Doxycycline Plus Bortezomib-Containing Regimens for the Treatment of Light-Chain Amyloidosis in the Frontline Setting: Experience from the Amyloidosis Program of Calgary.

Background: Pre-clinical and retrospective data suggest that doxycycline added to treatment regimens has benefit in AL amyloidosis. However, a recent multicenter, open-label, randomized controlled trial in AL amyloidosis patients treated with CyBorD did not demonstrate a progression-free survival (PFS) or cardiac PFS benefit with added doxycycline. Objective: The main objective of this study was to explore the role of doxycycline combined with bortezomib-containing regimens (BCRs) for newly diagnosed AL amyloidosis patients with cardiac involvement and to compare them with a cohort of concurrent patients treated with BCR only. Material and Methods: AL amyloidosis patients, newly diagnosed between January 2012 and March 2022, who were treated with BCR at the Amyloidosis Program of Calgary (APC) were evaluated. Results: Sixty-four concurrent patients were identified. Thirty-nine patients received doxycycline in addition to BCR (BCR-D) for a median of 8 months. The overall response rate was similar among the groups. No significant differences in VGPR/CR, dFLC at 1 month, time to first response, time to best response, or organ responses were noted between the BCR alone and BCR-D groups. Summary and Conclusions: Our retrospective study demonstrated that doxycycline combined with BCR failed to prolong OS, PFS, or cardiac responses compared with BCR alone in patients with cardiac AL amyloidosis.

Tandem Autologous Stem Cell Transplantation Does Not Benefit High-Risk Myeloma Patients in the Maintenance Era: Real-World Results from The Canadian Myeloma Research Group Database.

In patients with multiple myeloma (MM), the presence of high-risk cytogenetic abnormalities is associated with worse disease control and survival. Autologous stem cell transplant (ASCT) does benefit these patients. Tandem transplantation has been explored as a means to deepen responses and further improve survival however, its role remains controversial. This is particularly true in the era of novel agent induction and post-transplant maintenance therapy. The aim of this study was to use the Canadian Myeloma Research Group database and examine a large cohort of real-world patients comparing the outcomes of tandem versus single ASCT specifically in high-risk patients receiving novel agent-based induction and post-transplant maintenance. The data for this study was derived retrospectively from a comprehensive national-level database of Canadian patients with MM. High-risk cytogenetics was defined as presence of del17p, t(4;14), or t(14;16). Those receiving allogeneic transplant were excluded. Tandem transplantation was defined as a second ASCT performed consecutively without interim relapse or progression after first ASCT. Those with relapse or progressive disease within 3 months of completing a first transplant were excluded. We compared response depth, progression-free, and overall survival (OS) based on single or tandem transplantation procedures. The impact of covariates of interest was also assessed. A total of 381 patients with high-risk cytogenetics were identified. A total of 242 received single and 139 patients received tandem transplants. All received post-transplant maintenance. The most common induction regimen for these patients was cyclophosphamide, bortezomib, and steroids (CyBorD, 87%). Forty-one patients (10.8%) required reinduction prior to first ASCT. The best overall responses at any time were 98.3% (90.5% ≥ very good partial response [VGPR]) and 98.6% (89.9% ≥ VGPR) in the single and tandem ASCT groups, respectively. Survival outcomes were similar with the median progression-free survival for single or tandem ASCT of 35.2 and 35.3 months (P = .88) and the median OS were 92.6 and 88.9 months, respectively (P = .72). No statistically significant differences were seen based on type of cytogenetic abnormality or type of maintenance. This was confirmed on multivariate analysis. In the real-world setting, tandem ASCT does not improve outcomes for MM patients with high-risk cytogenetics. This may be driven by the use of effective pre- and post-ASCT therapies. The development of more potent induction and consolidation along with current nearly ubiquitous continuous maintenance therapies until disease progression does not support the use of a second high-dose procedure.

Long-term follow-up of outcomes including progression-free survival 2 in patients with transplant-ineligible multiple myeloma in the real-world practice: A multi-institutional report from the Canadian Myeloma Research Group (CMRG) database.

Multiple myeloma remains an incurable cancer mostly affecting older adults and is characterized by a series of remission inductions and relapses. This study aims to evaluate the outcomes in newly diagnosed transplant-ineligible patients using bortezomib/lenalidomide-based regimens in the Canadian real world as well as their outcomes in the second line. The Canadian Myeloma Research Group Database (CMRG-DB) is a national database with input from multiple Canadian Centres with now up to 8000 patients entered. A total of 1980 transplant ineligible patients were identified in the CMRG-DB between the years of 2007-2021. The four most commonly used induction regimens are bortezomib/melphalan/prednisone (VMP) (23%), cyclophosphamide/bortezomib/dexamethasone (CyBorD) (47%), lenalidomide/dexamethasone (Rd) (24%), and bortezomib/lenalidomide/dexamethasone (VRd) (6%). After a median follow-up of 30.46 months (0.89-168.42), the median progression-free survival (mPFS) and median overall survival (mOS) of each cohort are 23.5, 22.9, 34.0 months, and not reached (NR) and 64.1, 51.1, 61.5 months, and NR respectively. At the time of data cut-off, 1128 patients had gone on to second-line therapy. The mPFS2 based on first-line therapy, VMP, CyBorD, Rd, and VRd is 53.3, 48.4, 62.7 months, and NR respectively. The most common second-line regimens are Rd (47.4%), DRd (12.9%), CyBorD (10.3%), and RVd (8.9%) with a mPFS and a mOS of 17.0, 31.1, 15.4, and 14.0 months and 34.7, NR, 47.6, 33.4 months, respectively. This study represents the real-world outcomes in newly diagnosed transplant-ineligible myeloma patients in Canada. The spectra of therapy presented here reflect the regimens still widely used around the world. While this is sure to change with anti-CD38 monoclonal antibodies now reflecting a new standard of care in frontline therapy, this cohort is reflective of the type of multiple myeloma patient currently experiencing relapse in the real-world setting.

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.

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.

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.

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.

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.

Survival and Outcomes of Newly Diagnosed Multiple Myeloma Patients Stratified by Transplant Status 2007-2018: Retrospective Analysis from the Canadian Myeloma Research Group Database.

BACKGROUND: Considerable progress has been made in therapeutic options for multiple myeloma (MM). Understanding the current landscape of MM treatment options and associated outcomes in the real world is important in providing key insights into clinical and knowledge gaps which could be targeted for further optimization. METHODS: The Canadian Myeloma Research Group Database (CMRG-DB) is a prospectively maintained disease-specific database with >7000 patients. The objective of this study was to describe the trends in the treatment landscape and outcomes including early mortality, time to next treatment, and overall survival (OS) in each line of treatment stratified by autologous stem cell transplant (ASCT) receipt among newly-diagnosed MM patients in Canada between 2007 and 2018. RESULTS: A total of 5154 patients were identified among which 3030 patients (58.8%) received an upfront ASCT and 2124 (41.2%) did not. At diagnosis, the median age was 64 years and 58.6% were males. Bortezomib and lenalidomide were most frequently used (>50%) in first and second-line treatment respectively among both the ASCT and non-ASCT cohort. The median OS was 122.0 months (95% Cl 115.0-135.0 months) and 54.3 months (95% CI 50.8-58.8 months) for the ASCT and non-ASCT cohort respectively with an incremental decrease in OS in each subsequent line of treatment. CONCLUSION: We present the largest study to date in the Canadian landscape showing the characteristics, therapy usage, and outcomes among MM patients. This information will be critical in benchmarking current outcomes and provide key insight into areas of unmet needs and gaps for improvement of MM patients nationally.

Outcomes of daratumumab in the treatment of multiple myeloma: A retrospective cohort study from the Canadian Myeloma Research Group Database.

Daratumumab (dara) has significantly altered the therapeutic landscape of multiple myeloma (MM), especially in the relapsed setting. This study aimed to evaluate the outcomes of dara-containing regimens in the Canadian real-world setting among relapsed and refractory MM available within the national Canadian Myeloma Research Group Database (CMRG-DB). A total of 583 MM patients who received dara-based therapy in second-line or later treatment were included. After a median follow-up of 17.5 months, the median progression-free survival (PFS) and overall survival (OS) for the entire cohort were 13.1 and 32.9 months, respectively. The median PFS and OS were 23.5 and 49.1 months in second-line treatment and decreased to 12.8 and 43.0 months in third-line and 7.0 and 20.5 months in fourth-line treatment respectively. Dara in monotherapy with or without corticosteroids after a median of four prior lines of therapy resulted in a median PFS of 3.9 months and a median OS of 17.1 months. The addition of bortezomib, lenalidomide or pomalidomide to dara resulted in an improved median PFS and OS of 8.3 and 26.2 months; 26.8 and 43.0 months; and 9.7 and 31.4 months respectively. These retrospective data from the CMRG-DB suggest that outcomes are superior when dara is used in combination and in earlier lines of treatment.

Efficacy of Daratumumab-Containing Regimens Among Patients With Multiple Myeloma Progressing on Lenalidomide Maintenance: Retrospective Analysis.

BACKGROUND: Daratumumab, a monoclonal antibody directed against CD38 is a recent class of drugs introduced into the multiple myeloma therapeutic landscape. While clinical trial data have shown a remarkable impact on outcomes, the efficacy of daratumumab combination therapies in specific clinically relevant subgroups including among patients refractory to lenalidomide maintenance remains unknown. METHODS: In this study, retrospective data were reviewed from the Canadian Myeloma Research Group and the German Munster Myeloma databases to identify patients that received daratumumab in combination with pomalidomide (DPd), lenalidomide (DRd), and bortezomib (DVd) in a population that had relapsed on lenalidomide maintenance postautologous stem cell transplant. The primary aim of the study was to look at outcomes of these patients in different daratumumab combinations. RESULTS: A total of 73 patients were identified. The median age of the patients at the time of daratumumab initiation was 60 (38-72) and 64.4% (n = 47) were men. In the selected cohort, 43.8% (n = 32) were treated with DRd, 31.5% (n = 23) with DVd, and 24.7% (n = 18) with DPd regimen. The median progression-free survival (PFS) of the entire cohort was 15.8 months (95% CI, 12.9-37.1 months). The median PFS of the individual regimens was as follows: DPd 18.9 months (95% CI, 13.7-not reached), DRd 21.7 months (95% CI, 11.6-not reached), and DVd 12.9 months (95% CI, 3.1-not reached). CONCLUSIONS: Daratumumab-containing therapies are effective regimens in patients progressing on lenalidomide maintenance. Additional studies are required to decide the optimal regimen post-lenalidomide maintenance.