bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term remission and survival in patients with relapsed or refractory multiple myeloma after treatment of LCAR-B38M CAR-T: At least 5-year follow-up in LEGEND-2.
Authors: Mi Jian-Qing , Zhao Wan-Hong , Chen Li-Juan , Fu Wei-Jun , Wang Bai-Yan , Xu Jie , Liu Jie , Jin Shi-Wei , Zhu Han , Du Juan , Jiang Hua , Sun Huabin , Jia Yehui , Fan Xiao-Hu , Li Jian-Yong , Hou Jian , Chen Zhu , Zhang Wang-Gang , He Ai-Li , Chen Sai-Juan
Published: June 2023

8010

Background: LCAR-B38M CAR-T cells express a structurally differentiated CAR construct containing a 4-1BB costimulatory domain and 2 BCMA-targeting single-domain antibodies designed to confer avidity. LEGEND-2 was a first-in-human phase 1 study of LCAR-B38M conducted in China, which showed encouraging efficacy and manageable safety in 74 patients (pts) with RRMM. The US phase 1b/2 CARTITUDE-1 and Chinese phase 2 CARTIFAN-1 trials of ciltacabtagene autoleucel, which expresses the same CAR as LCAR-B38M, confirmed the efficacy observed in LEGEND-2. Here, we present ≥5-y FU data from LEGEND-2, the longest FU for any BCMA-targeted CAR-T cell therapy study. Methods: Study design was previously published. Pts underwent lymphodepletion with cyclophosphamide (cy) 300 mg/m2 (n=66) or cy 250 mg/m2 plus fludarabine 25 mg/m2 (n=8) prior to receiving LCAR-B38M at a median dose of 0.51 × 106 (range, 0.07-2.10 × 106) CAR-positive T cells/kg in a single (n=9) or 3 split (n=65) infusions. Results: Pts were enrolled from 30 Mar 2016 to 26 Nov 2017. As of 30 Nov 2022, median FU was 65.4 mo (range, 0.4-78.8). 74 pts had received LCAR-B38M (median age, 54.5 y; 60.8% male; median [range] 3 [1-9] prior lines of therapy [LOT]; 44.6% ISS stage I; 28.4% ISS stage III; 29.7% with extramedullary disease [EMD]; 35.7% cytogenetic high risk). No new CAR-T cell-related toxicities were reported in the analysis. ORR (87.8%), CR rate (73.0%), MRD-negative CR rate (67.6%), median DOR (23 mo), and median PFS (18 mo) were mature and the same as previously reported; median OS was previously not reached. At 65.4-mo median FU, median OS was 55.8 mo, with 33 (44.6%) pts alive and 13 (17.6%) still disease-free. Compared with pts with progressive disease (PD) or who died, pts without PD were more likely to have baseline ECOG performance status (PS) 0, IgG type MM, ISS stage I MM, numerically shorter time from diagnosis, fewer prior LOT, no light chain MM, and no EMD (Table). Conclusions: At ≥5-y FU in LEGEND-2, median OS was 55.8 mo and 18% of pts with RRMM were disease-free, raising the possibility of a cure in this heavily pretreated pt population. Our data suggest that pts who are less heavily pretreated or have good functional status may experience greater benefit, potentially being cured, from LCAR-B38M CAR-T cell therapy. Clinical trial information: NCT03090659 . [Table: see text]
Impact of bridging therapy (BT) on outcome of relapsed refractory multiple myeloma (RRMM) with Ide-cel CAR T-cell therapy: Real-world experience from the US myeloma CAR T consortium.
Authors: Afrough Aimaz , Hashmi Hamza , Hansen Doris K. , Sidana Surbhi , Ahn Chul , Dima Danai , Freeman Ciara L. , Castaneda Puglianini Omar Alexis , Kocoglu Mehmet H. , Atrash Shebli , Voorhees Peter M. , Shune Leyla , Simmons Gary , Sborov Douglas W. , Ferreri Christopher J. , Wagner Charlotte Burton , Patel Krina K. , Khouri Jack , Anderson, Jr Larry D. , Lin Yi
Published: June 2023

8013

Background: Ide-cel is an FDA-approved treatment for RRMM patients (pts). However, there is limited data on how BT for disease control during its manufacturing process affects clinical outcomes. Methods: Eleven US academic centers contributed data to this analysis without involvement from the manufacturer. By 5/1/2022, 235 pts had undergone leukapheresis, with 214 infused with a median follow up of 9 months (mos). BT was given between leukapheresis and CAR-T infusion. Results: In this analysis, 79% of pts (n = 170) received BT, which included alkylator-based in 35.5%, steroid and/or IMiD/Ab combos (IMiD combos) in 14%, PI combinations (PI combos) in 12%, and selinexor in 10%. BT recipients had higher ECOG PS 2-4, R-ISS 2-3, ferritin, and CRP before lymphodepleting (LD) chemo, however, no difference among BT subgroups. No difference in prior lines of therapy or penta-refractory between BT and No BT (NBT) groups or BT subgroups. Median cycle of the BT was 1 (1-7), with overall response rate (ORR) of 12%, with no difference among BT subgroups. Incidence and severity of CRS and ICANs were comparable in BT and NBT. However, pts who received BT had a longer median hospital stay compared to NBT, particularly in the alkylator/selinexor subgroups. There were no significant difference in cytopenias at day 90 post CAR-T between the BT and NBT or BT subgroups. For the 73% (n = 157) evaluable for day 90 response, there was no difference in the complete or ORR between the BT and NBT groups (41% vs. 52%; p = .2 and 84% vs. 87.5%, p = .8, respectively). Median PFS was worse at 8.1 mos in BT vs 11.5 mos in NBT (p = .03). Among BT subgroups, PFS was the longest with IMiD combos with median PFS not reached (NR), comparable to NBT, and was significantly longer than all other BT subgroups (p = 0.01). The median OS was 13.8 mos with BT and NR in NBT (p = .002). In BT subgroup analysis, alkylators had a shorter OS, although, this was not significant (p = .06). There was no significant difference in PFS and OS in relationship to response to BT (p = .6 and p = .9, respectively). Conclusions: Pts without BT had longer PFS and OS post ide-cel, likely reflective of less aggressive disease. Those who received BT with steroid/IMiD and Ab combos had similar PFS as NBT. However, BT choice is complicated by disease severity and should be evaluated per patient circumstances. [Table: see text]
A phase 1 study of belantamab mafodotin in combination with standard of care in newly diagnosed multiple myeloma: An interim analysis of DREAMM-9.
Authors: Usmani Saad Zafar , Mielnik Michał , Byun Ja Min , Alonso Aránzazu Alonso , Abdallah Al-Ola A. , Garg Mamta , Quach Hang , Min Chang-Ki , Janowski Wojciech , Ocio Enrique M. , Weisel Katja , Oriol Albert , Sandhu Irwindeep , Rodríguez-Otero Paula , Ramasamy Karthik , Egger Jacqueline L. , Williams Danae , Ma Jie , Kaisermann Morrys C. , Hus Marek
Published: June 2023

8018

Background: Belantamab mafodotin (belamaf) is a B-cell maturation antigen-binding antibody-drug conjugate that eliminates myeloma cells via direct cell killing and anti-myeloma immune responses. DREAMM-9 (NCT04091126) is an ongoing Phase 1, randomized, dose and schedule evaluation study. It aims to evaluate belamaf plus bortezomib, lenalidomide, and dexamethasone (VRd) in adult patients (pts) with transplant-ineligible (TI) newly diagnosed MM (NDMM) and to establish the recommended dose for future development of belamaf combination therapies in the 1st-line setting. Herein, we report updated interim-analysis data. Methods: Belamaf dose cohorts (Co1–7) are shown in the Table. VRd was given every 3 weeks (Q3W) until cycle 8, and Rd Q4W thereafter. Following safety data from Co2–5, Co6–7 were opened in parallel (randomized 1:1) and have shorter follow-up (Table). Safety was the primary endpoint; efficacy and tolerability were secondary endpoints. Minimal residual disease (MRD) was assessed by next-generation sequencing (10-5). Results: As of data cutoff (Oct 20, 2022), 93 pts were treated across Co1–7. Median age (range) was 73 (51–88) years, 55% of pts were male, and 84% were white. The most commonly reported non-ocular adverse events (AEs) across all Co were thrombocytopenia (46%), constipation (36%), diarrhea (34%), and peripheral sensory neuropathy (31%). Overall, belamaf-related Grade ≥3 AEs occurred in 35% of pts and led to belamaf dose reductions in 7% and dose delays in 63% of all treated patients. Grade ≥3 ocular AEs (keratopathy and visual acuity [KVA] scale) occurred in 53% of all pts and led to dose reductions in 12% and dose delays in 52% of overall pts. Fatal AEs occurred in 7 pts, all unrelated to study treatment. Efficacy results and ocular AEs are summarized in the Table: 100% of pts responded in Co1 (1.9 mg/kg Q3/4W) and Co3 (1.9 mg/kg Q6/8W). Median time to very good partial response or better (≥VGPR) ranged from 2.1 to 3.1 months (mo) across cohorts. Highest MRD negativity (MRD[-]) rates (≥VGPR) were seen in Co1 (83%) and Co3 (67%). Conclusions: This updated interim analysis demonstrates that belamaf plus VRd has no new safety signals and provides early and deep anti-myeloma responses in pts with TI NDMM, with high MRD[-] rates. Clinical trial information: NCT04091126 . [Table: see text]
Busulfan, melphalan, and carfilzomib (BuMelCar) conditioning for autologous stem cell transplant (ASCT) in multiple myeloma: Phase I/II data.
Authors: Norton Joseph Allan , Hagen Patrick , Tsai Stephanie , Smith Scott E. , Lee Mary , Campo Loredana , Oldenburg David , Stiff Patrick J.
Published: June 2023

8021

Background: Melphalan-200 high dose chemotherapy for ASCT has been the standard of care for multiple myeloma (MM) for over 30 years. Newer combination regimens such as Busulfan and Melphalan (BuMel) have demonstrated improved progression free survival (PFS) but with increased transplant related morbidity including mucositis and infections. Our group previously demonstrated that adding a proteasome inhibitor (bortezomib) to BuMel further increased PFS with mucositis ameliorated by Palifermin. Building on this effectiveness, we added carfilzomib to the BuMel backbone in a Phase I/II manner focused on safety and initial effectiveness of this novel regimen. Methods: This phase I/II open-label dose-escalation/expansion study (NCT03795597) enrolled patients with relapsed or high risk first remission MM. Patients received Busulfan over 4 days at a target total AUC of 20,000 mM-min followed by melphalan at 140mg/m2. Patients received 4 total doses of IV carfilzomib, 2 before melphalan and 2 after, with the final 2 doses escalated based on toxicity. Palifermin was given on days -11,-10, 0, and +1. Once MTD was determined, 10 more patients were treated at that level. Primary objective was safety and secondary outcomes were response to treatment at day 100 including MRD, engraftment kinetics, PFS, and OS. Results: Patients were predominantly male (79%) with median age 60.95 years. Median KPS was 80 and median HCT-CI was 2. The carfilzomib MTD was 36 mg/m2. One SAE of grade V ischemic colitis was seen at the 45 mg/m2 dose level. Toxicity at 36 mg/m2 yielded a similar pattern to our prior bortezemib containing regimen with grade 1 NSVT in 2 patients and hypertension in another. With a median follow up of 22 months, only 1 of the 13 MTD patients has progressed at 33mo. 2-year PFS and OS are both 100%. Analysis at D+100 showed 69% of MTD patients were MRD negative regardless of genetics. Conclusions: This novel BuMelCar ASCT regimen is safe and tolerable and appears to lead to a high % of MRD negative disease at D+100, which other studies correlate to a high PFS at 2 years. A comparison study with mel 200 is warranted to test whether BuMelCar can improve transplant outcomes especially in high-risk patients. Clinical trial information: NCT03795597 . [Table: see text]
Treatment patterns for extramedullary multiple myeloma and outcomes with CAR-T therapy and bispecific antibodies.
Authors: Zanwar Saurabh , Ho Matthew , Kapoor Prashant , Binder Moritz , Buadi Francis , Dispenzieri Angela , Dingli David , Fonder Amie L. , Gertz Morie A. , Gonsalves Wilson I. , Hayman Suzanne R. , Hwa Yi Lisa , Hobbs Miriam A. , Kourelis Taxiarchis , Lacy Martha , Leung Nelson , Muchtar Eli , Warsame Rahma M. , Rajkumar S. Vincent , Kumar Shaji
Published: June 2023

8022

Background: Extramedullary Multiple Myeloma (EMM) is an aggressive entity with a dismal prognosis. Immune effector therapies (IETs), including chimeric antigen receptor T-cell (CAR-T) therapies and bispecific T-cell engaging antibodies (BsAb), have demonstrated excellent efficacy in relapsed/refractory MM with limited data for efficacy in EMM. Here, we report the treatment outcomes for patients with EMM. Methods: We identified 299 patients with EMM diagnosed between 01/01/2000 and 12/31/2021 after excluding solitary plasmacytomas, paraskeletal MM and primary plasma cell leukemia. The IMWG criteria were used for response definition. Results: Of the 299 patients, 204 (68%) patients had secondary EMM (sEMM) and 95 (32%) patients had primary EMM (pEMM). For sEMM (n=204), the median progression free survival (PFS) with initial therapy was 2.9 (95% CI: 2.4-3.2) months. Initial treatment strategies for sEMM were heterogenous and demonstrated in the table; 44% patients achieved ≥partial response (PR) with initial treatment for sEMM. The median PFS in patients with ≥PR was 5.8 (95%CI: 4.5-6.9) months vs 1.8 (95%CI: 1.4-2; p <0.0001) months for <PR. For patients with pEMM (n=95), the median PFS was 12.9 (95% CI: 6.7-18) months; the median PFS was 17.4 (95%CI: 12.9-25.4) months for patients with ≥PR versus 1 month (95%CI: 0.8-2) in patients with <PR. Thirty patients (all sEMM and triple class refractory) were treated with IET after development of EMM: 18 with BCMA-directed CAR-T, 10 with BsAbs, and 2 with both CAR-T and BsAbs. In patients receiving CAR-T therapy, 75% (15/20) achieved ≥PR with 40% (n=8) achieving MRD negative (by flowcytometry) complete response. Fifteen (75%) patients receiving CAR-T had progressive disease (PD); 7 with systemic and EMM PD and 4 patients each with isolated EMM or systemic PD. The median PFS for patients treated with CAR-T was 4.9 months [3.1- not reached (NR)]. Among patients achieving a ≥PR with CAR-T, the median PFS was 5.8 (95%CI: 4.7-NR) months vs 1.4 months [(95%CI: 0.8-NR), p<0.001] for <PR. Among patients treated with BsAbs (10-BCMA, 1 each against FcRH5 and GPRC5D), 33% (4/12) achieved a ≥PR. Ten (83%) patients had PD on BsAb; 8 with both EMM and systemic PD and 1 patient each with isolated EMM or PD. The median PFS with BsAb was 2.9 months (95%CI: 2.2-NR). Conclusions: Patients with EMM continue to have dismal outcomes with conventional therapies. High response rates were noted with CAR-T therapy, but these tend to be short-lived. [Table: see text]
Durability of responses with biweekly dosing of teclistamab in patients with relapsed/refractory multiple myeloma achieving a clinical response in the majesTEC-1 study.
Authors: Usmani Saad Zafar , Karlin Lionel , Benboubker Lotfi , Nahi Hareth , San-Miguel Jesús , Trancucci Danielle , Qi Keqin , Stephenson Tara , Perales-Puchalt Alfredo , Chastain Katherine , Chari Ajai
Published: June 2023

8034

Background: Teclistamab is the first B-cell maturation antigen (BCMA) bispecific antibody approved for the treatment of relapsed/refractory multiple myeloma (RRMM) at a dose of 1.5 mg/kg weekly (QW) given subcutaneously. A less frequent dosing schedule offers added convenience and flexibility to patients, physicians, and caregivers. We evaluated the ability of patients to maintain their responses after transitioning from QW to every other week (Q2W) dosing schedules in the pivotal phase 1/2 MajesTEC-1 trial (NCT03145181/NCT04557098). Methods: Eligible patients had RRMM and received ≥3 prior lines of therapy including a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. Prior BCMA-targeted therapy was not allowed in this cohort. Patients received the recommended phase 2 dose (RP2D) of 1.5 mg/kg teclistamab QW, with the option to switch to Q2W dosing if patients achieved a confirmed partial response or better after ≥4 cycles of treatment (phase 1) or a confirmed complete response (CR) or better for ≥6 months (phase 2). Response was assessed per IMWG 2016 criteria. Results: As of Dec 9, 2022, 165 patients in the pivotal cohort had received teclistamab at the RP2D. Of 104 responders, 60 patients switched to Q2W dosing; 50 met the protocol-defined criteria for switching, and 10 switched who did not meet the criteria (4 due to adverse events [AEs]; 6 due to other reasons). Patients who switched had a median age of 64 years, 58% were male, 25% had high-risk cytogenetics, 7% had extramedullary plasmacytomas, and 3% had International Staging System stage III disease at baseline. Patients received a median of 4 prior lines of therapy, and 75% were triple-class refractory. At the time of switch, 49 (82%) patients achieved ≥CR, and 11 (18%) had a very good partial response. Median time to switch from QW to Q2W dosing was 11.1 months (range, 3–20). At median 11.1-month (range, 2–24) follow-up since switching, the median duration of response from the date of switch was 20.5 months (range, 1–23), with 40/60 patients still in response and ongoing treatment. Of the remaining patients, 13/60 have progressed (median time from switch to progression not estimable), 2 discontinued due to AEs, 1 discontinued for other reason, and 4 died. Additional results will be presented. Conclusions: Overall, patients from the MajesTEC-1 study who transitioned from QW to less frequent Q2W dosing of teclistamab had sustained remission, with a median duration of response of 20.5 months from the date of switch. Clinical trial information: NCT03145181 , NCT04557098 .
Adjusted indirect treatment comparison of progression-free survival (PFS) associated with DRd and VRd based on MAIA and SWOG S0777 individual patient-level data.
Authors: Durie Brian G. , Kumar Shaji , Ammann Eric M. , Fu Alex Z. , Kaila Shuchita , Lam Annette , Usmani Saad Zafar , Facon Thierry
Published: June 2023

8037

Background: Both daratumumab in combination with lenalidomide and dexamethasone (DRd) and bortezomib in combination with lenalidomide and dexamethasone (VRd) are endorsed by NCCN guidelines as preferred regimens for the treatment of transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM). DRd and VRd have each demonstrated superior efficacy relative to lenalidomide and dexamethasone (Rd) alone in the MAIA and SWOG S0777 trials, respectively, but have not been compared directly in a head-to-head trial. Naive comparisons of efficacy across the 2 trials may be biased because MAIA enrolled only TIE patients (median age 73 years), whereas S0777 enrolled a mixed transplant-not-intended (TNI) population, which included both TIE patients and patients choosing to defer/refuse frontline stem cell transplantation (median age 63 years). Methods: The present study leveraged individual patient-level data (IPD) from both trials to perform an anchored indirect treatment comparison of DRd vs VRd, adjusting for differences in trial eligibility criteria and baseline patient characteristics. Harmonized inclusion criteria (NDMM, age ≥65 years, ECOG performance status ≤2) were applied to both trial populations. Age ≥65 years served as a proxy for TIE status since S0777 enrolled a mixed TNI population. Propensity score (PS) reweighting was used to balance the 2 trial populations on key baseline prognostic factors including age, sex, ISS stage, ECOG performance status, hemoglobin, eGFR, lactate dehydrogenase (LDH) level, and cytogenetic risk. Missing data were addressed with multiple imputation. After alignment of inclusion criteria and PS reweighting, an anchored indirect comparison was performed wherein within-trial progression-free survival (PFS) hazard ratios (HRs) for DRd vs Rd and VRd vs Rd were estimated and used to make indirect inference about PFS for DRd vs VRd. Results: 727 MAIA participants and 198 S0777 participants were eligible for inclusion. After PS reweighting, the trial populations were balanced on the key baseline prognostic factors identified above (standardized difference < 0.1 for each). The adjusted PFS HRs were 0.53 (95% CI: 0.41–0.68; P< 0.0001) for DRd vs Rd in MAIA and 0.88 (0.63–1.23; P= 0.46) for VRd vs Rd in S0777. In the adjusted Rd-anchored indirect comparison, the PFS HR for DRd vs VRd was 0.60 (0.39–0.90; P= 0.02). Conclusions: In this adjusted indirect treatment comparison based on IPD from the MAIA and S0777 trials, PFS was significantly longer for DRd relative to VRd. In the absence of a head-to-head trial comparing DRd and VRd, the present study may help to inform treatment selection in TIE patients with NDMM.
Results from a first-in-human phase I study of F182112, a B-cell maturation antigen (BCMA)-CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma.
Authors: Sun Mingyuan , Qiu Lugui , Wei Yongqiang , Jin Jie , Li Xin , Liu Xue , Yin Shaohong , Qi Junyuan
Published: June 2023

8038

Background: F182112 is a BCMA x CD3 bispecific antibody that redirects CD3+ T cells to mediate T-cell activation and subsequent lysis of BCMA-expressing myeloma cells.NTP-F182112-001 is a First-in-human, Open-label, Multiple center Phase 1 Dose-Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetic, Immunogenicity, and Preliminary Efficacy of F182112 in Patients with Relapsed or Refractory Multiple Myeloma. Clinical trial information: NCT04984434. Methods: Eligible patients aged ≥ 18 years had received at least 2 prior multiple myeloma treatment regimens (not including autologous stem cell transplant) including a proteasome inhibitor, an immunomodulatory agent. Three dose cohorts (0.01, 0.1, and 0.3μg/kg) were planned for accelerated titration phase and the following dose cohorts (3, 10,20, and 30 μg/kg) were planed for the i3+3 dose escalation phase. F182112 were administered as QW or Q2W IV infusion. The primary endpoint was safety and tolerability assessed throughout the study by monitoring AEs per the CTCAE 5.0, except CRS per ASTCT 2018. Results: As of Feb 2,2023, 16 pts in the first 7 cohorts received F182112 (0.01-20 μg/kg). Median follow-up was 3.1 mo (range 0.9–11.7; median age 64 y [range 52–74]; 68% female). 9 (56%) pts had received ≥4 prior lines of therapy and 12 (75%) pts were refractory to last lines of therapy. The ORR was 43.8% (95% CI 19.8-70.1) among all enrolled patients (7/16). Of the 9 pts treated with ≥ 10 μg/kg F182112, 6 pts achieved a partial response (PR) or better (overall response rate; 66.7%), including 2 (22.2%) with a very good partial response or better.The most common treatment-related AEs were CRS (81%), lymphopenia (75%; grade 3/4: 69%), neutropenia (63%; grade 3/4: 44%), leukopenia (56%; grade 3/4: 50%), and anemia (31%). CRS and anemia events were all grade 1–2 and median duration time to CRS was 2 days (1-5). One dose-limiting toxicities (transient ALT elevation, grade 3) occurred at the dose group of 10 μg/kg. No pts required a F182112 dose reduction due to AEs. Conclusions: F182112 provides a novel immunotherapy approach for the treatment of Relapsed/ Refractory Multiple Myeloma that may yield improved clinical efficacy in heavily pretreated pts. Clinical trial information: NCT04984434.
Identification of cytokines associated with response and cytokine release syndrome: Analysis of MagnetisMM-3 cohort A.
Authors: Quach Hang , Bahlis Nizar J. , Rodríguez-Otero Paula , Viqueira Andrea , Wang Shen-Wu , Sathaiah Sangeetha , Robinson Douglas M , O'Brien Thomas , Weisel Katja
Published: June 2023

8044

Background: MagnetisMM-3 (NCT04649359) is a phase 2 study of elranatamab monotherapy in patients with multiple myeloma refractory to at least 1 proteasome inhibitor, 1 immunomodulatory drug, and 1 anti-CD38 antibody. Promising efficacy and safety have been observed in patients who were naïve to B-cell maturation antigen (BCMA)-directed therapy (Cohort A) in MagnetisMM-3 (Bahlis et al., ASH 2022). Methods: In MagnetisMM-3, patients received subcutaneous elranatamab in 28-day cycles with step-up doses of 12 mg on C1D1 and 32 mg on C1D4 followed by 76 mg QW beginning C1D8. Serum samples were collected on C1D1 prior to first priming dose, and on C1D2, pre-dose C1D4, C1D5, pre-dose C1D8, C1D15, and C1D22. Levels of 45 peripheral cytokines were analyzed by proximity extension assay and a longitudinal mixed effects model was applied to each cytokine separately. Cytokines with a significant 2-fold differential expression (responders [defined as patients with best overall response of very good partial response or better] vs non-responders [defined as patients with best overall response of partial response or worse]; cytokine release syndrome [CRS] vs no CRS) at any timepoint are reported. Clinical data cutoff was in Oct 2022 with median follow up of 10.4 months. Results: Baseline levels of IL-6 (2.6-fold), IL-17C (2.0-fold), and MIP-1α (2.1-fold) were lower in patients who achieved a response. After the first priming dose, 13 cytokines in the panel, including CCL8, IFN-γ, IL-2, and IL-27, were differentially expressed in responders vs non-responders. At baseline, no cytokines were found to predict CRS. After the first priming dose, 18 cytokines in the panel, including CCL8, IFN-γ, IL-10, IL-2, IL-27, IL-6, and IL-17A, were differentially expressed in patients with CRS vs no CRS. The maximal differential expression for 17/18 cytokines occurred at C1D2, ~24 hours post the first priming dose. Conclusions: Lower baseline levels of IL-6, IL-17C, and MIP-1α correlated with a response of VGPR or better in BCMA-naïve patients from MagnetisMM-3, suggesting that lower levels of these cytokines might reflect a favorable immune environment. Many cytokines were differentially expressed at higher levels in patients who experienced CRS vs those who did not; the most prominent cytokines included CCL-8, IFN-γ, and IL-10. The timing of induction of CCL-8, IFN-γ, and IL-10 occurred by C1D2 suggesting a potential contribution of these cytokines in driving CRS. Clinical trial information: NCT04649359 .
Three-dimensional telomere profiling to predict risk of progression in smoldering multiple myeloma.
Authors: Kumar Shaji , Rajkumar S. Vincent , Jevremovic Dragan , Kyle Robert A. , Mai Sabine , Louis Sherif
Published: June 2023

8056

Background: Multiple myeloma (MM) is preceded by monoclonal gammopathy of undetermined significance (MGUS). A transitional stage of smoldering multiple myeloma (SMM) can be identified between MGUS and MM. While MGUS carries a steady risk of progression of 1% per year, SMM is more heterogenous with nearly 40% of patients progressing in the first 5 years, 15% in the next 5 years, reaching the same low risk as MGUS after 10 years. SMM with its high risk of progression in the initial years after diagnosis presents a viable opportunity for early intervention. For implementing early intervention, the ability to identify SMM patients at the highest risk of progression is critical. This has led to the development of several risk stratification systems. Using these systems high risk SMM patients studied in phase 3 trials demonstrated delayed progression to MM and improved overall survival with early initiation of therapy. However, these approaches showed limited specificity exposing patients at lower risk of progression to therapy. To date, identifying high risk SMM patients and confirming disease stability in low risk SMM patients remain an important clinical need. Genomic instability has been shown to be a sensitive indicator of disease progression in cancer. Telomere dysfunction is an early event in genomic instability. The 3-dimensional spatial profiling of telomeres using TeloView technology allows for quantification of telomere dysfunction, and was shown to be instrumental in risk stratification of cancer patients generally, but particularly in selected hematological malignancies. Importantly, in a previous SMM proof-of-concept study telomeric parameters measured by TeloView technology was found to be significantly different between SMM patients who progressed to active MM within 2 years and those who remained stable for over 5 years. Methods: We analyzed a total of 162 SMM patients using TeloView technology. 88 patients were employed as training dataset in Receiver Operating Curve (ROC) modeling to develop a scoring model that stratifies individual SMM patients based on risk of progression to full stage MM. An additional cohort of 74 SMM patients was used for blind validation of the developed scoring model. Results: We report area-under-the-curve (AUC) in the ROC analysis of 0.8 (accuracy 80%) achieved by the scoring model developed using the training dataset. Furthermore, the independent blind validation achieved positive predictive value of 83% and negative predictive value of 71%, with sensitivity and specificity of 80% and 76% respectively. Conclusions: The result of this study supports presenting TeloView as an accurate prognostic biomarker which appears able to stratify SMM patients into their respective risk groups with high sensitivity and specificity. This will potentially allow for evidence-based treatment decisions for high risk SMM patients and confident monitoring of stable patients.
Genomic landscape of multiple myeloma with extramedullary disease: Results from a large patient database.
Authors: Mejia Saldarriaga Mateo , Jayabalan David , Sowa Aubrie , Monge Jorge , Rosenbaum Cara , Pearse Roger , Niesvizky Ruben , Patel Sajay , Bustoros Mark
Published: June 2023

8058

Background: Extramedullary disease (EMD) is associated with poor outcomes and the biological mechanisms driving this phenotype are poorly understood. We used the CoMMpass registry data to explore the genomic characteristics of EMD. Methods: The CoMMpass study is a prospective, international registry of newly diagnosed MM. 1143 patients had clinical data. Patients were classified as EMD if they had EMD at any point. Genomic data from bone marrow (BM) samples at diagnosis (whole genome sequencing, whole exome sequencing (WES), and RNA sequencing (RNAseq)) were compared between EMD and non-EMD. A multivariable model was constructed based on univariable results. Differential expression (DEA) and gene set enrichment analysis (GSEA) were performed after normalization using Hallmark and MM transcriptomic subgroups. The top 24 most mutated genes in MM were selected. Results: The median overall survival (mOS) and progression free survival (PFS) was shorter for EMD. The presence of EMD, anemia at diagnosis, age >65 years at diagnosis, ISS stage, and use of ASCT at the first line were independently associated with worse mOS and PFS. EMD was associated with worse mOS (HR 1.7, 95% CI 1.3 - 2.2 p <0.01) and PFS (HR 1.5, 95% CI 1.23 - 1.8, p <0.01) in multivariable analysis and was not abrogated by ASCT, triplet induction or maintenance. Results did not vary when landmark analysis was used. MYC amplification, deletion 18q and 1q amplification were enriched in EMD cases. TP53 mutations and TP53 bi-allelic inactivation (mutation and deletion) were enriched in EMD (Table). DEA identified 1552 genes with increased and 3344 with decreased expression (2.7%, 5.4% of total genes respectively) in EMD when compared to non-EMD. On GSEA, EMD cases were enriched for the CD-1, PR, and CTA myeloma gene expression signatures, in addition to the Hallmark pathways MYC target, E2F targets, G2M checkpoint and unfolded protein response, while the adhesion molecules pathway and MM gene signatures LB, MS, and MF were downregulated in EMD. Conclusions: EMD cases were enriched for TP53 mutations and bi-allelic TP53 inactivation, both of which are prognostic. In addition, MYC amplification, 18q deletion and 1q gain were enriched in EMD which are novel CNA associated with EMD. EMD is also enriched for distinct molecular subgroup, including enrichment for CD-1, PR, and CTA signatures, the latter two are associated with poor outcomes, and the Hallmark pathways MYC, E2F and G2M checkpoints consistent with MYC amplification and PR molecular subgroup. WES and RNAseq of matching BM and EMD tissue samples from our institution is currently being performed. [Table: see text]
Exploratory biomarker analysis of the phase 3 KEYNOTE-604 study of pembrolizumab plus etoposide for extensive-stage SCLC.
Authors: Rudin Charles M. , Kim Hye Ryun , Navarro Alejandro , Gottfried Maya , Peters Solange , Csoszi Tibor , Cheema Parneet Kaur , Rodriguez-Abreu Delvys , Wollner Mira , Yang James Chih-Hsin , Mazieres Julien , Kato Terufumi , Kalemkerian Gregory Peter , Dettman Elisha , Edmondson Mackenzie , Vajdi Amir , Loboda Andrey , El-Osta Hazem Edmond , Zhao Bin , Awad Mark M.
Published: June 2023

8503

Background: In the phase 3 KEYNOTE-604 study of extensive-stage small-cell lung cancer (ES-SCLC; NCT03066778), first-line pembrolizumab (pembro) plus etoposide and platinum (EP) significantly improved PFS vs placebo (pbo) plus EP (HR, 0.75; P = 0.0023), with favorable OS (significance threshold not met; HR, 0.80; P = 0.0164). PFS/OS were similar regardless of PD-L1 CPS. In this exploratory analysis, tumor mutational burden (TMB), 18-gene T cell–inflamed gene expression profile (TcellinfGEP) and SCLC transcriptional subtypes were assessed as correlates of survival. Methods: Patients (pts) eligible for this analysis of KEYNOTE-604 had previously untreated ES-SCLC with evaluable pretreatment tumor samples. TMB was assessed by whole-exome sequencing (WES) of tumor and matched normal DNA. RNA-seq was used to determine TcellinfGEP and SCLC transcriptional subtypes (ASCL1, POU2F3, NEUROD1, YAP1, or inflamed). Associations of TMB, TcellinfGEP, and SCLC subtype with OS were analyzed using an adjusted Cox proportional hazards model. 1-sided (pembro + EP) and 2-sided (pbo + EP) P values were calculated for TMB and TcellinfGEP (prespecified α = 0.05); 2-sided P values were calculated for SCLC subtype (multiplicity-adjusted, α = 0.10). Clinical utility was assessed using prespecified cutoffs of ≥175 mut/exome for TMB and the first tertile for TcellinfGEP. Clinical data cutoff date was Dec 2, 2019. Results: Of 453 pts randomized in KEYNOTE-604 (ITT), 318 had WES data (pembro + EP, n = 167; pbo + EP, n = 151), and 316 had RNA-seq data (pembro + EP, n = 159; pbo + EP, n = 157). High TMB was positively associated with OS in the pbo + EP group ( P = 0.005) but not the pembro + EP group ( P = 0.450). There was a positive association between higher TcellinfGEP and OS in the pembro + EP ( P = 0.003) and pbo + EP ( P < 0.005) groups. SCLC subtypes were not associated with OS in either group (pembro + EP, P = 0.960; pbo + EP, P = 0.999). Clinical benefit of pembro + EP over pbo + EP was demonstrated for TMB <175 mut/exome, but not for TMB ≥175 mut/exome. Pembro + EP benefit over pbo + EP was consistent across TcellinfGEP subgroups. Conclusions: In this exploratory analysis of biomarker subgroups of KEYNOTE-604, TMB and SCLC subtypes were not associated with OS in the pembro + EP group in pts with ES-SCLC. While TcellinfGEP was positively associated with OS in both treatment groups, no additional OS benefit was observed with pembro + EP. Further research is warranted to better identify predictive biomarkers to immunotherapy. Clinical trial information: NCT03066778 . [Table: see text]
Phase II study of durvalumab plus olaparib as maintenance therapy in extensive-stage small-cell lung cancer (TRIDENT): Preliminary efficacy and safety results.
Authors: Huang Yan , Jia Jun , Wang Qiming , Liu Xianling , Zhang Li
Published: June 2023

8518

Background: First-line durvalumab in extensive-stage small-cell lung cancer (ES-SCLC) demonstrated significant improvement of OS in phase Ⅲ CASPIAN trial. PARP inhibitors have the potential to confer antitumor activity, modify tumor immunogenicity, and sensitize tumors to anti-PD-1/PD-L1 therapy. Durvalumab in combination with Olaparib (a PARPi) had clinical activity in relapsed SCLC in a phase Ⅰ/Ⅱ study. This phase Ⅱ study aimed to assess the efficacy and safety of durvalumab plus olaparib as maintenance therapy in patients with ES-SCLC. Methods: TRIDENT is a single arm, multicenter, phase Ⅱ study. Treatment-naive ES-SCLC aged ≥18 with ECOG PS 0-2 were eligible. Durvalumab (1500 mg) was concurrently administered with platinum–etoposide every 3 weeks for 4 cycles, followed by durvalumab 1500 mg every 4 weeks plus olaparib 300 mg twice daily until disease progression or unacceptable toxicity. The primary endpoint was the rate of progression free survival (PFS) at 12 months, the secondary endpoints included progression free survival, objective response rate (ORR) according to RECIST 1.1, duration of response (DoR), overall survival (OS) and safety profile. All patients should provide tumor sample for biomarker analysis (exploratory endpoint). Results: Between August 2021 and August 2022, 60 eligible patients were enrolled from 4 sites in China. At data cut-off (Jan 16th, 2023), 18 (30%) patients were still on treatment. The median age was 63 years (range 57-68). The median cycle of durvalumab was 7 (range 1-17), and durvalumab plus olaparib as maintenance therapy was 3.5 (range 1-13). The PFS rate at 6-, 9-, 12-month were 49.7% [95%CI 37.8%-65.4%], 26.3% [95%CI 13.8%-40.3%] and 18% [95%CI 9.3%-34.7%], respectively. ORR was 75% (45/60), the median DoR was 5.0 months [95%CI 3.8-6.5]. With a median follow-up of 10.5 months, the median PFS was 5.8 months [95%CI 4.9-7.7] as calculated from the first cycle of durvalumab plus chemotherapy. The median OS was not reached [95%CI 10-NA]. Of all, treatment emergent adverse event (AE) occurred in 93.3% (56/60) patients, and AEs ≥ grade 3 occurred in 36.7% (22/60) patients. There were no unexpected adverse events identified in this study. There were 5 patients (8.3%) discontinued treatment and 1 death (1.6%) due to AE. Biomarker analysis is still on-going and will be presented in the meeting. Conclusions: TRIDENT is the first study to evaluate the efficacy and safety of durvalumab plus olaparib as maintenance therapy in Chinese ES-SCLC patients to date. The preliminary result warrant further investigation of this treatment modality in ES-SCLC. Clinical trial information: NCT05245994 .
Pembrolizumab vs placebo for early-stage non‒small-cell lung cancer after resection and adjuvant therapy: Subgroup analysis of patients who received adjuvant chemotherapy in the phase 3 PEARLS/KEYNOTE-091 study.
Authors: Oselin Kersti , Shim Byoung Yong , Okada Morihito , Bryl Maciej , Bonanno Laura , Demirag Guzin , Colantonio Ida , Kimmich Martin , Janzic Urska , Vansteenkiste Johan F. , Bernabe Caro Reyes , Scherz Amina , Curioni-Fontecedro Alessandra , Früh Martin , Wollner Mira , Yang Jing , Shariati Nazly , Marreaud Sandrine , Peters Solange , O'Brien Mary ER
Published: June 2023

8520

Background: In the randomized, triple-blind, phase 3 PEARLS/KEYNOTE-091 study (NCT02504372), at the second interim analysis, pembrolizumab (pembro) significantly prolonged DFS vs placebo (pbo) in the overall population of patients (pts) with completely resected stage IB–IIIA NSCLC per AJCC v7 who may or may not have received adjuvant chemotherapy (chemo; up to 4 cycles) as recommended per local guidelines (n = 1177; HR, 0.76 [95% CI, 0.63–0.91]; P = 0.0014). Here we present outcomes for those pts who received 1–4 cycles of prior adjuvant chemo, per protocol. Methods: Eligible adults had pathologically confirmed, completely resected stage IB (T ≥4 cm), II, or IIIA NSCLC (AJCC v7) of any PD-L1 expression, ECOG performance status of 0 or 1, and had not received neoadjuvant radiotherapy or chemo. Pts were randomized 1:1 to pembro 200 mg or pbo Q3W for 18 doses (~1 year); receipt of adjuvant chemo (yes vs no) was one of the stratification factors. Dual primary endpoints were DFS in the ITT and PD-L1 TPS ≥50% populations. No alpha was assigned to this subgroup analysis of pts who received adjuvant chemo for 1–4 cycles per local guidelines. Results: Of 1177 pts in the ITT population, 1010 (85.8%) received adjuvant chemo and were included in this analysis (pembro, n = 506; pbo, n = 504). Pts received a median of 17 and 18 study doses, respectively. As of data cutoff (Sep 20, 2021), 52.6% in the pembro arm vs 64.9% in the pbo arm had completed treatment. Median time from randomization to data cutoff was 37.4 mo. Median (95% CI) DFS was 58.7 mo (39.2 mo–not reached [NR]) in the pembro arm vs 34.9 mo (28.6 mo–NR) in the pbo arm (HR, 0.73 [95% CI, 0.60–0.89]). Estimated 18-mo DFS rates were 73.8% and 63.1%, respectively. In pts with PD-L1 TPS ≥50% (pembro, n = 143; pbo, n = 141), median DFS was NR in both treatment arms (HR, 0.80 [95% CI, 0.54–1.20]). Grade 3–5 adverse events (AEs) occurred in 170 pts (34.3%) in the pembro arm and 128 (25.7%) in the pbo arm (grade 5, 2.2% vs 1.0%). Immune-mediated AEs and infusion reactions occurred in 195 pts (39.3%) in the pembro arm and 69 (13.8%) in the pbo arm. Conclusions: Consistent with the ITT population, pembro substantially improved DFS vs pbo in the subgroup of pts with stage IB (T2a ≥4 cm), II, or IIIA NSCLC who received adjuvant platinum-based chemo following complete resection. Based on these results, pembro was approved for adjuvant treatment in this pt population by the US FDA. Clinical trial information: NCT02504372 .
Clinical outcomes with neoadjuvant nivolumab (N) + chemotherapy (C) vs C by definitive surgery in patients (pts) with resectable NSCLC: 3-y results from the phase 3 CheckMate 816 trial.
Authors: Spicer Jonathan , Forde Patrick M. , Provencio Mariano , Lu Shun , Wang Changli , Mitsudomi Tetsuya , Broderick Stephen , Swanson Scott , Awad Mark M. , Felip Enriqueta , Brahmer Julie R. , Kerr Keith , Saylors Gene Brian , Chen Ke-Neng , Tanaka Fumihiro , Cai Junliang , Mahmood Javed , Hu Nan , Tran Phuong , Girard Nicolas
Published: June 2023

8521

Background: In CheckMate 816, neoadjuvant N + C demonstrated statistically significant and clinically meaningful improvements in event-free survival (EFS) and pathologic complete response (pCR) vs C in pts with resectable NSCLC. Here, we report clinical outcomes in pts with or without definitive surgery following neoadjuvant treatment (tx). Methods: Adults with stage IB (tumors ≥ 4 cm) to IIIA (per AJCC 7th ed) resectable NSCLC, ECOG PS ≤ 1, and no known EGFR/ ALK mutations were randomized 1:1 to 3 cycles of N 360 mg + C Q3W or C Q3W, followed by definitive surgery within 6 wk of tx. Primary endpoints were EFS and pCR, both per blinded independent review. Exploratory analyses included EFS (secondary definition; no censoring for subsequent tx), time to death or distant metastasis (TTDM), and EFS2 (EFS on next-line tx) in pts with or without surgery. Results: Among 358 randomized pts, 149 (83%; N + C) and 135 (75%; C) had definitive surgery. Baseline characteristics were similar in pts with or without surgery (N + C, 30; C, 44) and between tx arms, except that a higher proportion of pts who did not have surgery had ECOG PS 1 (both arms) or were from Europe (N + C arm). Surgery was canceled due to progressive disease (PD) in 11 (N + C) and 17 (C) pts; PD was locoregional in 4 and 15 pts and distant in 3 and 2 pts, while 4 pts in the N + C arm had both locoregional and distant PD. At database lock (October 14, 2022; median f/u: 41.4 mo), EFS, TTDM, and EFS2 were numerically improved in pts with vs without surgery, regardless of tx arm. In pts with surgery, median TTDM was not reached (NR) vs 46.8 mo (HR, 0.55) with N + C vs C, respectively; 3-y TTDM rates were 77% vs 59%. In pts without surgery, median TTDM was 24.8 vs 15.6 mo (HR, 0.63) with N + C vs C; 3-y rates were 36% vs 13%. Among pts without surgery, 17 (57%) vs 28 (64%) pts in the N + C vs C arms, respectively, received subsequent tx: radiotherapy 37% vs 41%; surgery 3% vs 2%; systemic tx 50% vs 52%. Grade 3/4 tx-related AEs occurred in 38% (N + C) and 36% (C) in pts with surgery, and 26% and 46% in pts without surgery. Conclusions: In CheckMate 816, neoadjuvant N + C demonstrated long-term clinical benefit vs C in pts with resectable NSCLC who received definitive surgery. In pts who did not receive definitive surgery, these exploratory analyses showed that neoadjuvant N + C was associated with numerically improved TTDM. Clinical trial information: NCT02998528 . [Table: see text]
IMpower010: Exploratory analysis of disease-free survival by KRAS status in patients with stage II-IIIA NSCLC treated with adjuvant atezolizumab vs best supportive care.
Authors: Reck Martin , Srivastava Minu K , Wakelee Heather A. , Felip Enriqueta , Altorki Nasser K. , Csoszi Tibor , Moiseyenko Vladimir , Akopov Andrey , Smolin Alexey , Chella Antonio , Vallieres Eric , Martinez-Marti Alex , Zou Wei , McNally V. , Bennett Elizabeth , Prizant Hen , Nabet Barzin , Ballinger Marcus , Gitlitz Barbara J. , Zhou Caicun
Published: June 2023

8522

Background: The Phase III IMpower010 trial (NCT02486718) met its primary disease-free survival (DFS) endpoint leading to approval of atezolizumab after adjuvant platinum-based chemotherapy for completely resected PD-L1 TC ≥1% or ≥50% stage II-IIIA NSCLC in the US, EU and other regions. Mutant KRAS (mKRAS) is the most prevalent oncogenic driver in metastatic NSCLC (27% mKRAS [KRAS G12C,11%]; Osta et al, J Thorac Oncol 2019). Here, we report exploratory DFS outcomes by KRAS mutational status in patients from IMpower010. Methods: The study design and primary results of IMpower010 have been reported (Felip et al, Lancet 2021). After complete resection, patients received cisplatin-based doublet chemotherapy (1-4 21-day cycles) and were subsequently randomized to receive atezolizumab 1200 mg q3w (16 cycles) or best supportive care (BSC). This post hoc analysis evaluated DFS in subgroups of patients by KRAS mutational status. KRAS mutational status was assessed retrospectively using whole-exome sequencing (WES) on resected tumor tissue. Analyses were conducted in patients whose tumors harbored any mKRAS type, including G12C. A separate analysis of the KRAS G12C subgroup was not conducted due to limited patient numbers. Results: Of the 1005 patients in the intention-to-treat population (all randomized patients with stage IB-IIIA NSCLC), 603 comprised the WES biomarker-evaluable population (WES-BEP), and of these, 536 had stage II-IIIA NSCLC. Within the stage II-IIIA WES-BEP, the prevalence of mKRAS and KRAS G12C was 22% (n=118) and 10% (n=52), respectively. mKRAS was enriched in White, non-squamous and smoker populations. Atezolizumab showed DFS improvement vs BSC regardless of KRAS status in the stage II-IIIA WES-BEP (Table). In the mKRAS stage II-IIIA WES-BEP, atezolizumab showed DFS improvement vs BSC regardless of PD-L1 status. Conclusions: In IMpower010, the prevalence of mKRAS and KRAS G12C was similar to that seen in metastatic NSCLC. Despite limited patient numbers in this exploratory analysis, DFS appeared to be consistent and in favor of atezolizumab across subgroups regardless of KRAS status. Clinical trial information: NCT02486718 . [Table: see text]