cBTKis revolutionized CLL/SLL treatment following ibrutinib's approval in 2014. Second-generation cBTKis—acalabrutinib and zanubrutinib—displayed enhanced CVD safety profiles. This research evaluated the real-world treatment patterns and pre-treatment CVD burden in CLL/SLL patients.

Background: POEMS (Polyneuropathy, Organomegaly, Endocrinopathies, Monoclonal protein, Skin changes) syndrome is a rare paraneoplastic syndrome and therapies are directed against plasma cells that produce the proteins that cause this syndrome. Novel therapies are widely used in multiple myeloma aiming for plasma cell eradication. However, data on their use in POEMS syndrome are lacking. Aims: To provide the Mayo Clinic experience in treating 16 patients with relapsed POEMS syndrome with novel agents (daratumumab, carfilzomib, pomalidomide, and elotuzumab). Methods: We identified all POEMS patients seen at Mayo Clinic Rochester, Minnesota using a prospectively maintained database of patients seen at our center between June 1979 and May 2021. Of these patients, we identified all the patients that were treated with a “novel” agent, defined as daratumumab, carfilzomib, pomalidomide or elotuzumab. The primary endpoints were response to therapy (hematological, PET, VEGF and clinical, which will be referred to as responseH, P, V, C, respectively), and time to next therapy (TTNT), defined as time from institution of regimen of interest to next therapy. The secondary outcome was safety. Results: The median age at POEMS diagnosis was 57 years (range 39-79) and 15 patients (93%) were men. Among all patients at diagnosis, 10 (63%) had skin changes, 15 (94%) had signs of extravascular volume overload, and 15 (94%) patients had endocrine disorders. Ten and six patients had IgA and IgG isotypes, respectively, and all the patients had lambda light chain isotype. Radiological evidence for sclerotic lesions were found in 13 (81%) patients. The median time from diagnosis to novel agent’s first dose administration was 50 months (IQR 23-122) and the median lines of therapy prior to novel agent was 2 (range 1-4). Twelve patients (75%) underwent prior autologous stem cell transplantation (ASCT), and 5 patients had prior lenalidomide. The median age at novel agent administration was 63 years (IQR 51-70) and 4 patients (24%) were 70 years or older. The patients were treated with a a doublet including dexamethasone (N=5) (31%) or in various combinations with other agents: DRd (N=6), DC(V)d (N=3), KRd (N=3), KPd (N=1), DP(V)d (N=5), and EloRd (N=1). The outcomes with novel agent therapies were favorable (Table 1). Among patients treated with daratumumab based therapies (N=17), 9 patients achieved CR/VGPRH, 7 patients achieved CRV, and 5 patients achieved CRP. Among patients treated with carfilzomib-based therapies (N=6), 3 patients achieved CR/VGPRH and one achieved PRH. Only one patient treated with carfilzomib-based therapies achieved a clinical response. Neither patient who received pomalidomide and dexamethasone or elotuzumab with lenalidomide and dexamethasone responded. At a median follow-up of 38 months since starting of the novel agent (IQR 24-57), 15 of the patients (94%) are still alive, and the median TTNT was not reached. None of the patients discontinued therapy due to adverse events and no deaths occurred on therapy. Novel therapies were safe with 7 events of hospitalization due to pneumonia (4 in daratumumab-based therapies and 3 on carfilzomib-based therapies), and 4 patients were hospitalized due to volume overload (all received dexamethasone with therapy). Three patients experienced infusion-related reactions (IRR) to the first dose of IV daratumumab. Image:Summary/Conclusion: Response rate was high and the responses were deep. Novel agent therapies were safe, and no death case occurred on therapy. Future studies are needed to clarify the optimal sequence of novel agents and the best combination.

Achievement of a complete response (CR) in multiple myeloma (MM) correlates with improvement in survival outcomes; however, its impact on prognostic variables at baseline outside of clinical trial settings is not well described. We sought to determine the impact of achieving a CR within 2 years from diagnosis, its effect on the prognostic value of fluorescence in situ hybridization (FISH) and International Staging System (ISS) risk, and examined additional predictors of outcome among those achieving a CR in a routine clinical setting. We evaluated 1869 newly diagnosed MM patients who had ≥ 2 monoclonal protein immunofixation studies in the serum and urine available within 24 months from diagnosis, categorizing those with ≥ 2 negative serum and urine immunofixations as achieving CR. With a landmark at 24 months, median progression-free survival (PFS) for CR versus non-CR patients was 29.8 versus 20.9 months ( p ≤ .0002); median overall survival (OS) was 104 versus 70 months ( p < .0001). The impact of achieving a CR was retained after adjusting for FISH, ISS, sex, transplant status, and involved heavy chain. Baseline FISH and ISS stage were not associated with PFS or OS among patients achieving a CR. The following variables were found as predictors of inferior OS within the CR cohort: age > 75 years, male gender, hypoalbuminemia, and non-immunoglobulin G involved heavy chain. Our study confirms that achievement of CR within 2 years from diagnosis is associated with improvement in survival outcomes and neutralization of the impact of FISH and ISS risk, thereby confirming observations from the clinical trial setting among a clinical practice cohort.

Background: Thrombosis is the main life-threatening complication of paroxysmal nocturnal hemoglobinuria (PNH), a rare acquired hematologic disease. Pegcetacoplan (PEG) is a C3 complement-inhibitor approved by the FDA/EMA for treatment of adults with PNH. Aims: This post hoc analysis examined incidence of thrombosis, anti-thrombotic therapy (ATT), and D-dimer normalization in adult patients with PNH treated with PEG in the Phase 3 PEGASUS (NCT03500549) and PRINCE (NCT04085601) studies. Methods: PEGASUS enrolled adult patients with PNH with prior suboptimal response to eculizumab (ECU) despite stable ECU treatment (≥3 months) and hemoglobin (Hb) levels <10.5 g/dL at screening. For the randomized controlled period (RCP), patients were randomized 1:1 to ECU (n=39) or PEG (n=41; 1080 mg subcutaneously [sc] 2x weekly) for 16 weeks. Thereafter, ECU patients were switched to PEG monotherapy and PEG RCP patients remained on PEG during the open-label period (OLP, n=77) through Week 48. PRINCE compared PEG treatment (n=35; 1080 mg sc 2x weekly) in complement-inhibitor-naïve patients to patients receiving control treatment (CTRL; excluding complement-inhibitors i.e., ECU/ravulizumab; n=18). CTRL patients had the option to escape to the PEG group if Hb levels decreased ≥2 g/dL from baseline (n=11). Safety analyses in all trials included monitoring of thrombotic events. D-dimer normalization, defined as D-dimer level less than the upper limit of normal (0.5 µg/mL) was examined at baseline, Week 8, and the end of the study period (PEGASUS: 16 weeks [RCP] and 48 weeks [OLP], PRINCE: 26 weeks). Results: Prior to study entry, 31% (n=25) of PEGASUS patients (6 of these while on ECU therapy) and 9% (n=5) of PRINCE patients experienced at least one type of thrombosis. During the PEGASUS OLP, 2 of 77 patients experienced a thrombotic event, one in the setting of non-Hodgkin’s lymphoma and one during sepsis; neither event was deemed related to PEG. No patients in the PEGASUS RCP or PRINCE trial experienced a thrombotic event. Pooled analysis of completed clinical trials of PEG including PEGASUS and PRINCE indicated there were 2 cases of thrombosis in 164 patients comprising 130 patient-years (1.54 events per 100 patient-years), compared to 1.77 events per 100 patient-years for patients on ECU treatment before entry into PEGASUS. In PEGASUS, 34% (n=27) of patients were on ATT prior to study entry. During the PEGASUS RCP, concomitant ATT was observed in 37% (PEG, n=15) and 33% (ECU, n=13) of patients, and during the PEGASUS-OLP in 23% (n=18) of patients (PEG monotherapy). In PRINCE, concomitant ATT decreased from 21% (n=11) prior to the study to 7% (PEG, n=3) and 0% (CTRL, n=0) during the study. In PEGASUS, D-dimer normalization in the PEG arm increased from 73% (baseline, n=30) to 89% (Week 8, n=33) and was largely sustained at Week 16 and Week 48 (Table 1). D-dimer normalization in the ECU arm increased once ECU patients switched to PEG monotherapy, from 76% (Week 16, n=29) to 89% (Week 48, n=17) (Table 1). In PRINCE, D-dimer normalization in the PEG arm increased from 51% (baseline, n=18) to 67% (Week 8, n=18) and increased further to 68% (n=19) at Week 26 (Table 1). Image:Summary/Conclusion: Overall, these results demonstrate that PEG treatment can increase D-dimer normalization and reduces incidence of thrombotic events in patients with PNH who are complement-inhibitor naïve or remained anemic after ECU treatment, suggesting that PEG treatment is as effective as ECU in these outcomes.

Background: Systemic light chain (AL) amyloidosis is a clonal plasma cell disorder characterized by multiorgan deposition of fibrils composed of misfolded immunoglobulin light chains. Current treatment strategies targeting the plasma cell clone do not result in immediate organ recovery, and thus effective fibril-directed therapies are needed. Doxycycline has been shown to disrupt amyloid fibril formation in preclinical models. In 2012, we reported initial results on the impact of posttransplant prophylaxis with doxycycline using data from 445 AL amyloidosis patients; prophylaxis with doxycycline was associated with improved survival compared to penicillin in those achieving hematologic response. Since then, few studies have evaluated doxycycline use in AL amyloidosis, mainly in combination with induction chemotherapy, with mixed results. We provide here updated results on outcomes of AL amyloidosis patients who received doxycycline prophylaxis post autologous stem cell transplantation (ASCT) in our institution. Aims: To evaluate the impact of doxycycline use for post-ASCT antimicrobial prophylaxis on survival in AL amyloidosis patients. Methods: We included 553 patients who underwent ASCT from July 1996 to June 2014. We excluded patients who died within 100 days of ASCT. Doxycycline 100 mg daily was substituted for penicillin prophylaxis in patients with penicillin allergy; since 2013, doxycycline has become the standard for prophylaxis in AL amyloidosis at our institution. Prophylaxis was typically continued for a year after ASCT. Antibiotic type was determined by review of medical records. The Kaplan-Meier method was used to estimate time to next treatment (TTNT) and overall survival (OS), both measured from the time of transplant; curves were compared using the log-rank test. Results: Median age was 59 and 60% were male. The median time from diagnosis to ASCT was 4 months; 90% had early ASCT (within 1 year of diagnosis) and 57% received upfront ASCT without prior induction. Penicillin was used for prophylaxis in 67% (372 patients); the rest received doxycycline. Hematologic and organ response rates were similar in the 2 groups. Median follow up from ASCT was 10.5 vs. 13.6 years in the doxycycline and penicillin groups, respectively. Among patients with early ASCT, TTNT was 5.5 (95%CI: 4.2-8.1) vs. 5.8 (95%CI: 4.7-6.8) years, respectively (P=0.95). Median OS was 12.0 (95%CI: 11.0-19.6) vs. 11.0 (95%CI: 9.6-12.7) years, respectively (P=0.17); 5- and 10-year OS rates were 81% vs. 75% and 62% vs. 54% in the doxycycline and penicillin groups, respectively. Among patients with day 100 hematologic response, there was a non-statistically significant trend towards improved OS with doxycycline, but no difference in those without hematologic response: median OS with doxycycline vs. penicillin was 21.1 vs. 14.6 years in patients with day 100 dFLC <4 mg/dL (P=0.18) Figure 1a. In patients with normal day 100 FLCr, median OS was NR vs. 12.8 years, respectively (P=0.10) Figure 1b. There was no difference between the 2 groups when OS was stratified by Mayo 2012 stage (1-2 vs 3-4), number of involved organs (1 vs. >1), ASCT period (before or after 2012), or pre-ASCT induction (Yes vs. No). Image:Summary/Conclusion: After 13 years of follow up we observed a trend towards improved OS with doxycycline as post-ASCT prophylaxis in patients who achieve a hematological response. Prospective studies are needed to elucidate whether doxycycline improves outcomes in AL amyloidosis and identify the optimal dose, duration, timing, and the subset of patients likely to benefit.

8024 Background: Minimal residual disease (MRD) is prognostic for survival in multiple myeloma (MM). MRD is usually assessed in the bone marrow (BM) by flow cytometry or NGS. MRD by FDG PET/CT provides a global representation of the tumor burden, including response assessment of extramedullary disease. We examined MRD status in MM pts using both BM and PET/CT at Mayo Clinic. Methods: Medical records were reviewed retrospectively for MM pts who received CAR-T between 4/2018 and 12/2022. All PET/CT scans were assessed by radiologists. BM MRD was assessed by flow cytometry with a sensitivity of 10-5. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier method. Results: Among the 157 CAR-T pts, including 89 pts who received FDA-approved CAR-T, median age was 63 years, 59% (92/157) were males, 42% (66/157) had high risk cytogenetics with median of 5 prior lines of therapy, 36% (57/157) had plasmacytoma. Incidence of CRS was 83%, 5% grade ≥ 3 CRS. Incidence of ICANS was 19%, 4% grade ≥ 3 ICANS. CR/sCR rate was 37%. One hundred and thirty-seven pts (87%) had evaluable BM at month (mo) 1, 85% (117/137) were BM MRDneg at mo 1. Baseline demographics were comparable between the two groups except age, % BM plasma cells and use of bridging therapy. Among the MRDneg pts, CR/sCR rate was 44% (51/117) and 95% (111/117) had sFLC below normal. At median follow-up of 13.8 months, median PFS among pts with BM MRDneg at 1 mo was 12 mo (95% CI: 11, 30) vs 3 mo (95%CI: 2, 7) for BM MRDpos (p<0.001). Median OS among pts with BM MRDneg at 1 mo was 34 mo (95% CI: 24, NR) vs 22 mo (95%CI: 7, NA) for BM MRDpos (p<0.01). At month 1, 112 pts had both BM and PET/CT assessments available, 64/112(57%) were both BM MRDneg/PET MRDneg, 38/112 (34%) were MRDneg for either BM or PET and 10/112 (9%) were positive for both BM and PET (MRDpos/PET MRDpos). Baseline demographics except age were comparable between the 2 groups (Table). Rate of conversion from MRDpos to MRDneg was low. Rate of sustained BM and PET MRDneg at mo 12 was 44% (8/18). The median PFS and OS for BM MRDneg/PET MRDneg was significantly longer as compared to others (Table). Conclusions: Achieving FLC below normal, BM MRDneg and PET MRDneg at 1 month, regardless of IMWG response at that time, is prognostic for both PFS and OS in MM pts receiving CAR-T. Failure to achieve any of these confers poor prognosis. [Table: see text]

Systemic amyloidosis is a rare protein misfolding and deposition disorder leading to progressive organ failure. There are over 15 types of systemic amyloidosis, each caused by a different precursor protein which promotes amyloid formation and tissue deposition. Amyloidosis can be acquired or hereditary and can affect various organs, including the heart, kidneys, liver, nerves, gastrointestinal tract, lungs, muscles, skin and soft tissues. Symptoms are usually insidious and nonspecific resulting in diagnostic delay. The field of amyloidosis has seen significant improvements over the past decade in diagnostic accuracy, prognosis prediction and management. The advent of mass spectrometry-based shotgun proteomics has revolutionized amyloid typing and has led to the discovery of new amyloid types. Accurate typing of the precursor protein is of paramount importance as the type dictates a specific management approach. In this article, we review each type of systemic amyloidosis to provide the practitioner with practical tools to improve diagnosis and management of these rare disorders.

Background:Venetoclax is a B cell lymphoma 2 (BCL‐2) inhibitor that has shown activity as a single agent and in combination with other therapies in patients with multiple myeloma, particularly those harboring t(11;14) associated with high BCL‐2 expression. Although early clinical trial data is encouraging (monotherapy response rate of 21% and 40% amongst t(11;14) and a response rate of 97% when used in combination with bortezomib and dexamethasone), data on outcomes in patients treated outside of clinical trial setting are sparse.Aims:We aimed to identify the efficacy of venetoclax in patients with multiple myeloma treated outside clinical trial.Methods:We conducted a retrospective review of all patients with multiple myeloma treated with venetoclax between December 2016 and February of 2019 at the Mayo Clinic outside of a clinical trial setting.Results:A total of 29 patients that were treated with venetoclax for relapsed or refractory multiple myeloma were identified. Characteristics of the cohort are reported in Table 1. Two thirds of the cohort had t(11;14) detected on cytogenetic studies and 48% (n = 14) had presence of high risk abnormalities. Median number of prior therapies was 6 (range 1–15) and 21% (n = 6) of patients had received ≥10 prior lines of therapy. Eighty three percent (n = 24) of patients had received prior autologous transplant and 76% (n = 22) were penta refractory or exposed. Median time from diagnosis of myeloma to initiation of venetoclax therapy was 5.3 years (range 0.8–23.6 years).Venetoclax used as monotherapy or a doublet in combination with dexamethasone in 59% (n = 17) of patients and a triplet or quadruplet in 41% (n = 12) given at 800 mg (55%) or 400 mg (35%) daily. Triplet and quadruplet regimens combined venetoclax with a variety of proteasome inhibitors or daratumumab. One patient had a quadruplet of venetoclax, carfilzomib, pomalidomide and dexamethasone. 93% (n = 27) patients were refractory to at least on proteasome inhibitor and immunomodulatory drug. Dose titration and escalation was used in 31% (n = 9) of patients. None of the patients experienced tumor lysis syndrome. At last follow‐up 55% (n = 16) of patients remain on venetoclax therapy. Overall response rate in the 24 patients evaluable for response was 46% (21% CR, 8% VGPR, 17% PR). Patients with t(11;14) had a numerically higher response rate than those without (50% vs 33%, p = 0.64). Patients with high risk cytogenetic abnormalities were less likely to respond (ORR 69% for standard risk vs 18% for high risk, p = 0.019). Median time to response was 2.6 months (range 1.1–6.9 months). Median duration of response was 5.2 months (range 2.2–12.9 months). After a median follow‐up time of 7.2 months for the cohort, the median PFS and OS are 5.8 and 14.6 months, respectively, Figure 1A/B. High risk cytogenetic abnormalities were associated with a shorter PFS (median PFS 3 months vs 14 months for standard risk, p = 0.002). The outcomes with venetoclax monotherapy and combination therapies are reported separately in the Table.Summary/Conclusion:Venetoclax is an effective oral agent in relapsed and/or refractory myeloma and can produce deep and durable responses in heavily pretreated patients. Further studies are needed to elucidate its role earlier in the disease and its effectiveness in combination with other anti‐myeloma therapies.image

Longer survival from modern therapies has increased the number of patients with immunoglobulin light-chain (AL) amyloidosis receiving kidney transplantation (KTx). This study evaluates the outcomes of 60 patients with AL amyloidosis who underwent a KTx based on their hematologic response. Outcomes were recorded for death, graft failure, and complications. Hematologic responses prior to KTx were: no response (NR, n=3), partial response (PR, n=5), very good partial response (VGPR, n=6), complete response (CR, n=37), and treatment-naive (n=9). After KTx, with 7 out of 9 of the treatment-naive patients achieving a CR posttransplant. The Median follow-up was 61 months. The estimated median OS from the time of KTx was 123 months for the entire groups. Median OS was not reached for VGPR+CR, 47 months for NR+PR and 117 months for treatment-naive groups (p<0.001). Median OS of VGPR was 81 months while median was not reached in the CR group (p=0.156). The time to amyloid recurrence was longer in CR compared to VGPR (median 181 vs 81 months, p=0.023). Death-censored graft survival at 1-, and 5-years was 98.3%, and 95.8%, for the overall groups. Three (5.0%) patients had allograft failure, 19 (31.7%) died with a functioning graft, and 13 (21.7%) had an amyloid recurrence. Outcomes after kidney transplant in patients with AL amyloidosis seem acceptable if a VGPR or CR is achieved either before or after KTx.

Systemic amyloidosis is a rare protein misfolding and deposition disorder leading to progressive organ failure. There are over 15 types of systemic amyloidosis, each caused by a different precursor protein which promotes amyloid formation and tissue deposition. Amyloidosis can be acquired or hereditary and can affect various organs, including the heart, kidneys, liver, nerves, gastrointestinal tract, lungs, muscles, skin and soft tissues. Symptoms are usually insidious and nonspecific resulting in diagnostic delay. The field of amyloidosis has seen significant improvements over the past decade in diagnostic accuracy, prognosis prediction and management. The advent of mass spectrometry-based shotgun proteomics has revolutionized amyloid typing and has led to the discovery of new amyloid types. Accurate typing of the precursor protein is of paramount importance as the type dictates a specific management approach. In this article, we review each type of systemic amyloidosis to provide the practitioner with practical tools to improve diagnosis and management of these rare disorders.