bluuebunny/crossref_metadata_2025_split huggingface dataset:
Updated OS of patients with AL amyloidosis after CAEL-101.
Authors: Hughes Michael Sang , Pan Samuel M , Chakraborty Rajshekhar , Raikhelkar Jayant , Maurer Mathew , Mapara Markus Y. , Eisenberger Andrew , Lentzsch Suzanne , Bhutani Divaya 
Published: June 2023

8026 Background: Morbidity and mortality remain high in immunoglobulin light chain (AL) amyloidosis due to organ involvement despite hematologic remission. Few anti-amyloid fibril therapies for AL amyloidosis exist. We previously published the results of the phase 1a/1b study of CAEL-101 in AL amyloidosis showing significant improvement in organ response rates.1 We report long-term outcomes. Methods: Patients enrolled in NCT02245867 with relapsed/refractory AL amyloidosis received in phase 1a, a one-time dose-finding CAEL-101 infusion and in phase 1b, 4 weekly CAEL-101 infusions with preplanned dose escalation. Patients were evaluated for organ response for 12 weeks after last infusion. We extracted clinical, laboratory, and pathology data regarding clinical course beyond 12 weeks after last treatment. We performed a review of all AL amyloidosis patients at our center not treated with CAEL-101 1/01/2012-12/30/19 as clinical comparisons. Results: 22 patients were enrolled in CAEL-101. 5 patients were treated in both phase 1a and phase 1b. With median follow-up of 81.3 months (IQR 60.4-87.7), long term follow-up data are available for 19/22 patients. 5 patients died during long term follow-up: 3 from progressive AL amyloidosis; 1 from organ transplantation complication; and 1 from venous thromboembolism sequelae. Among patients with organ data available, 10/17 had hematologic progression and received next line therapy. 5/17 patients had organ progression. All patients with organ PD had previous/concomitant hematologic PD. Median OS was not reached; median organ PFS was 93.3 months (38.9-NR). No delayed adverse events occurred. Comparison with historical control groups revealed trends toward improved OS: HR 0.42 (0.09-1.81 p=0.23) in all comers AL amyloid controls, and HR 0.20 (0.03-1.16 p=0.07) in cardiac controls. Kaplan-Meier analysis and Cox regression were performed. Conclusions: Patients with relapsed/refractory AL amyloidosis who received a low cumulative amount of the novel anti-amyloid CAEL-101 in a phase 1a/1b study had lengthy overall and progression-free survival compared to historical controls. Patterns of organ progression after initial response may reflect intrinsic differences in organ vulnerability. The CAEL101-301 and CAEL101-302 phase 3 clinical trials are underway to confirm these findings. Reference: 1. Edwards CV, Rao N, Bhutani D, et al: Phase 1a/b study of monoclonal antibody CAEL-101 (11-1F4) in patients with AL amyloidosis. Blood 138:2632-2641, 2021. [Table: see text]
Long-term outcomes with isatuximab-carfilzomib-dexamethasone (Isa-Kd) in relapsed multiple myeloma patients with 1q21+ status: Updated results from the phase 3 IKEMA study.
Authors: Facon Thierry , Moreau Philippe , Spicka Ivan , Suzuki Kenshi , Yong Kwee , Mikhael Joseph , Fukao Taro , Bisht Kamlesh , Armstrong Nicole , Macé Sandrine , Risse Marie-Laure , Martin Thomas G. 
Published: June 2023

8029 Background: Gain or amplification of 1q21 (1q21+, ≥3 copies), a chromosomal abnormality frequently observed in multiple myeloma (MM), has a negative impact on prognosis due to its potential involvement in resistance to MM therapy and disease progression. In the prespecified, long-term analysis of the Phase 3 IKEMA trial in relapsed MM patients (pts), treatment with Isa-Kd showed continued, significant improvement in progression-free survival (PFS) vs Kd (HR 0.58; 95.4% CI 0.42–0.79), with meaningful increase in depth of response (complete response or better [≥CR] 44.1% vs 28.5%; minimal residual disease negativity [MRD-] 33.5% vs 15.4%, MRD- ≥CR 26.3% vs 12.2%), and a manageable safety profile. In this subgroup analysis of IKEMA, we evaluated efficacy of Isa-Kd in pts with 1q21+ status (with or without high-risk chromosomal abnormalities [HRCA]) and related subgroups – isolated 1q21+ (≥3 copies without HRCA), gain(1q21), amp(1q21) – at long-term follow-up (44.2 months). Methods: Pts with 1–3 prior lines of therapy were randomized to Isa-Kd (n=179) or Kd (n=123). Assessment was prespecified (at 30% cut-off by FISH) for 1q21+ status as ≥3 copies, gain(1q21) as 3 copies, and amp(1q21) as ≥4 copies. Results: In the Isa-Kd and Kd arms, 41.9% and 42.3% of pts had 1q21+ status, 26.3% and 25.2% isolated 1q21+, 24.0% and 30.1% gain(1q21), 17.9% and 12.2% amp(1q21) respectively. Greater PFS benefit was achieved with Isa-Kd vs Kd in pts with 1q21+ status (HR 0.58, 95% CI 0.37–0.92) and in pts with isolated 1q21+, gain(1q21), or amp(1q21) (Table). Responses deepened by adding Isa to Kd, with increased rates of very good partial response or better (≥VGPR), ≥CR, MRD-, and MRD- ≥CR (Table). Conclusions: 1q21 abnormalities affect PFS in MM pts. Our results at long-term follow-up of pts with 1q21+ status (with or without HRCA) in the IKEMA study continue to show greater PFS benefit and deeper responses with Isa-Kd than Kd, consistent with the overall population and earlier 1q21+ subgroup interim analyses. Thus, they support Isa-Kd as an effective treatment option also for difficult-to-treat, 1q21+ pts with relapsed MM. Clinical trial information: NCT03275285.[Table: see text]
Patient-derived MicroOrganoSpheres (MOS) and precision clinical decision-making for patients with multiple myeloma.
Authors: Xi Rui , Wang Xiaobei , Baro Nicholas , Raman Renuka , Steele Shaun , Helman Elena , Ding Shengli , Kang Yubin , Shen Xiling 
Published: June 2023

8047 Background: There are many multiple myeloma (MM) treatments and nearly all patients undergo continual cycles of treatment, response, and resistance. Selecting an effective therapeutic strategy is of critical importance; but there is currently a lack of patient-derived MM models that can enable functional precision medicine to help real-time clinical decision-making to guide individual patient treatment. Methods: We show a method to rapidly establish MM patient-derived MicroOrganoSheres (MOS), which are microscale, droplet-sized patient avatars that sustain the native tumor niche, including both stromal and immune compartments. We generated first-of-its-kind data showing that MM MOS predicted patient treatment outcomes and have the potential to guide clinical treatment decisions. We further developed high-throughput drug screen to demonstrate MM MOS response to FDA-approved single and combination therapies and developed MOS assays to predict patient responses to immunotherapies including bispecific and phagocytosis-inducing antibodies. Results: MM MOS established from patient bone marrow (BM) biopsies preserved CD138/CD38 tumor cells, stromal (e.g., osteoblast) cells, and all major immune cell populations (T, NK, B, macrophage, dendritic, and myeloid-derived suppressor cells) for 11 days in culture. We performed single and combo drug testing on MOS derived from 7 MM patients within 10 days of biopsy collection. Patients went on receiving treatments and their responses were assessed using International Myeloma Working Group response criteria. The MOS assay predicted responses of both treatment-naïve and refractory patient to standard-of-care regimens, including combinations of proteasome inhibitors (bortezomib, carfilzomib), immunomodulatory agents (lenalidomide) and DCEP. Moreover, the BM biopsy-derived MOS enabled high-throughput drug testing of single agents and combinations in 9-dose titrations, providing clinicians the ability to evaluate alternative treatment options. Furthermore, because MOS retain the immune compartments of the original tumor niche, we were able to evaluate patients’ response to bispecific T cell engagers and developed a phagocytosis assay to measure anti-tumor phagocytosis activity, which showed efficacy in both single-agent and combo settings. Multi-modal profiling and an AI image analysis pipeline provided robust measurements that confirmed the unique phenotypic profile of each patient sample, highlighting the critical unmet need to guide each patient to the optimal treatment. Conclusions: Based on this groundbreaking feasibility study, a subsequent clinical trial of 40 patients is current under IRB review to further validate the clinical power of MM MOS to predict patient outcome and to demonstrate utility as a viable functional precision medicine approach to inform treatment decisions in the clinic.
Outcomes of patients with primary refractory multiple myeloma in the era of triplet and quadruplet induction therapy.
Authors: Charalampous Charalampos , Goel Utkarsh , Kapoor Prashant , Binder Moritz , Buadi Francis , Cook Joselle , Dingli David , Dispenzieri Angela , Gertz Morie A. , Gonsalves Wilson I. , Hayman Suzanne R. , Hobbs Miriam A. , Hwa Yi Lisa , Kourelis Taxiarchis , Lacy Martha , Leung Nelson , Lin Yi , Warsame Rahma M. , Rajkumar S. Vincent , Kumar Shaji 
Published: June 2023

8051 Background: Patients with multiple myeloma (MM) that do not respond to initial therapy have worse outcomes compared to primary responders, and effective treatments are lacking in this population. However, the outcomes of primary refractory disease in the modern treatment era have not been studied. Methods: From 2007-2019, we reviewed MM patients treated with triplet/quadruplet therapy in our institution to assess the incidence of primary refractory disease and the impact of salvage therapies in this population. Primary refractory disease was defined as either progressive disease or stable disease at 4-6 cycles. The Kaplan-Meier estimates were used for survival probabilities. PFS and OS were calculated from MM diagnosis to progression, escalation/change of treatment, or death, respectively. For the primary refractory group, the second PFS and second OS were measured from the start of second-line therapy. The Cox regression model was used for multivariable analysis with the following variables (age, ISS, induction therapy, FISH, and bone marrow plasma cells at diagnosis). Results: We identified 1127 patients, of which 1086 were evaluated for hematologic response after 4-6 cycles. Of these, 93.3% (1013) had evidence of response, while 6.7% (73) had primary refractory disease. With a median OS of 50.7 months, patients with primary refractory disease had an increased risk for shorter survival in univariable and multivariable analysis (HR: 3.6, 95% CI = 2.61 – 4.96, HR = 3.89, 95% CI = 2.68 – 5.65, respectively). In subgroup analysis of primary refractory patients, the median second PFS and second OS from the first relapse were 11.9 months (95% CI: 8.7 – 17.3 months) and 43.4 (95% CI: 31.4– 75.9 months), respectively. Patients that received 2nd line ASCT had increased second PFS (20.9 vs. 8.1 months, respectively, p < 0.01) and second OS (74.7 vs. 31.3 months, respectively, p = 0.02) compared to patients that did not. Patients that took daratumumab as the second line did not have any significant survival differences compared to those who did not, p = NS. Conclusions: We conclude that early progression remains a significant factor for shorter OS in the current era, and salvage ASCT could be the most beneficial option for this population. [Table: see text]
Curability of multiple myeloma (MM) based on relative survival rate (RSR) in patients (pts) treated on earlier total therapy (TT) protocols.
Authors: Al Hadidi Samer , Ababneh Obada Ehab , Schinke Carolina D. , Thanendrarajan Sharmilan , Bailey Clyde , Zangari Maurizio , Tricot Guido , Shaughnessy John D. , Zhan Fenghuang , Sawyer Jeffrey , van Rhee Frits , Barlogie Bart 
Published: June 2023

8059 Background: Long term overall survival (OS) follow-up data in pts with MM treated on clinical trials is limited. TT approach uses all MM-active drugs upfront to target drug-resistant subclones during initial treatment to prevent later relapse. We report the longest follow up of MM trials (TT1 (NCT00580372), TT2 (NCT00083551), TT3a (NCT00081939) and TT3b (NCT00572169)) reported to date with RSRs to assess for curability. Methods: Pts treated on TT1, TT2, TT3a and TT3b were followed at the University of Arkansas for Medical Sciences after completion of therapy including multi-agent chemotherapy, high dose melphalan followed by tandem autologous stem cell transplantation (ASCT) and fixed duration maintenance therapy with introduction of thalidomide (thal) (TT2+thal vs TT2-thal), bortezomib (TT3a) and lenalidomide (TT3b). Expected survival rate was defined as probability of a population surviving from yr to yr. RSR was defined as ratio between observed survival of trials to expected survival in population adjusting for age and sex based on enrollment year. Data cut-off was October 10, 2022. Results: 1379 pts were enrolled (TT1:231, TT2:668, TT3a:303, TT3b:177) with median follow up duration of 16.6 years (yrs) (TT1:25 yrs, TT2:18.4 yrs, TT3a:16.2 yrs, TT3b:14.2 yrs). 10-yr PFS increased from 8.8% (TT1) to 15.5% (TT2-thal) to 25.1% (TT2+thal) to 32.9% (TT3a) to 42.4% (TT3b). Median OS improved over time (TT1:5.8 yrs, TT2:10.4 yrs, TT3a:11.9 yrs, TT3b:10.1 yrs). 15-yrs OS improved from 24.2% in TT1, 33% in TT2, 40% in TT3a and 37% in TT3b. 20-yr OS is 24.4% for pts treated on TT2 protocol. Outcomes were better for standard risk disease defined by low-risk gene expression profiling (GEP) with 20-yrs OS of 30% in TT2 and 15-yrs OS of 45% in TT3a. RSRs approach 1 at 10-15 yrs for TT1, but this occurs earlier, at 5-10 yrs, for TT2+Thal, TT3a and TT3b [Table]. No difference in RSR between TT3a and TT3b was noted. Relative excess risk (RER) showed an estimated 23%, 44% and 54% lower excess mortality when comparing TT2 (+ thal), TT2 (-thal) and TT3a with TT1, respectively. Conclusions: In the longest follow up duration of any MM clinical trial, a subset of MM pts are cured as evidenced by RSRs approaching 1. Approximately one third of pts treated on TT2 protocol and one-half pts treated on TT3a are alive at 20 year and 15 yrs from initial diagnosis, respectively. Incorporation of immunomodulatory drugs and proteasome inhibitors along with tandem ASCT resulted in cumulative improvement of OS as evidenced by lower RER of mortality. Clinical trial information: NCT00580372 , NCT00083551 , NCT00081939 , NCT00572169 . [Table: see text]
T cell exhaustion markers in multiple myeloma patients before and after physical activity intervention.
Authors: Joseph Janine , Hillengass Michaela , Tario Joseph , Attwood Kristopher , Groman Adrienne , Cannioto Rikki A. , Moysich Kirsten B. , Abrams Scott I , Hillengass Jens , Wallace Paul K 
Published: June 2023

8060 Background: There is substantial evidence that the immune system is dysfunctional in multiple myeloma (MM). Adaptive immune cells, such as CD4+ and CD8+ T cells, are ineffective at controlling MM progression, suggesting immunosuppression. Therefore, efforts to overcome immunosuppression are likely key to more effective tumor control. Recent evidence from pre-clinical models suggests that exercise represents a non-pharmaceutical means to reduce immune exhaustion, but few studies have examined the relationship between an exercise intervention and biomarkers of immune exhaustion in cancer patients, especially in MM – the objective of this study. Methods: In this feasibility trial, 24 MM patients participated in a six-month physical activity intervention. The strength training arm (n=12) performed twice weekly supervised resistance trainings. The walking arm (n=12) engaged in an unsupervised, home-based wearable activity tracker intervention. Subjects provided peripheral blood samples before the start and at the conclusion of the intervention. Comprehensive flow cytometry was utilized to assess the frequency of mononuclear cells of interest, including CD4+ and CD8+ T cells and subpopulations expressing the markers of exhaustion PD-1 and/or TIGIT, which are the two exhaustion markers with the highest expression in this study sample. Ratios of exhausted cells (expressing any, one, or both of those markers) to non-exhausted cells (expressing no exhaustion markers) were calculated. Changes in the median values of these ratios were compared using Wilcoxon signed-rank tests. Results: Results from the immune panels are shown for the combined sample (n=24). All ratios of exhausted to non-exhausted cells were lower at the end of the six-month intervention, compared to baseline. The ratio of CD4+ TIGIT+ to non-exhausted CD4+ cells was significantly reduced, from 0.71 to 0.57 (p=0.04). The ratio of CD8+ PD-1+ to non-exhausted CD8+ cells was borderline significantly reduced, from 1.81 to 1.48 (p=0.06). Conclusions: This pilot study suggests that physical activity induces changes in MM patients’ immune systems, potentially rendering a less exhausted T cell state. Larger studies are warranted to examine how exercise alters activation vs exhaustion phenotypes within specific T cell subsets (naïve, central memory, effector memory, regulatory) and to elucidate the effects of strength-based vs aerobic exercise on T cell function. [Table: see text]
Clinical and financial implications of ADUARA trial on a real-world population.
Authors: Muthusamy Bharathi , Zabor Emily Craig , Pennell Nathan A. 
Published: June 2023

8526 Background: In the ADAURA trial, adjuvant (adj) osimertinib improved disease free survival (DFS) in resected, EGFR-mutant ( EGFRm) Stage IB-IIIA NSCLC compared to placebo. Based on these results, the FDA approved osimertinib in the adj setting. In this study, we have evaluated the hypothetical clinical and financial effects of adj osimertinib on the early-stage, EGFRm NSCLC patients at Cleveland Clinic who were treated prior to the FDA approval. Methods: Starting in 2010, Cleveland Clinic has been performing targeted molecular testing in all resected NSCLCs. With this information, we created a database of patients from 01/2010 to 01/2021 with resected, non-squamous NSCLC. The standard of care (SOC) arm of this study consisted of patients with stage IB-IIIA, EGFRm disease from our internal database. Data for the adj osimertinib arm were obtained through a microsimulation study by first generating the per-stage DFS distribution in the SOC arm, and then applying the per-stage hazard ratios from ADAURA to obtain the parameters of the exponential DFS distribution with osimertinib treatment. Outcomes and costs, such as treatment and imaging, were directly calculated for the SOC arm based on the amount of time each patient spent in a recurrence-free or recurrent state, and whether there was CNS involvement at recurrence. Costs and outcomes were averaged across 1000 simulated datasets for the osimertinib arm. Based on ADAURA we assumed that 78.4%, 16.2%, and 5.4% of DFS events were CNS- recurrence, CNS+ recurrence, or death. Results: 1,487 patients were included in the database. 724 of these patients had stage IB-IIIA disease and EGFR testing. 82 patients were EGFRm+ (exon 19 deletion or the L858R mutation), and their survival outcomes were used in the SOC arm. At 5 years, 32 (39%) of the patients were alive and disease free. With the addition of adj osimertinib, an estimated average of 61 (71.4%) of patients would have been disease free and alive. This corresponds to an average improvement in 5-year DFS of 35.4%. The cost of testing all 724 patients would have been $2,865.80 per patient eligible for osimertinib with single-gene EGFR testing or $5,279.11 per eligible patient with targeted NGS testing. The total treatment and healthcare costs with adj osimertinib in the 82 patients would have been $49,057,952.75 or $598,267.72 per patient. With SOC (surveillance +/- adj chemotherapy + osimertinib only upon recurrence), total and per patients costs were $12,297,374.11 and $149,967.98 respectively. This corresponds to an average increase in total costs of $448,299.74 per person with the use of adj osimertinib. Conclusions: Over a decade at Cleveland Clinic, about 5.5% (82/1,487) patients with early stage NSCLC would have been affected by the adj osimertinib approval. In our simulation, we estimated adj osimertinib would have improved 5-year DFS by 35.4% (29 more patients) but with a significant financial cost of about $450,000 per eligible patient.
Phase I/II combination study of tifcemalimab with toripalimab in patients with refractory extensive stage small cell lung cancer (ES-SCLC).
Authors: Cheng Ying , Wang Jie , Yu Yan , Wang Qiming , Yang Runxiang , Lv Dongqing , Xia Bing , Yi Tienan , Li Chong , Wang Xicheng , Zhang Wei , Han Liang , Liu Xiaoqing , Shen Minjie , Xu Jing , Xue Peng , Wang Weihua 
Published: June 2023

8579 Background: The B- and T-lymphocyte attenuator (BTLA) is a novel inhibitory co-signaling receptor expressed on B cell, T cells and NK cells. Co-blockade of the BTLA and PD-1 pathways improved antigen specific anti-tumor T cell response. Tifcemalimab (JS004 or TAB004) is a humanized IgG4 monoclonal antibody with a hinge mutation (S228P) that binds BTLA and blocks its interaction with its ligand HVEM. In previous phase I studies, tifcemalimab has shown preliminary anti-tumor activities as monotherapy or in combination with toripalimab (anti-PD-1) with a manageable safety profile in patients with advanced malignancies. Methods: Eligible ES-SCLC patients refractory to prior therapies were enrolled in this I/II study (NCT05000684). Patients received 200mg tifcemalimab and 240mg toripalimab intravenously once every three weeks until disease progression, intolerable toxicity or 2 years of treatment. Study objectives included safety, anti-tumor activity and correlative biomarkers. Results: As of Jan 31, 2023, a total of 43 ES-SCLC patients refractory to prior therapy were enrolled. The median age was 60.0 (range 38-75) years. The median prior line of therapy was 1 and 14 (32.6%) patients received prior anti-PD-1/L1 treatment. By the cut-off date, the median follow-up duration was 12.1 weeks. Thirty-two (74.4%) patients experienced treatment-emergent adverse events (TEAEs); 12 (27.9%) patients experienced grade ≥ 3 TEAEs. The most common TEAEs were hyponatraemia (16.3%), alanine aminotransferase increased (14%), aspartate aminotransferase increased (14%), and blood creatine phosphokinase increased (14%). Three (7.0%) patients experienced treatment-related adverse events (TRAEs) led to interruption of study drugs and no TRAEs led to discontinuation of study drugs were reported. Fifteen (34.9%) patients experienced immune related AE (irAEs), and 2 (4.7%) patients experienced grade ≥ 3 irAEs. Among 38 efficacy evaluable patients, the ORR was 26.3% and the DCR was 57.9%. The ORR was 8.3% in immunotherapy treated patients and 40.0% in immunotherapy naïve patients. By the cut-off date, 70.0% of the responses were ongoing and the median duration of response was not reached. Tumor expression of HVEM and PD-L1 was evaluated to explore the correlation with clinical response. Conclusions: Tifcemalimab in combination with toripalimab were well tolerated in patients with refractory ES- SCLC. Further clinical evaluation of this combination treatment in SCLC is warranted. Clinical trial information: NCT05000684 .