanisms of action and toxicities that are different to previous treatments for myeloma, so experiences from clinical trials and early access programmes are essential for providing specific recommendations for management of patients, especially as these agents become available across many parts of the world. Here, we provide expert consensus clinical practice guidelines for the use of bispecific antibodies for the treatment of myeloma. The International Myeloma Working Group is also involved in the collection of prospective real-time data of patients treated with such immunotherapies, with the aim of learning continuously and adapting clinical practices to optimise the management of patients receiving immunotherapies.

Evaluation of administration-related reactions with subcutaneous daratumumab with and without premedication.

BACKGROUND: Daratumumab-hyaluronidase-fihj (Dara-SQ) is frequently used in the treatment of plasma cell disorders and is associated with improved outcomes. Dara-SQ was shown to be non-inferior to intravenous daratumumab (Dara-IV) in efficacy, safety, and associated with fewer administration-related reactions (ARRs). Despite the lower ARR risk with Dara-SQ, package labeling still recommends indefinite premedication. In this study, we investigated the safety of premedication discontinuation after one cycle of Dara-SQ. MATERIALS AND METHODS: This pre-post interventional quality improvement study included all patients aged 18 years and older diagnosed with multiple myeloma or light chain (AL) amyloidosis who received at least one dose of Dara-SQ. Patients in Arm 1 received Dara-SQ per package labeling, while patients in Arm 2 had premedication omitted (excluding dexamethasone) after cycle 1. The primary endpoint was the incidence of ARR after cycle 1. Overall ARR rate and therapy time saved were also evaluated. RESULTS: A total of 102 patients (63 in Arm 1 and 39 in Arm 2) were included. There were zero reactions in either arm after cycle 1 across 1479 Dara-SQ doses administered over a 30-month period with or without premedication omission. The overall ARR rate was 2.9% (3/102), which all occurred prior to premedication omission. Therapy timed saved from premedication omission was 194 hours in a 6-month period, equating to approximately $140 000 USD. CONCLUSION: ARRs to Dara-SQ were rare, mild, and occurred during cycle 1 prior to premedication omission. Omission of noncorticosteroid premedication is safe, feasible, and carries substantial time and cost savings for patients and infusion centers.

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).

Polyclonal immunoglobulin recovery in patients with newly diagnosed myeloma receiving maintenance therapy after autologous haematopoietic stem cell transplantation with either carfilzomib, lenalidomide and dexamethasone or lenalidomide alone: Subanalysis of the randomized phase 3 ATLAS trial.

Previous studies suggest that postautologous stem cell transplant (ASCT) recovery of polyclonal immunoglobulin from immunoparesis in patients with multiple myeloma is a positive prognostic marker. We performed a longitudinal analysis of polyclonal immunoglobulin concentrations and unique B-cell sequences in patients enrolled in the phase 3 ATLAS trial that randomized 180 subjects to either carfilzomib, lenalidomide, dexamethasone (KRd) or lenalidomide (R) maintenance. In the KRd arm, standard-risk patients with minimal residual disease negativity after six cycles de-escalated to R alone after cycle 8. One year from the initiation of maintenance at least partial recovery of polyclonal immunoglobulin was observed in more patients on the R arm (58/66, p < 0.001) and in those who de-escalated from KRd to R (27/38, p < 0.001) compared to the KRd arm (9/36). In patients who switched from KRd to R, the concentrations of uninvolved immunoglobulin and the number of B-cell unique sequences increased over time, approaching values observed in the R arm. There were no differences in progression-free survival between the patients with at least partial immunoglobulin recovery and the remaining population. Our analysis indicates that patients receiving continuous therapy after ASCT experience prolonged immunoparesis, limiting prognostic significance of polyclonal immunoglobulin recovery in this setting.

Measurable residual disease in peripheral blood in myeloma: dream or reality.

PURPOSE OF REVIEW: Therapeutic advancements in multiple myeloma have led to increasingly deeper and more durable responses, creating a need for highly sensitive and applicable techniques for measurable residual disease (MRD) assessment. Bone marrow assays can deeply assess for MRD, but it is not conducive to performing frequent and dynamic evaluations, which may be needed for MRD-adapted treatment approaches. Recently, numerous techniques for MRD assessment in peripheral blood have come under investigation, and their integration into routine clinical practice is eagerly anticipated. RECENT FINDINGS: The identification of circulating tumor cells (CTCs), evaluation of cell-free DNA, and measuring monoclonal protein concentration with mass spectrometry are promising research areas for assessing myeloma in peripheral blood. CTCs assessment and cell-free DNA may carry prognostic significance, but they lack the sensitivity of bone marrow-based techniques. Mass spectrometry has already been implemented in clinical practice in certain centers, but its full potential has yet to be fully realized. This review focuses on recent developments in these fields, emphasizing the potential future roles of these assessments. SUMMARY: MRD assessment in peripheral blood is still in the development stage but holds promise for not only complementing bone marrow based evaluations but also potential for improving sensitivity.

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.

Carfilzomib, lenalidomide, and dexamethasone plus transplant in newly diagnosed multiple myeloma.

In this phase 2 multicenter study, we evaluated the incorporation of autologous stem cell transplantation (ASCT) into a carfilzomib-lenalidomide-dexamethasone (KRd) regimen for patients with newly diagnosed multiple myeloma (NDMM). Transplant-eligible patients with NDMM received 4 cycles of KRd induction, ASCT, 4 cycles of KRd consolidation, and 10 cycles of KRd maintenance. The primary end point was rate of stringent complete response (sCR) after 8 cycles of KRd with a predefined threshold of ≥50% to support further study. Seventy-six patients were enrolled with a median age of 59 years (range, 40-76 years), and 35.5% had high-risk cytogenetics. The primary end point was met, with an sCR rate of 60% after 8 cycles. Depth of response improved over time. On intent-to-treat (ITT), the sCR rate reached 76%. The rate of minimal residual disease (MRD) negativity using modified ITT was 70% according to next-generation sequencing (<10-5 sensitivity). After median follow-up of 56 months, 5-year progression-free survival (PFS) and overall survival (OS) rates were 72% and 84% for ITT, 85% and 91% for MRD-negative patients, and 57% and 72% for patients with high-risk cytogenetics. For high-risk patients who were MRD negative, 5-year rates were 77% and 81%. Grade 3 to 4 adverse events included neutropenia (34%), lymphopenia (32%), infection (22%), and cardiac events (3%). There was no grade 3 to 4 peripheral neuropathy. Patients with NDMM treated with KRd with ASCT achieved high rates of sCR and MRD-negative disease at the end of KRd consolidation. Extended KRd maintenance after consolidation contributed to deepening of responses and likely to prolonged PFS and OS. Safety and tolerability were manageable. This trial was registered at www.clinicaltrials.gov as #NCT01816971.

Fair Allocation of Scarce CAR T-Cell Therapies for Relapsed/Refractory Multiple Myeloma.

This Viewpoint discusses the unfairness of current CAR T-cell therapy allocation practices and offers alternative methods to more fairly allocate therapy.

Bendamustine-induced nephrogenic diabetes insipidus
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A 59-year-old man presented with polyuria and polydipsia immediately following his sixth cycle of rituximab and bendamustine for chronic lymphocytic leukemia. He initially compensated by increasing his oral fluid intake at home, but later developed septic shock and was admitted with orders to be kept nil per os (NPO). This prompted an episode of acute hypernatremia during which he exhibited continued polyuria with inappropriately dilute urine. Desmopressin challenge yielded no response in the urine osmolality, indicating a nephrogenic source of his diabetes insipidus (DI). He had no known exposure to other causative agents and had demonstrated a robust response to chemotherapy. The patient became eunatremic once oral intake was resumed and his infection was treated. Two months after presentation, he remained symptomatic. A trial with hydrochlorothiazide resulted in a significant increase in urine osmolality and subsequent decrease in urine output. To our knowledge, this is the first case of nephrogenic diabetes insipidus after rituximab and bendamustine exposure. We propose that bendamustine, similar to the alkylating agent ifosfamide, is toxic to the glomerulus and proximal tubule cells and is the most likely cause of the patient's nephrogenic DI.
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Risk Factors, Diagnosis, Management, and Outcome of Splanchnic Vein Thrombosis: A Retrospective Analysis.

OBJECTIVES: This study aims to determine the risk factors, diagnostic methods employed, treatment modalities, and outcome in patients with splanchnic vein thrombosis (SVT). METHODS: A retrospective chart review of patients, age 18 to 90 years, diagnosed with SVT at a single institution from January 1, 2010 to November 10, 2012. They were grouped as portal vein thrombosis (PVT)-including those combined with splenic vein thrombosis (SPVT) or mesenteric vein thrombosis (MVT)-and Budd-Chiari syndrome (BCS). RESULTS: Overall 246 SVT patients were identified, including 225 PVT and 21 BCS. Risk factors were liver disease, upper abdominal (regional) cancer and surgery, pancreatitis, and hereditary thrombophilia. The most common symptom was abdominal pain and most patients had abnormal liver function. Among those tested, the JAK2 V617F mutation was present in only 20% of the patients with PVT and 14% of the patients with BCS. Most patients were diagnosed by computed tomography. Anticoagulants were given to 30% of the patients with PVT and to 60% of the patients with BCS, with recurrence of SVT in 15% of the patients with PVT and 24% of the patients with BCS, regardless of anticoagulation. CONCLUSION: As compared with published literature on SVT, we found a higher incidence of regional cancer and surgery and a lower incidence of the JAK2 V617F mutation.

Measurable Residual Disease and Decision-Making in Multiple Myeloma.

Measurable (minimal) residual disease (MRD) has already proven to be one of the most important prognostic factors in multiple myeloma (MM). Each improvement in the depth of MRD testing has led to superior discrimination of outcomes, and sustained MRD negativity seems to be paramount to durable responses. Peripheral blood assays to assess for MRD are still under investigation but hold promise as complementary tools to bone marrow MRD assays such as next-generation sequencing and flow cytometry. Herein, the authors explore the evidence and potential benefits and drawbacks of MRD-adapted clinical decision-making in MM.

Optimization of Metabolic Tumor Volume as a Prognostic Marker in CAR T-Cell Therapy for Aggressive Large B-cell NHL.

BACKGROUND: CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has become a standard of care in relapsed/refractory (R/R) aggressive large B-cell non-Hodgkin lymphomas (B-NHL) though the majority of recipients do not receive durable disease benefit, prompting the need to better define risk factors for relapse/progression. OBJECTIVES: We performed a single-center, retrospective analysis of patients treated with commercial CAR T-cell therapy to evaluate the impact of tumor burden, as measured by whole-body metabolic tumor volume (MTV) from 18F fluorodeoxyglucose PET imaging, on treatment outcomes. STUDY DESIGN: Sixty-one patients treated with CAR T-cell therapy for R/R B-NHL between May 2016 and November 2021 were included. RESULTS: Using a receiver operating characteristic curve-based MTV optimization cutoff of 450 mL, 1-year progression-free survival (PFS) was 22% for high MTV versus 54% for low MTV (P < .01), and 1-year overall survival (OS) was 37% and 73%, respectively (P = .01). In a subset of 46 patients, residual MTV of less than 106 mL at the day 30 (D30) disease assessment was associated with significantly improved outcomes (1-year OS 85% vs. 13%, P < .01). Incorporation of pretreatment MTV to the International Prognostic Index (IPI) scoring system significantly distinguished 2-year PFS and OS outcomes by 3 risk groups. CONCLUSIONS: Our findings suggest that both pretreatment and D30 MTV are predictive of outcomes among R/R B-NHL patients treated with CAR T-cell therapy. These data indicate that efforts to reduce pretreatment tumor burden may improve longitudinal clinical outcomes. Furthermore, D30 postinfusion MTV quantification may aid clinicians in optimally identifying patients at high-risk for progression, and in whom closer disease monitoring should be considered. MTV also adds prognostic value to patients with high-risk IPI and holds promise for incorporation in novel risk scoring systems which can identify patients prior to CAR T-cell therapy at highest risk of adverse outcomes.

Panel Interview of ONcology practices with Emergent Experience of teclistamab in the Real world: the TecPIONEER Study.

OBJECTIVE: To understand clinicians' current teclistamab step-up dosing (SUD) model and how they envision future administration models, as well as perceived barriers and facilitators to these models in day-to-day clinical practice. METHODS: Interviews of clinicians with RW experience administering teclistamab, with a subsequent roundtable discussion to discuss interview findings. Topics of interest included managing adverse events (AE), and handling logistics of SUD and transition of care (ToC). RESULTS: 20 clinicians representing 19 practices participated. Of 14 practices administering inpatient teclistamab SUD, 12 (86%) utilized a single admission. A day 1-3-5 dosing schedule with a 7-day length of stay was planned in 10/14 (71%). The remaining 5 practices employed outpatient or hybrid SUD. SUD models depended on cellular therapy experience, patient volume, and monitoring capabilities. Clinicians desired to administer SUD outpatient for convenience and reduced healthcare resource use. 11% of practices reported using tocilizumab for cytokine release syndrome (CRS) prophylaxis, whilst it was uniformly used to treat grade 2+ CRS. Corticosteroids were the preferred treatment for neurotoxicity. Infection prophylaxis with intravenous immunoglobulin was reported by 89% of practices. Patient- and institution-level factors affected decision-making of transitioning patients back to referring sites after SUD. CONCLUSION: The results consolidated practice-based experiences and indicated diverse RW SUD models and patient management strategies in practices with familiarity with teclistamab AE management and ToC protocols. Inpatient SUD is common, with expectations that approaches will evolve toward outpatient or community-based administration. Further research is needed to investigate outcomes of different care models and AE management strategies.

Multiple myeloma is a blood cancer that forms in plasma cells. Teclistamab is a new treatment for patients with multiple myeloma who have received prior treatment but for whom their multiple myeloma has come back or stopped responding to treatment multiple times. Because teclistamab works differently than other existing multiple myeloma treatments, there is a need to understand how oncologists who have experience with teclistamab are managing their patients in order to inform best practices for use by more healthcare providers. We interviewed oncologists that treat patients with multiple myeloma to understand their experiences with teclistamab, including how they manage initial dosing (step-up dosing) processes, treat adverse events, and transition patients to outpatient or external clinics for continued care. Most practices were administering step-up dosing of teclistamab in an inpatient setting soon after teclistamab became a treatment option, with a high level of desire to move the initial dosing to an outpatient setting in the near future. Those that were already administering step-up dosing in an outpatient setting had models unique to their practice. Oncologists described numerous processes for monitoring and managing adverse events of the treatment, including treating patients with preventative medications and regularly monitoring vital signs throughout step-up dosing. Oncologists expected that their teclistamab administration processes will likely evolve over time as they gain more familiarity with the treatment, and will need to consider patient-level factors to administer step-up dosing in an outpatient setting.

Optimization of Older Adults by a Geriatric Assessment-Guided Multidisciplinary Clinic Prior to CAR T-Cell Therapy.

The optimal means of assessing candidacy of older (65 years) adults for CAR T-cell therapy (CAR-T) are unknown. We explored the role of a geriatric assessment (GA)-guided multidisciplinary clinic (GA-MDC) in selecting and optimizing older adults for CAR-T. From 12/2017 - 4/2022, 61 patients were evaluated in a GA-MDC (median age, 73 years; range, 58-83). Most common diagnoses were NHL (n=42) and multiple myeloma (n=14). A non-binding recommendation ('Proceed' or 'Decline') regarding suitability for CAR-T was provided on each patient based on GA results. Fifty-three patients ultimately received CAR-T (Proceed=47, Decline=6). Among patients who received BCMA-directed (n=11) and CD19-directed (n=42) CAR-T, median OS was 14.2 months and 16.6 months, respectively. GA uncovered high rates of geriatric impairment among patients proceeding to CAR-T, with fewer impairments in those recommended 'Proceed'. Patients recommended 'Proceed' had shorter median length of stay (17 vs 31 days; p=0.05), lower rates of ICU admission (6% vs 50%; p=0.01) and were less likely to require rehabilitation services after discharge (11% vs 67%; p=0.01) than those recommended 'Decline'. In patients receiving CD19- and BCMA-directed CAR-T, a 'Proceed' recommendation was associated with superior OS compared to 'Decline' (median 16.6 vs 11.4 months, p=0.02 and median 16.4 vs 4.2 months, p=0.03, respectively). When controlling for Karnofsky performance status, CRP and LDH at time of lymphodepletion, the GA-MDC treatment recommendation remained prognostic for OS (HR 3.26; p=0.04). Patients optimized via the GA-MDC without serious vulnerabilities achieved promising outcomes while patients with high vulnerability experienced high toxicity and poor outcomes following CAR-T.

Final analysis of a phase II trial of daratumumab, carfilzomib, lenalidomide, and dexamethasone in newly diagnosed multiple myeloma without transplant.

We evaluated the efficacy and safety of 24 cycles of Dara in combination with carfilzomib (K), lenalidomide (R), and dexamethasone (d) without autologous stem cell transplant (ASCT) in newly diagnosed multiple myeloma (NDMM) irrespective of ASCT eligibility in a single-arm, phase II study. The primary endpoint was the rate of stringent complete response (sCR) and/or measurable residual disease (MRD) < 10-5 by next-generation sequencing (NGS) at the end of cycle 8 (C8). MRD was also assessed on peripheral blood samples using both the EXENT® system and liquid chromatography-mass spectrometry (LC-MS). Forty-two patients entered the treatment phase; forty were evaluable for the primary endpoint. The rate of sCR and/or MRD < 10-5 following C8 was 30/40 (75%), meeting the statistical threshold for efficacy. The 10-6 MRD negative rate improved with treatment beyond C8. Agreement between EXENT® and NGS was high and increased over time; agreement between LC-MS and NGS was lower. The estimated 3-year progression-free survival progression-free survival was 85%, and 3-year overall survival was 95%. Upper respiratory infections occurred in 67% (7% grade 3-4). There were no treatment-related deaths. Extended frontline Dara-KRd induced a high rate of sCR and/or MRD negativity; the rate and depth of MRD negativity improved beyond C8.

Breast cancer in postmenopausal women after non-melanomatous skin cancer: the Women's Health Initiative observational study.

An increased risk of breast cancer has been reported in patients with non-melanomatous skin cancer (NMSC), but this association has not been studied in a large, multi-geographic population. We utilized data from the Women's Health Initiative observational study to assess whether history of NMSC is associated with breast cancer risk. This analysis included 70,246 postmenopausal White and Hispanic women aged 50-79, in which 4,247 breast cancer cases were identified over a mean (SD) of 11.3 (3.2) years. Baseline information was collected on demographics, medical history, sun exposure, and vitamin D intake. Cox proportional hazards regression was used to calculate hazard ratios (HRs) with 95 % confidence intervals (CIs). The relationship between NMSC and breast cancer was examined as a time-dependent exposure using updated information on NMSC gathered during follow-up visits. All statistical tests were two sided. There were 5,595 women diagnosed with NMSC at study entry. The annualized rate of breast cancer was 0.64 % among women with a history of NMSC and 0.55 % among women with no history of NMSC. The multivariable-adjusted HR for breast cancer among women with a history of NMSC versus no history of NMSC was 1.07 (95 % CI 0.95-1.20, P = 0.27). Further evaluation stratified by tumor characteristics showed an increased risk of lymph node-positive disease, HR = 1.30 (95 % CI 1.01-1.67, P = 0.04), and regional-stage disease, HR = 1.33 (95 % CI 1.05-1.70, P = 0.02), among women with NMSC. There was no significant overall association between NMSC and breast cancer; however, there was an increased risk of more advanced-stage breast cancer which needs further exploration.