Dingli, David

PURPOSE Cytokine release syndrome (CRS) of any grade occurs in 56%-80% of bispecific antibodies (BsAbs) used in multiple myeloma (MM). Risk mitigation strategies are required to expedite escalation of care if toxicities develop. The rarity of grade 3 or 4 CRS compels protocolized outpatient management of BsAbs as outpatient practice may avoid hospital admissions and costly resource utilization without compromising safety. MATERIALS AND METHODS Patients with MM who received BsAb step-up dosing (SUD) from August 23, 2023, to March 29, 2024, were enrolled. Baseline demographics, patient outcomes, and CRS management were reviewed to assess the safety of outpatient practice. Resource utilization was also analyzed. RESULTS In this study, 34 patients received outpatient SUD of BsAbs (teclistamab n = 17, talequetamab n = 17) with 16 remaining outpatient throughout the entire SUD period. CRS occurred in seven patients who did not require hospitalization, demonstrating the safety of outpatient management of BsAb toxicity, regardless of low-grade CRS. CRS was observed in 24 patients (maximum grade 2) and immune effector cell–associated neurotoxicity syndrome in four patients (maximum grade 3). All patients with CRS received steroids, including 12 patients at home when instructed. Tocilizumab was given to 13 patients, accounting for 18 doses. If all doses of BsAbs and tocilizumab were given outpatient, the medication margin would be $115,004 in US dollars (USD). CONCLUSION An outpatient-based practice for BsAb administration demonstrated safety and cost savings. The description of our practice and results of this study provide valuable insights into the safety, feasibility, and resource stewardship of outpatient management of BsAbs. Future research should attempt to predict and stratify CRS risk to deliver a tailored supportive strategy and continued increase of outpatient management.

ABSTRACTThe optimal conditioning schedule and CD34+ cell dose for autologous stem cell transplantation (ASCT) for AL amyloidosis is unknown. Patients (n = 1704) who underwent ASCT for AL amyloidosis between 2003 and 2020 in 9 centers were included. Data on melphalan conditioning dose, number of conditioning days, whether a rest day between conditioning and stem cell infusion was given or not, and infused CD34+ cell dose were collected. Full‐dose melphalan (≥ 180 mg/m2) was administered in 63.7% of the patients, and 80.4% had melphalan split into 2‐day conditioning. A rest day (day −1) between the conditioning regimen and stem cell infusion was provided in 52.5% of patients. The median infused CD34+ cell count was 4.7 × 106/kg. An infused CD34+ cell count ≥ 4.5 × 106/kg was associated with a shorter time to neutrophil and platelet engraftment. In a nominal regression analysis, full‐dose melphalan, 1‐day melphalan conditioning, and omitting a rest day between conditioning and stem cell infusion were independent predictors of post‐ASCT higher deep hematological response. The median follow‐up was 8.6 years, and 38% of patients died. Independent predictors of superior overall survival in multivariate Cox regression analysis included full‐dose melphalan, having no rest day, and infused CD34+ cells ≥ 4.5 × 106/kg. Independent predictors of higher day‐100 transplant‐related mortality (TRM) in nominal logistic regression analysis included poorer performance status, NT‐proBNP/BNP ≥ 1800/400 pg/mL, serum albumin < 2.5 g/dL, CD34+ cells < 4.5 × 106/kg, and not having a rest day. In conclusion, 1 day of melphalan conditioning and administration of CD34+ cells ≥ 4.5 × 106/kg are recommended for ASCT in AL amyloidosis.

ABSTRACTTransplant‐associated thrombotic microangiopathy (TA‐TMA) is an endothelial dysfunction syndrome observed after allogeneic hematopoietic cell transplant (alloHCT). Our aim was to externally validate the impact of high‐risk features on the clinical outcomes of adult patients meeting the updated TA‐TMA harmonizing criteria. Between 2005 and 2022, 99 patients were diagnosed with TA‐TMA at Mayo Clinic Rochester (incidence 6.2%) after a median of 137 days post alloHCT (IQR: 34–283 days). The development of TA‐TMA was associated with an inferior overall survival posttransplant (HR: 3.8, 95% CI: 2.97–4.72). High‐risk features, including concomitant infection, acute graft‐versus‐host disease (GVHD), and organ dysfunction, were associated with poor survival, while LDH elevation was not associated with inferior outcomes. The most common treatment strategy for TA‐TMA was discontinuation of calcineurin or mTOR inhibitors in 80 (81%) patients. Thirty (37.5%) patients experienced worsening of GVHD with this strategy, of which 26 (86.7%) patients had died at last follow‐up. The most common cause of death among these patients was worsening GVHD (69%; n = 18), followed by infection (11%; n = 3), disease relapse (8%; n = 2), other/unknown causes (8%; n = 2), or TA‐TMA (4%; n = 1). Objective response rate (ORR) to initial treatment for the cohort was 56.6%. Eculizumab was used in 11 patients with an observed ORR of 70%, including 5 complete responses. In conclusion, TA‐TMA remains a significant contributor to non‐relapse mortality and is associated with worse survival following alloHCT. Not all high‐risk features, particularly LDH elevation, have consistently demonstrated a negative impact in adult cohorts. Patients with TA‐TMA may benefit from immune suppression dose adjustment, rather than a discontinuation, and the addition of complement‐directed therapy, particularly among high‐risk patients.

AbstractBackgroundSince FDA approval in 2017, CAR‐T therapy has seen rapid clinical adoption. Shifting clinical trends have emerged with increasing utilization of CAR‐T therapies and a downward trend in HSCTs. Given the overlapping resources required for the manufacture and storage of these products, we sought to examine trends over a 6‐year period.MethodsThe apheresis patient database and Lab database were reviewed to compile a list of patients that underwent either CAR‐T or HSCT (autologous) collections, and/or received CAR‐T or autologous HSCT infusions between January 1, 2018 and December 12, 2023. This was further examined by year and disease group.ResultsThe total number of patients collecting for CAR‐T increased from 52 in 2018 to 150 in 2023 (slope = 21.97; p = .0013), accompanied by a decrease in the number of patients collecting for HSCT, from 425 in 2018 to 341 in 2023 (slope = −21.2; p = .0177). Neither total number (calculated as number of HSCT + CAR‐T) of patients collected (mean 476 + 20.4 per year), nor collection procedures (mean 972 ± 75.8 per year) changed significantly over the 6‐year period. The total number of CAR‐T infusions increased from 24 in 2018 to 111 in 2023 (slope = 17.7; p = .004), with a decrease in auto‐HSCT from 400 to 289 (slope = −28.7; p = .008). The overall number of infusions (calculated as number of HSCT + CAR‐T) did not change significantly (slope = −10.9; p = .13) over the 6‐year period.DiscussionOur findings confirm the increasing adoption of CAR‐T therapy occurring alongside a decreasing stem‐cell transplants, with stable overall resource utilization.

Abstract In this study, we first analyzed data from 147 patients with solitary plasmacytomas treated at the Mayo Clinic between 2005 and 2022 and then expanded our investigation through a systematic review and meta-analysis of 62 studies, encompassing 3487 patients from the years 1960 to 2022. Our findings reveal that patients with up to 10% clonal plasma cells in their bone marrow (BM), denoted as plasmacytoma +, had a significantly reduced median disease-free survival (DFS) of 15.7 months vs 79 months, P &lt; .05, observed in patients with true solitary plasmacytomas, with no clonal cells in the BM. Risk factors identified for shorter DFS included the presence of clonal plasma cells in the marrow and a difference between involved and uninvolved free light chains of &gt;5 mg/dL. The meta-analysis portion of our study highlighted a male predominance among patients, with a median age of 58 years, and confirmed radiation therapy as the predominant treatment modality. We also found that DFS rates at 3, 5, and 10 years were 66.9%, 55%, and 42.1%, respectively, and noted a significant difference in outcomes between patients with bone and extramedullary plasmacytomas, with the latter group exhibiting better survival rates. This dual-faceted approach provides a thorough overview of survival rates and critical risk factors for patients with plasmacytoma, underscoring the vital role of accurate disease staging at diagnosis and the impact of tumor location on patient prognosis.

Importance There is a lack of long-term efficacy and safety data on hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and on RNA interference (RNAi) therapeutics in general. This study presents the longest-term data to date on patisiran for hATTR-PN. Objective To present the long-term efficacy and safety of patisiran in adults with hATTR-PN. Design, Setting, and Participants This global open-label extension (OLE) of the APOLLO randomized clinical trial and phase 2 OLE study enrolled patients from 43 hospitals or clinical centers across 19 countries between July 2015 and August 2017, with follow-up until November 2022. Of 212 eligible patients with hATTR who completed the phase 3 APOLLO or phase 2 OLE parent studies, 211 enrolled in and 138 completed the global OLE. Intervention Patisiran, 0.3 mg/kg, intravenously once every 3 weeks for up to 5 years. Main Outcomes and Measures Outcomes evaluated at year 5 of the global OLE included disability (polyneuropathy disability [PND] score); polyneuropathy severity (Neuropathy Impairment Score [NIS]), nutritional status (modified body mass index [mBMI]), quality of life (Norfolk Quality of Life–Diabetic Neuropathy [Norfolk QOL-DN]), and Rasch-Built Overall Disability Scale (R-ODS), with no statistical hierarchy. Safety, survival probability, and mortality were also assessed. Results At the global OLE baseline, the mean (SD) age was 61.3 (12.3) years, and 156 patients (73.9%) were male. In 138 patients completing the study, PND scores remained stable or improved in 89 patients (65.0%), NISs showed a mean (SD) change of 10.9 (14.7), and mean (SD) mBMI (calculated as weight in kilograms divided by height in meters squared times serum albumin in grams per liter) increased by 46.4 (120.7) over 5 years from baseline. Norfolk QOL-DN and R-ODS scores showed mean (SD) changes of 4.1 (16.7) and –3.7 (6.2), respectively. Adverse events (AEs) leading to study withdrawal occurred in 47 patients (22.3%). Infusion-related reactions were the most common treatment-related AE (n = 34 [16.1%]). Overall, 41 patients (19.4%) died during the study. Patisiran treatment in the parent study and low familial amyloid polyneuropathy score at parent study baseline were associated with significantly improved survival. Conclusions and Relevance In the longest study of an RNAi therapeutic for any disease, patisiran treatment resulted in modest changes for patients with hATTR-PN with an acceptable safety profile. These results highlight the importance of initiating early treatment for hATTR and the potential of RNAi therapeutics in medicine. Trial Registration ClinicalTrials.gov Identifier: NCT02510261

Background Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder characterized by uncontrolled terminal complement activation. Treatment with terminal complement inhibitors ravulizumab or eculizumab has led to improved clinical outcomes for patients with PNH. Evidence on real-world treatment patterns and healthcare resource utilization (HRU) in this patient population, which includes emerging data on pegcetacoplan, is limited. Objective To describe real-world drug adherence and persistence in patients with PNH receiving ravulizumab, eculizumab or pegcetacoplan, and compare HRU for patients pre- and post-ravulizumab initiation in the USA. Methods ADVANTAGE is a retrospective, longitudinal analysis using the Komodo Health Research Database, a large multi-payer US health insurance claims dataset, among patients with PNH and ≥ 1 claim for ravulizumab, eculizumab or pegcetacoplan. Patients aged ≥ 18 years at index date (defined as the date of first claim for a given complement inhibitor on/after 1 January, 2019), with ≥ 12 months enrollment prior to this date, ≥ 1 claim with an ICD-10-CM code indicating PNH prior to/at index date and no ICD-10-CM code suggesting an alternative indication, were included. Patients were followed until the end of continuous enrollment, death, or end of data availability. Adherence was assessed by proportion of days covered (PDC) and treatment duration was estimated using Kaplan-Meier analysis. The HRU analysis included patients with ≥ 12 months follow-up and compared rates of HRU per-patient per-year (PPPY) in the 12 months pre- and post-ravulizumab treatment initiation. Pre-post differences in HRU were estimated using generalized estimating equations with robust standard errors. Results The sample included 344, 342 and 97 patients with index treatments for ravulizumab, eculizumab or pegcetacoplan, respectively. Age and sex distribution of patients were similar among patients treated with ravulizumab (mean age: 44 years; 57% female), eculizumab (mean age: 44 years; 60% female), or pegcetacoplan (mean age: 45 years; 62% female). More patients in the ravulizumab cohort were complement inhibitor-naive (31%) compared with eculizumab (20%) or pegcetacoplan (24%). Mean (standard deviation [SD]) duration of follow-up was 25.3 (15.9), 33.5 (18.9) and 13 (8.0) months, and mean (SD) proportion of days covered (PDC) was 0.98 (0.05), 0.90 (0.14) and 0.77 (0.30) for the ravulizumab, eculizumab and pegcetacoplan cohorts, respectively. The percentage of patients with PDC ≥ 0.8 (a widely used threshold for treatment adherence) was 98.5% for ravulizumab, and 84.5% and 78.4% for eculizumab and pegcetacoplan, respectively. The median (interquartile range [IQR]) duration on ravulizumab treatment was 48.4 (11.5, not reached [NR]) months, compared with 7.6 (3.4, 23.3) for eculizumab and 14.6 (0.2, NR) for pegcetacoplan. Among patients with ≥ 12 months on ravulizumab treatment (n = 183), a 24.8% reduction in all-cause HRU was observed during the first 12 months of treatment compared with the prior 12 months. Statistically significant reductions were observed in mean (SD) all-cause hospitalizations (0.2 [0.6] PPPY during follow-up; % difference -44.6%, p = 0.014), outpatient visits (24.3 [17.8] PPPY; % difference -19.1%, p &lt; 0.001) and emergency room visits (0.5 [1.3] PPPY; % difference -39.8%, p = 0.008). Similar results were observed for PNH-related HRU, including a 32.1% reduction in the overall number of visits (p &lt; 0.001). Notably, a statistically significant reduction in PNH-related hospitalizations (0.2 [0.5] PPPY; % difference -37.8%, p = 0.044) and outpatient visits (14.3 [10.7] PPPY; % difference -22.4%, p &lt; 0.001) was observed. Ravulizumab initiation was also associated with fewer PNH-related emergency room visits (0.2 [0.7] PPPY; % difference -32.7%, p = 0.170) and blood transfusions (0.8 [2.9] PPPY; % difference -30.7%, p = 0.277); however, these changes were not statistically significant. Conclusions In this retrospective analysis, patients demonstrated higher adherence and persistence to ravulizumab treatment compared to other complement inhibitors. HRU decreased following ravulizumab initiation, indicating an alleviated burden of disease in these patients after treatment initiation. These real-world data provide further evidence of the benefit of ravulizumab in patients with PNH.

Monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and active multiple myeloma (MM) represent a continuum across the spectrum of plasma cell disorders. While patients with MGUS can be observed, it has a risk of progression to MM, while patients with SMM have a higher risk of progression to MM. Determining the risk of progression is important for proper patient care and elimination of anxiety, especially for patients identified at very low risk of progression. In contrast, identifying patients at high risk may reduce morbidity by more active surveillance or the introduction of therapy. We hypothesized that Fourier Transform InfraRed Spectroscopic analysis of serum combined with machine learning (FTIR/ML) could be used to facilitate this decision-making and correctly stratify patients' risk. Methods: After Institutional Review Board approval, we identified 99 patients with MGUS who did not progress to SMM/MM or AL amyloidosis, 96 patients with SMM who did not progress to active MM over a 2-year interval from diagnosis, and another 96 SMM patients who progressed to MM within two years of diagnosis. The patients had been diagnosed and followed up at Mayo Clinic in Rochester. Serological molecular fingerprint analysis was then performed using surface- and chemical-enhanced infrared absorption FTIR spectroscopy combined with artificial neural network ML. A randomized 10-fold cross-validation analysis was performed using 262 samples for training and the remaining 29 samples for validation to assess the model across ten independent iterations. Receiver operator characteristic (ROC) analysis was used to assess the FTIR/ML algorithm output compared to the clinical outcome data. Results: The patients with both MGUS and SMM had a similar median age (64.4 years), but patients with SMM tended to have lower hemoglobin compared to MGUS (median 12.4 versus 13.8g/dl respectively). As expected, patients with SMM also had a higher serum M-spike (2.0g/dl versus 1.2) and a higher clonal plasma cell burden in the bone marrow (20% versus 9%). FTIR/ML was able to correctly classify sera into MGUS in 95.8% of samples and SMM in 92.9% of samples. This gave an average accuracy of 94.8%. We performed ROC analysis and determined an area under the curve of 98.7%. The F1 score/precision was 94.9%, with a recall of 94.8%. After establishing a suitable threshold, the ML algorithm was able to correctly classify MGUS in 96.8% and SMM in 97.2% of cases. Conclusion: A single serum test at the time of diagnosis can correctly distinguish between MGUS that will not progress to another plasma cell disorder from smoldering multiple myeloma with a high degree of accuracy. Given that the patients with MGUS that were chosen had not progressed to a plasma cell disorder and were correctly identified, this methodology offers an opportunity to provide reassurance and minimize the need for repeat testing and follow-up of such patients.

The prognosis of patients with immunoglobulin light or heavy chain amyloidosis (AL/AH) has improved with the advent of more effective therapies. However, diagnosis is often delayed, with a negative impact on overall survival due to irreversible end-organ damage. Therefore, technologies that could facilitate the diagnosis or raise early suspicion of AL/AH amyloidosis in patients would be beneficial to improve outcomes. We hypothesized that Fourier transform infrared spectroscopic analysis of serum combined with machine learning (FTIR/ML) may be able to correctly diagnose AL/AH amyloidosis compared to patients with monoclonal gammopathy of undetermined significance or smoldering multiple myeloma. Methods: After institutional Review Board approval, we identified 90 patients with AL/AH amyloidosis, 99 patients with MGUS, and 192 patients with smoldering multiple myeloma (96 each who did/did not progress to active myeloma within two years of diagnosis) that had been diagnosed and followed up at Mayo Clinic in Rochester. We then performed surface- and chemical-enhanced infrared absorption FTIR/ML-based molecular fingerprint analysis on serum samples taken from the time of diagnosis to train an AI algorithm to distinguish between the two cohorts. A randomized 10-fold cross-validation analysis was performed using 253 samples (90% from each group) for training and the remaining 29 for testing to assess the model across ten independent iterations. We performed a Receiver Operator Characteristic analysis of the outcomes to measure the model's performance. Results: The patients with immunoglobulin-related amyloidosis had involvement of one or more of the following organs: heart, kidneys, liver, nerve, and gastrointestinal tract. Patients diagnosed with amyloidosis had lower serum albumin (3.0 versus 3.6 g/dl) and higher lambda immunoglobulin-free light chain values compared to those with MGUS (28.4 versus 1.92mg/dl). The predominance of lambda immunoglobulin-free light chains is not unexpected but not diagnostic by itself of AL/AH amyloidosis. Patients with SMM had higher serum M protein, higher immunoglobulin kappa free light chains, and higher bone marrow plasma cell burden (20%) compared to either MGUS (9%) or AL amyloidosis patients (10%). However, none of these are diagnostic features. FTIR/ML was able to correctly classify AL/AH amyloidosis in 80% of samples and MGUS in 83.8%, for an accuracy of 82% with an area under the curve of 89.2%. The precision was 82%, with a recall of 82%. After setting an appropriate threshold, the algorithm was able to correctly identify AL/AH amyloidosis in 86.1% of patients and MGUS in 86.6% of patients. When we compared AL/AH amyloidosis with SMM, FTIR/ML correctly classified AL/AH amyloidosis in 94.4% and SMM in 96.4% for an accuracy of 95.7% and an area under curve of 97.5%. The precision was 95.8%, with a recall of 95.7%. After setting a threshold, the algorithm was able to correctly diagnose SMM in 98.3% and AL/AH amyloidosis in 96.2%. Discussion: FTIR/ML analysis of serum can distinguish between AL/AH amyloidosis and both MGUS and SMM with a high degree of accuracy. Given that the diagnosis of immunoglobulin related amyloidosis is often delayed, our approach, based on a single analysis of a serum sample could potentially accelerate the diagnosis of AL/AH amyloidosis and implementation of life saving therapy.

INTRODUCTION Primary plasma cell leukemia (pPCL) is a rare and aggressive form of multiple myeloma (MM) with poor survival outcomes. Fluorescence in situ hybridization (FISH) evaluation is essential for the initial risk stratification in MM, and the presence of multiple high-risk (HR) cytogenetic abnormalities by FISH portends a worse prognosis in MM. We have previously observed that the presence of HR cytogenetic abnormalities by FISH at diagnosis is known to confer a poor overall survival (OS) in patients with pPCL. However, less is known about the cumulative effect of multiple HR cytogenetics abnormalities compared to a single HR cytogenetic abnormality on the OS outcomes of patients with pPCL. AIM To evaluate the prognostic implications of additive HR cytogenetics abnormalities by FISH in patients with pPCL treated with novel agents. METHODS We evaluated patients with newly diagnosed pPCL at the Mayo Clinic Comprehensive Cancer Center from 2014 - 2023 that received induction with novel agent combinations. pPCL was defined as patients meeting the diagnostic criteria for MM with 5% or more circulating plasma cells (cPCs) present on morphologic evaluation of their peripheral blood smear. HR cytogenetics abnormalities by FISH was defined by the presence of any one of the following: 1q gain/amplification, t(4;14), t(14;16), t(14;20), and del(17p). Time to next treatment (TTNT) and OS analysis were performed using the Kaplan-Meier method, and differences were assessed using the log-rank test. Statistical analyses were performed using the SAS biostatistical software JMP 17.0.1 (SAS Institute Inc). RESULTS We included 89 patients with newly diagnosed pPCL who received novel agents as first-line therapy between 2014 to 2023. The median follow-up was 45 months (95% CI: 35 - 65). At diagnosis, the median bone marrow plasma cell content was 80% (Range: 10 - 100), and the median cPC% on the peripheral smear was 21% (range: 5 - 85). There were 51 patients (59%) who had 20% or more cPCs on their peripheral smear. There was a preponderance of pPCL patients who had t(11; 14) as their primary cytogenetic abnormality (43%). The median lines of therapy received were 2 (Range: 1 - 9). There were 12 (13%) patients who received intensive induction therapy containing continuous infusional chemotherapy regimens at the onset of their diagnosis. Of the remaining patients, 35 (45%) were treated with a quadruplet (anti-CD38 antibody, proteasome inhibitor and immunomodulator), 24 (31%) with a triplet (proteasome inhibitor and immunomodulator) and 18 (23%) with a doublet (proteasome inhibitor only). The median OS for all pPCL patients in this cohort was 47 months (95% CI: 37 - 100). However, when stratified by cytogenetic risk, the median OS was 101 months (95% CI: 57 - NR) for those patients without any HR cytogenetic abnormalities (N = 24, 27%) vs. 37 months (95% CI: 22 - 63) for those with one or more HR cytogenetic abnormalities (N = 65, 73%) (P = 0.006). Of the patients with any HR cytogenetic abnormalities, 33 (36%) had one HR cytogenetic abnormalities and 32 (34%) had two or more HR cytogenetic abnormalities. The median OS for patients with one compared to two or more HR cytogenetic abnormalities were 47 (95% CI: 38 - 111), and 22 (95% CI: 17 - 37) months, respectively (P = 0.031). The median TTNT was 22 months (95% CI: 16 - 58) for those patients without any HR cytogenetic abnormalities vs. 16 months (95% CI: 9 - 21) for those with one or more HR cytogenetic abnormalities (P = 0.09). The median TTNT from the time of diagnosis for pPCL patients with one compared to two or more HR cytogenetic abnormalities were 18 (95% CI: 6 - 41) and 16 (95% CI: 10 - 19) months, respectively (p = 0.247). CONCLUSION Patients with pPCL with more than one HR cytogenetic abnormality had an inferior OS compared to those with only one HR cytogenetic abnormality, implicating the additive adverse effects of multiple HR cytogenetics abnormalities. In contrast, patients with pPCL without any HR cytogenetic abnormalities had a relatively long median OS (over 100 months).