Long-term survivorship care after CAR-T cell therapy.

While cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome are well-recognized acute toxicities of chimeric antigen receptor (CAR) T cell therapy, these complications have become increasingly manageable by protocolized treatment algorithms incorporating the early administration of tocilizumab and corticosteroids. As CAR-T cell therapy expands to new disease indications and the number of long-term survivors steadily increases, there is growing recognition of the need to appropriately evaluate and manage the late effects of CAR-T cell therapy, including late-onset or persistent neurotoxicity, prolonged cytopenias, delayed immune reconstitution and infections, subsequent malignancies, organ dysfunction, psychological distress, and fertility implications. In this review, we provide a practical approach to the long-term survivorship care of the CAR-T cell recipient, with a focus on the optimal strategies to address the common and challenging late complications affecting this unique population.

Real-world results of autologous stem cell transplantation in newly diagnosed multiple myeloma: a report from the Canadian Myeloma Research Group database.

Autologous stem cell transplant (ASCT) remains an important option for eligible multiple myeloma (MM) patients as part of initial therapy. Using the Canadian Myeloma Research Group (CMRG) national database, we examined the details and outcomes of ASCT performed as first-line therapy in eligible Canadian MM patients between 2007 to 2021. We included 3821 patients with 72% receiving CyBorD induction and 2061 patients receiving maintenance, consisting of lenalidomide +/- steroids in 78.3%. The median PFS and OS for patients given a single ASCT were 35.4 and 126 months. Those receiving a second induction regimen had significantly inferior outcomes, although when maintenance was used, results were comparable regardless of the number of induction regimens administered (median PFS 55.3 vs 51.1 months [p = 0.11]; median OS 158.6 vs not yet reached [p = 0.13]). Consolidation patients had a longer median PFS (55.3 vs 34.4 months [p = 0.001]), but no significant gain in median OS (p = 0.065). Patients who received lenalidomide-based maintenance experienced a median PFS of 53.7 months and OS of 159 months. In the multivariable analysis, use of any type of maintenance therapy vs no maintenance was associated with a lower risk of progression (HR 0.52 (95% CI 0.47-0.57)) and death (HR 0.58 (95% CI 0.51-0.67)). This real-world study demonstrates that, overall, first-line treatment sequence in transplant-eligible patients produces a median OS of ≥10 years. It also highlights the contribution of post-ASCT maintenance, particularly lenalidomide given until progression.

Outcome of carfilzomib/pomalidomide-based regimens after daratumumab-based treatment in relapsed multiple myeloma: A Canadian Myeloma Research Group Database analysis.

INTRODUCTION: Although daratumumab-containing regimens improve multiple myeloma (MM) outcomes, recurrence is inevitable. METHODS AND OBJECTIVE: We performed a retrospective study using the Canadian Myeloma Research Group Database to benchmark the efficacy of carfilzomib- or pomalidomide-based therapies immediately following progression on daratumumab treatment. RESULTS: We identified 178 such patients; median number of prior lines of therapy was 3, 97% triple-class exposed, and 60% triple-class refractory. In our cohort, 75 received a subsequent carfilzomib-based therapy, 79 received a pomalidomide-based therapy, and 24 received a treatment with both immunomodulatory drug (IMiD) and proteasome inhibitor (PI) using carfilzomib and/or pomalidomide. The median progression-free survival (PFS) and overall survival (OS) for the entire cohort were 4.5 and 14.2 months, respectively. Carfilzomib-based therapy yielded a median PFS and OS of 4.5 and 10.2 months, respectively, compared to 5.2 and 21.7 months for pomalidomide-based therapy. Patients who received both IMiD and PI with carfilzomib and/or pomalidomide had a median PFS and OS of 4.1 and 14.5 months, respectively. CONCLUSION: Our observations demonstrate the poor outcome of MM patients when standard regimens based on carfilzomib and/or pomalidomide are utilized directly after daratumumab-based therapy given in the relapsed setting. Novel therapies, including immune therapies, are urgently needed to improve the outcomes of these daratumumab-exposed patients.

Redefining attrition in multiple myeloma (MM): a Canadian Myeloma Research Group (CMRG) analysis.

While most patients diagnosed with multiple myeloma (MM) receive initial therapy, reported attrition rates are high. Understanding attrition rates and characteristics of patients not receiving subsequent therapy is useful for MM stakeholders. We performed an analysis of attrition rates in a large disease-specific database of patients with newly diagnosed MM who received at least one line of therapy between Jan 1/10-Dec 31/20. Attrition was defined as failure to receive a subsequent line of therapy despite progression of MM or due to death. A total of 5548 patients were identified, 3111 autologous stem cell transplant (ASCT) patients and 2437 non-ASCT. In the ASCT cohort, the attrition rate was 7% after line 1, 12% after line 2, and 23% after line 3. In non-ASCT patients, the attrition rate was 19% after line 1, 26% after line 2, and 40% after line 3. Death was the dominant contributor to attrition across all cohorts, with a minority of patients alive with progressive disease in the absence of further therapy at each line. Multivariable analysis identified older age, shorter time to progression, and inferior response as independent risk factors for attrition. Our data show that attrition rates increase with each line of therapy and are higher in non-ASCT patients but are appreciably lower than previously reported. This study supports a revision of the previous definition of attrition, demonstrating that most patients who do not receive subsequent therapy are either continuing their current therapy and/or are in remission off-treatment rather than being irreversibly lost to attrition.

Corticosteroids as graft-versus-host disease prophylaxis for allogeneic hematopoietic cell transplant recipients with calcineurin inhibitor intolerance.

BACKGROUND AIMS: Although calcineurin inhibitors (CNIs) have a well-established role in the prevention of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT), their use can be limited by significant toxicities, which may result in premature treatment discontinuation. The optimal management of patients with CNI intolerance is unknown. The objective of this study was to determine the effectiveness of corticosteroids as GVHD prophylaxis for patients with CNI intolerance. METHODS: This retrospective single-center study included consecutive adult patients with hematologic malignancies who underwent myeloablative peripheral blood allogeneic HCT with anti-thymocyte globulin, CNI, and methotrexate GVHD prophylaxis in Alberta, Canada. Multivariable competing-risks regression was used to compare cumulative incidences of GVHD, relapse, and non-relapse mortality between recipients of corticosteroid versus continuous CNI prophylaxis, and multivariable Cox proportional hazards regression was applied to compare overall survival, relapse-free survival (RFS) and moderate-to-severe chronic GVHD and RFS. RESULTS: Among 509 allogeneic HCT recipients, 58 (11%) patients developed CNI intolerance and were switched to corticosteroid prophylaxis at median 28 days (range 1-53) after HCT. Compared with patients who received continuous CNI prophylaxis, recipients of corticosteroid prophylaxis had significantly greater cumulative incidences of grade 2-4 acute GVHD (subhazard ratio [SHR] 1.74, 95% confidence interval [CI] 1.08-2.80, P = 0.024), grade 3-4 acute GVHD (SHR 3.22, 95% CI 1.55-6.72, P = 0.002), and GVHD-related non-relapse mortality (SHR 3.07, 95% CI 1.54-6.12, P = 0.001). There were no significant differences in moderate-to-severe chronic GVHD (SHR 0.84, 95% CI 0.43-1.63, P = 0.60) or relapse (SHR 0.92, 95% CI 0.53-1.62, P = 0.78), but corticosteroid prophylaxis was associated with significantly inferior overall survival (hazard ratio [HR] 1.77, 95% CI 1.20-2.61, P = 0.004), RFS (HR 1.54, 95% CI 1.06-2.25, P = 0.024), and chronic GVHD and RFS (HR 1.46, 95% CI 1.04-2.05, P = 0.029). CONCLUSIONS: Allogeneic HCT recipients with CNI intolerance are at increased risks of acute GVHD and poor outcomes despite institution of corticosteroid prophylaxis following premature CNI discontinuation. Alternative GVHD prophylaxis strategies are needed for this high-risk population.

Diagnostic accuracy of bone scintigraphy imaging for transthyretin cardiac amyloidosis: systematic review and meta-analysis.

BACKGROUND: Bone scintigraphy imaging is frequently used to investigate patients with suspected transthyretin cardiac amyloidosis (ATTR-CM). However, the reported accuracy for interpretation approaches has changed over time. We performed a systematic review and meta-analysis to determine the diagnostic accuracy of visual planar grading, heart-to-contralateral (HCL) ratio, and quantitative analysis of SPECT imaging and evaluate reasons for shifts in reported accuracy. METHODS: We performed a systematic review to identify studies of the diagnostic accuracy of bone scintigraphy for ATTR-CM from 1990 until February 2023 using PUBMED and EMBASE. Studies were reviewed separately by two authors for inclusion and for risk of bias assessment. Summary receiver operating characteristic curves and operating points were determined with hierarchical modeling. RESULTS: Out of a total of 428 identified studies, 119 were reviewed in detail and 23 were included in the final analysis. The studies included a total of 3954 patients, with ATTR-CM diagnosed in 1337 (39.6%) patients and prevalence ranging from 21 to 73%. Visual planar grading and quantitative analysis had higher diagnostic accuracy (.99) than HCL ratio (.96). Quantitative analysis of SPECT imaging had the highest specificity (97%) followed by planar visual grade (96%) and HCL ratio (93%). ATTR-CM prevalence accounted for some of the observed between study heterogeneity. CONCLUSIONS: Bone scintigraphy imaging is highly accurate for identifying patients with ATTR-CM, with between study heterogeneity in part explained by differences in disease prevalence. We identified small differences in specificity, which may have important clinical implications when applied to low-risk screening populations.

Definition and Clinical Significance of the Monoclonal Gammopathy of Undetermined Significance-Like Phenotype in Patients With Monoclonal Gammopathies.

PURPOSE: The existence of patients with multiple myeloma (MM) and light-chain (AL) amyloidosis who present with a monoclonal gammopathy of undetermined significance (MGUS)-like phenotype has been hypothesized, but methods to identify this subgroup are not standardized and its clinical significance is not properly validated. PATIENTS AND METHODS: An algorithm to identify patients having MGUS-like phenotype was developed on the basis of the percentages of total bone marrow (BM) plasma cells (PC) and of clonal PC within the BM PC compartment, determined at diagnosis using flow cytometry in 548 patients with MGUS and 2,011 patients with active MM. The clinical significance of the algorithm was tested and validated in 488 patients with smoldering MM, 3,870 patients with active MM and 211 patients with AL amyloidosis. RESULTS: Patients with smoldering MM with MGUS-like phenotype showed significantly lower rates of disease progression (4.5% and 0% at 2 years in two independent series). There were no statistically significant differences in time to progression between treatment versus observation in these patients. In active newly diagnosed MM, MGUS-like phenotype retained independent prognostic value in multivariate analyses of progression-free survival (PFS; hazard ratio [HR], 0.49; P = .001) and overall survival (OS; HR, 0.56; P = .039), together with International Staging System, lactate dehydrogenase, cytogenetic risk, transplant eligibility, and complete remission status. Transplant-eligible patients with active MM with MGUS-like phenotype showed PFS and OS rates at 5 years of 79% and 96%, respectively. In this subgroup, there were no differences in PFS and OS according to complete remission and measurable residual disease status. Application of the algorithm in two independent series of patients with AL predicted for different survival. CONCLUSION: We developed an open-access algorithm for the identification of MGUS-like patients with distinct clinical outcomes. This phenotypic classification could become part of the diagnostic workup of MM and AL amyloidosis.

Monoclonal Gammopathy of Undetermined Significance in Patients With Transthyretin Amyloidosis (ATTR): Analysis Using the iStopMM Criteria.

INTRODUCTION: To identify the prevalence of monoclonal gammopathy of undetermined significance (MGUS) in patients with transthyretin amyloid (ATTR). We used the iStopMM study revised reference ranges for serum free light-chain (sFLC) corrected for eGFR to identify ATTR patients with light-chain MGUS (LC-MGUS). Characteristics and frequencies of the ATTR cohort with underlying MGUS was compared to a cohort of MGUS patients without ATTR. PATIENTS AND METHODS: A retrospective analysis of ATTR and MGUS patients evaluated at our center between January 2014 to December 2021. A total of 149, predominantly male (87.5%) ATTR patients with a median age of 82 were included. This cohort was compared to 228 MGUS patients. RESULTS: Of the 149 ATTR patients, 27 (18.1%) had coexisting MGUS. Among ATTR patients with MGUS, 12/27 (44%) had LC-MGUS based on sFLC abnormalities assessed using the iStopMM reference ranges. Of the MGUS only cohort, 44/228 (19.3%) met criteria for LC-MGUS. Utilizing the iStopMM reference ranges, 6 ATTR patients did not meet criteria for abnormal sFLCs, uncovering a 20% false-positive rate. CONCLUSION: We noted higher rates of MGUS, particularly LC-MGUS, among ATTR patients when compared to our MGUS only cohort. The high prevalence remained after utilizing the iStopMM sFLC corrected for eGFR reference ranges. Additionally, 6 ATTR patients with renal-dysfunction would have met MGUS criteria if not evaluated using the iStopMM revised measures. These findings emphasize careful interpretation of sFLC abnormalities and encourage providers to keep ATTR on the differential when work-up uncovers sFLC aberrations.

A Comprehensive Multidisciplinary Diagnostic Algorithm for the Early and Efficient Detection of Amyloidosis.

Amyloidosis is a rare protein misfolding disease caused by the accumulation of amyloid fibrils in various tissues and organs. There are different subtypes of amyloidosis, with light chain (AL) amyloidosis being the most common. Amyloidosis is notoriously difficult to diagnose because it is clinically heterogeneous, no single test is diagnostic for the disease, and diagnosis typically involves multiple specialists. Here, we propose an integrated, multidisciplinary algorithm for efficiently diagnosing amyloidosis. Drawing on research from several medical disciplines, we have combined clinical decisions and best practices into a comprehensive algorithm to facilitate the early detection of amyloidosis. Currently, many patients are diagnosed more than 6 months after symptom onset, yet early diagnosis is the major predictor of survival. Our algorithm aims to shorten the time to diagnosis with efficient sequencing of tests and minimizing uninformative investigations. We also recommend typing and staging of confirmed amyloidosis to guide treatment. By reducing time to diagnosis, our algorithm could lead to earlier and more targeted treatment, ultimately improving prognosis and survival.

Real-world Outcomes With Cumulative Bortezomib Dose and Efficacy in the Treatment of Transplant-ineligible Multiple Myeloma With Cyclophosphamide, Bortezomib, and Dexamethasone.

BACKGROUND: Higher cumulative dose of bortezomib, a key component of Multiple Myeloma (MM) treatment regimens, has been shown to improve outcomes in MM patients, but must be balanced with toxicities including peripheral neuropathy. In this study, we studied the effect of cumulative bortezomib dose on survival, depth of response, and discontinuation rate in transplant ineligible MM patients. PATIENTS AND METHODS: Data from 70 patients treated with Cyclophsophamide, Bortezomib, and Dexamethasone (CyBorD) in a single Canadian center were grouped according to above vs below median cumulative bortezomib dose and analyzed for progression-free survival (PFS), overall survival (OS), depth of response, and discontinuation rate. RESULTS: There was a trend for lower discontinuation rate (45.7% vs. 68.6%, P = .052) and significantly lower rate of neuropathy-related discontinuation (5.7% vs. 22.9%, P = .035) in patients who received higher than 43.1 mg/m² of bortezomib. The higher-dose group showed a trend for higher rate of complete response (14.3% vs. 5.7%, P = .225) and significantly higher rate of very good partial response or better (77.1% vs. 51.4%, P = .024). There was significantly longer PFS (24.3 vs. 9.1 months, P = .012) and a trend for longer OS (22.4 vs. 61.3 months, P = .061) in the higher-dose group. In landmark analysis after 180 days, PFS (23.5 vs. 24.3 months, P = .941) and OS were similar in both groups. CONCLUSION: Higher cumulative bortezomib dose showed a lower rate of discontinuation, longer survival, and deeper response. Determining risk of treatment intolerance remains important for treatment.

Real-world data on lenalidomide dosing and outcomes in patients newly diagnosed with multiple myeloma: Results from the Canadian Myeloma Research Group Database.

Using the Canadian Myeloma Research Group Database, a retrospective study of 167 newly diagnosed, transplant-ineligible patients with multiple myeloma (MM) that received lenalidomide-dexamethasone as front-line treatment was conducted to understand the impact of lenalidomide dosing. Starting dose modifications were common, 42% of patients started on lenalidomide <25 mg with normal renal function. During treatment course, 35% of patients required further dose reduction. Dose reductions in the first year did not have an impact on progression free survival or overall survival. Further studies need to be conducted to understand the impact of dosing strategies of anti-MM agents in the real world.

Understanding real-world treatment patterns and clinical outcomes in AL amyloidosis patients diagnosed in Canada: A population-based cohort study.

Amyloid light chain (AL) amyloidosis is a rare and chronic bone marrow disorder. Existing claims data can be used to help understand the real-world treatment patterns and outcomes of this patient population. Various population-based administrative databases in Alberta, Canada were queried from 2010 to mid-2019 to identify cases of AL amyloidosis. Baseline patient and disease characteristics, sequencing of pharmacologic therapies, overall survival, and healthcare resource utilization were evaluated. A total of 215 individuals with AL amyloidosis were included. Among patients diagnosed between 2012 and 2019, 149 (85.1%) initiated first-line, 67 (38.3%) initiated second-line, 22 (12.6%) initiated third-line, and 11 (6.3%) initiated fourth-line systemic therapy. In the first-line setting, 99/149 (66.4%) received bortezomib, cyclophosphamide, and dexamethasone (CyBorD) and 21/149 (14.1%) received another bortezomib-based regimen. Survival from time of diagnosis improved over time, with a median overall survival of 25.8 months (95% CI: 9.8, 57.1) for individuals diagnosed in 2010-2011 versus 52.1 months (95% CI: 25.6, NA) for those diagnosed in 2012-2019. Despite this improvement, the proportion of individuals diagnosed in 2012-2019 who survived beyond five-years remained low (5-year survival: 48.4%; 95% CI: 40.9, 57.2) which highlights an unmet need for more efficacious therapies.

Carfilzomib usage patterns and outcomes in patients with relapsed multiple myeloma: A multi-institutional report from the Canadian Myeloma Research Group (CMRG) Database.

Carfilzomib is an active and commonly used treatment in patients with multiple myeloma (MM). Using the Canadian Myeloma Research Group Database, we performed a retrospective observational study of patients treated with carfilzomib for relapse of MM in a real-world setting in Canada between years 2007 and 2020. A total of 445 patients were included in this study: the doublet (Kd/p, n = 218) and triplets (KCd, n = 88; KRd, n = 99; KPd/p, n = 40). One hundred and twenty-two (27%) received carfilzomib-based treatment in line 2, 133 (30%) in line 3, 90 (20%) in line 4, and 100 (23%) in line 5 or higher. Carfilzomib was dosed weekly in 40% of patients and twice weekly in 60%. The overall response rate of the entire cohort was 57.7%, with 33.6% of patients achieving very good partial response or better. Median progression-free survival for the overall cohort was 6.3 months with overall survival 19.7 months. This study provides a benchmark for carfilzomib-based regimens in the real world, demonstrating that these regimens are effective in treating patients with relapsed MM.

Incomplete chimerism following myeloablative and anti-thymocyte globulin-conditioned hematopoietic cell transplantation is a risk factor for relapse and chronic graft-versus-host disease.

BACKGROUND AIMS: The value of routine chimerism determination after myeloablative hematopoietic cell transplantation (HCT) is unclear, particularly in the setting of anti-thymocyte globulin (ATG)-based graft-versus-host disease (GVHD) prophylaxis. METHODS: Blood samples were collected at 3 months post-HCT from 558 patients who received myeloablative conditioning and ATG-based GVHD prophylaxis. Chimerism was assessed using multiplex polymerase chain reaction of short tandem repeats in sorted T cells (CD3+) and leukemia lineage cells (CD13+CD33+ for myeloid malignancies and CD19+ for B-lymphoid malignancies). ATG exposure was determined using a flow cytometry-based assay. The primary outcomes of interest were relapse and chronic GVHD (cGVHD). RESULTS: Incomplete (<95%) T-cell chimerism and leukemia lineage chimerism were present in 17% and 4% of patients, respectively. Patients with incomplete T-cell chimerism had a significantly greater incidence of relapse (36% versus 22%, subhazard ratio [SHR] = 2.03, P = 0.001) and lower incidence of cGVHD (8% versus 25%, SHR = 0.29, P < 0.001) compared with patients with complete chimerism. In multivariate modeling, patients with high post-transplant ATG area under the curve and any cytomegalovirus (CMV) serostatus other than donor/recipient seropositivity (non-D+R+) had an increased likelihood of incomplete T-cell chimerism. Patients with incomplete leukemia lineage chimerism had a significantly greater incidence of relapse (50% versus 23%, SHR = 2.70, P = 0.011) and, surprisingly, a greater incidence of cGVHD (45% versus 20%, SHR = 2.64, P = 0.003). CONCLUSIONS: High post-transplant ATG exposure and non-D+R+ CMV serostatus predispose patients to incomplete T-cell chimerism, which is associated with an increased risk of relapse. The increased risk of cGVHD with incomplete B-cell/myeloid chimerism is a novel finding that suggests an important role for recipient antigen-presenting cells in cGVHD pathogenesis.

Amyloidosis and COVID-19: experience from an amyloid program in Canada.

Severe acute respiratory syndrome coronavirus (SARS-CoV2) and associated COVID-19 infection continue to impact patients globally. Patients with underlying health conditions are at heightened risk of adverse outcomes from COVID-19; however, research involving patients with rare health conditions remains scarce. The amyloidoses are a rare grouping of protein deposition diseases. Light-chain and transthyretin amyloidosis are the most common disease forms, often present with systemic involvement of vital organs including the heart, nerves, kidneys, and GI tracts of affected individuals. The Amyloidosis Program of Calgary examined 152 ATTR patients and 103 AL patients analyzing rates of vaccination, COVID-19 testing, infection outcomes, influence referrals, and excess deaths. Results showed 15 total PCR-confirmed COVID-19 infections in the tested population of amyloid patients, with a higher frequency of infections among patient with AL compared to the ATTR cohort (26.2% vs 5.1%). Four patients (26.6%) required hospital admission for COVID-19 infection, 2 ATTR, and 2 AL patients. Of the confirmed cases, 1 (0.07%) unvaccinated ATTR patient died of a COVID-19 infection. An excess of deaths was found in both the ATTR and AL cohorts when comparing pre-pandemic years 2018 and 2019 to the pandemic years of 2020 and 2021. The finding suggests that amyloidosis patients are likely at a high risk for severe COVID-19 infection and mortality, especially those of advanced age, those on an active treatment with chemotherapy, and those with concomitant B-cell or plasma cell disorder. The impact of virtual healthcare visits and pandemic measures on the excess of deaths observed requires further research.

Real-world treatment patterns for patients with newly diagnosed multiple myeloma in Alberta, Canada.

The purpose of this study is to describe the real-world multiple myeloma (MM) population in Alberta by examining patient/clinical characteristics and the treatment landscape. A retrospective, observational study was conducted using province-wide, administrative health data from Alberta, Canada evaluating newly diagnosed MM (NDMM) patients. Between 1 April 2011 and 31 March 2017, 1377 treated NDMM cases were identified. Of those, 328 (23.8%) received an autologous stem cell transplant (ASCT) within the first year of diagnosis. In the ASCT group, 189 advanced to second-line (57.6%), 103 (32.6%) to third-line and 97 (29.5%) had four or more lines of therapy. In non-ASCT patients, 553 (52.7%) advanced to second-line, 238 (22.7%) to third-line, and 154 (14.7%) had 4 or more lines of therapy. We observed a significant treatment attrition rate in NDMM. Therefore, the use of best therapy upfront and novel strategies aiming to decrease attrition rates in MM is encouraged.