- CAR-T Cell Therapies
- Bispecific Antibodies
- Monoclonal Antibodies & BCM-AB Drug Conjugates
- Ixazomib & Iberdomid & Real world data
CAR-T Cell Therapies
P08: CARTITUDE-2 UPDATE: CILTACABTAGENE AUTOLEUCEL, A B-CELL MATURATION ANTIGEN–DIRECTED CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPY, IN LENALIDOMIDE-REFRACTORY PATIENTS WITH PROGRESSIVE MULTIPLE MYELOMA AFTER 1-3 PRIOR LINES OF THERAPY
H Einsele1*; AD Cohen2; M Delforge3; J Hillengass4; H Goldschmidt5; K Weisel6; M-S Raab7; C Scheid8; JM Schecter9; KC De Braganca9; H Varsos9; T-M Yeh9; L Wang9; M Vogel10; C Corsale10; M Akram11; L Pacaud11; T Nesheiwat11; M Agha12; YC Cohen13
1Universitätsklinikum Würzburg, Medizinische Klinik und Poliklinik II; 2Abramson Cancer Center, University of Pennsylvania; 3University Hospitals (UZ) Leuven; 4Roswell Park Comprehensive Cancer Center; 5Department of Internal Medicine, University Hospital Heidelberg and National Center of Tumor Diseases; 6University Medical Center Hamburg-Eppendorf; 7University Hospital Heidelberg, and Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center; 8Department of Internal Medicine, University Hospital of Cologne; 9Janssen Research & Development; 10Janssen Global Services, LLC; 11Legend Biotech USA; 12UPMC Hillman Cancer Center; 13Tel-Aviv Sourasky (Ichilov) Medical Center, and Sackler School of Medicine, Tel Aviv University
Introduction: Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T-cell (CAR-T) therapy expressing two B-cell maturation antigen (BCMA)-targeting, single-domain antibodies. The multicohort, open-label, phase 2 CARTITUDE-2 study (NCT04133636) is assessing cilta-cel in patients (pts) with multiple myeloma (MM) under various clinical settings and evaluating the suitability of outpatient administration. Updated results of CARTITUDE-2 cohort A are presented here.
Methods: Cohort A pts had progressive MM after 1–3 prior lines of therapy (LOT; included proteasome inhibitor [PI] and immunomodulatory drug [IMiD]), were lenalidomide-refractory, and had no previous exposure to BCMA-targeting agents. A single cilta-cel infusion at a target dose of 0.75×106 CAR+ viable T cells/kg was given 5–7 d after start of lymphodepletion (cyclophosphamide [300 mg/m2] and fludarabine [30 mg/m2] for 3 d). The primary endpoint was minimal residual disease (MRD) negativity at 10-5 at any time point. Secondary endpoints were overall response rate (ORR), duration of response (DOR), time and duration of MRD negativity, and incidence and severity of adverse events (AEs). Response was assessed per International Myeloma Working Group criteria and AEs were graded by Common Terminology Criteria for Adverse Events version 5.0 (cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS] by American Society for Transplantation and Cellular Therapy).
Results: As of April 15, 2021 (median follow-up of 9.7 mo), 20 pts (65% men; median age 60 y [range 38–75]) received cilta-cel, with 1 pt treated in an outpatient setting. Pts had a median of 2 prior LOT (range 1–3); 60% had 1–2 prior LOT and 40% had 3 prior LOT. All pts were exposed to a PI, IMiD, and dexamethasone; 95% were exposed to alkylating agents and 65% to daratumumab. 95% of pts were refractory to last LOT; 40% were triple-class refractory. ORR was 95% (95% CI 75.1–99.9); 85% (95% CI 62.1–96.8) had ≥complete response (CR), and 95% (95% CI 75.1–99.9) had ≥very good partial response (Figure). Median time to first response was 1.0 mo (range 0.7–3.3) and median time to ≥CR was 2.6 mo (range 0.9–7.9). Median DOR was not reached; progression-free survival (PFS) at 6 mo was 90% (95% CI 65.6–97.4). Of 13 MRD-evaluable pts, 92.3% (95% CI 64.0–99.8) were MRD-negative at 10-5. Hematologic AEs (≥20% of pts) were neutropenia (95%; grade [gr] 3/4: 95%), thrombocytopenia (80%; gr 3/4: 35%), anemia (75%; gr 3/4: 45%), lymphopenia (65%; gr 3/4: 60%) and leukopenia (55%; gr 3/4: 55%). 95% of pts had CRS (gr 3/4: 10%); median time to onset was 7 d (range 5–9) and median duration was 4 d (range 2–11). Four pts (20%) had CAR-T neurotoxicity (all gr 1/2). Three pts (15%) had ICANS (all gr 1/2); median time to onset was 8 d (range 7–10) and median duration was 3 d (range 1–3). One pt had facial paralysis (gr 2) with time to onset of 29 d and duration of 51 d. No movement and neurocognitive treatment-emergent adverse events (TEAEs) were reported. One death due to COVID-19 was assessed as treatment-related. Safety was manageable in the pt treated in an outpatient setting.
Conclusions: A single cilta-cel infusion led to early and deep responses in pts with MM who had 1–3 prior LOT and were lenalidomide-refractory. No movement and neurocognitive TEAEs occurred, suggesting successful implementation of monitoring and pt management strategies across phase 2/3 studies in the CARTITUDE program.
P19: BASELINE CORRELATES OF COMPLETE RESPONSE TO IDECABTAGENE VICLEUCEL (IDE-CEL, BB2121), A BCMA-DIRECTED CAR T CELL THERAPY IN PATIENTS WITH RELAPSED AND REFRACTORY MULTIPLE MYELOMA: SUBANALYSIS OF THE KARMMA TRIAL
P Rodríguez-Otero1; N Shah2; N Munshi3; J Berdeja4; S Jagannath5; O Finney6; N Martin7; A Agarwal7; E Rowe7; T Campbell7; J San-Miguel1
1Clínica Universidad de Navarra, Pamplona (Spain); 2UCSF Medical Center, San Francisco (USA); 3Dana-Farber Cancer Institute, Boston (USA); 4Sarah Cannon Cancer Center and Tennessee Oncology, Nashville (USA); 5Mount Sinai Medical Center, New York (USA); 62seventybio, Cambridge (USA); 7Bristol Myers Squibb, Princeton (USA).
Introduction: In the pivotal phase 2 KarMMa trial (NCT03361748), in heavily pretreated RRMM, 33% of patients (pts) who received ide-cel, a B-cell maturation antigen (BCMA)-directed CAR T cell therapy, had complete response (CR) or stringent CR (sCR), with a median duration of response of 21.5 months (Anderson et al. ASCO 2021. Poster 8016). This subanalysis aimed to identify baseline correlates of pts attaining CR/sCR in KarMMa.
Methods: Pts with ≥3 prior lines of therapy (including an immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody), and MM refractory to last regimen per IMWG criteria received ide-cel infusion (target doses 150–450 x 106CAR+ T cells) after lymphodepletion. Bridging therapy was optional. Endpoints included overall response rate (primary) and CR/sCR rate (key secondary). Baseline characteristics were collected prior to lymphodepletion and for select biomarkers on day of infusion. Univariate and multivariate logistic regression models were used to identify baseline characteristics correlating with the likelihood of achieving CR/sCR.
Results: Of 128 pts who received ide-cel (data cutoff Dec 21, 2020), 42 pts achieved CR/sCR and 86 had non-CR/sCR (very good partial response, partial response, or no response). In pts with CR/sCR, 32 (76%) were negative for minimal residual disease (MRD) (sensitivity level of <10-5) and 19 maintained MRD negativity at 12-mo follow-up. Baseline characteristics were generally balanced between pts with CR/sCR and non-CR/sCR; notable exceptions included revised International Staging System (ISS) stage III disease, IgG chain type, CD138+ plasma cell percentage, and β-2-microglobulin levels (Table). Univariate analysis of CR/sCR by baseline characteristics showed that IgG heavy chain versus other heavy chain types (odds ratio [OR]: 0.162, P<0.0001), high sBCMA (OR: 0.646, P=0.0007), β-2-microglobulin (≥5.5 vs <3.5 mg/L; OR: 0.201, P=0.0072), and presence of extramedullary disease (OR: 0.428, P=0.0394) were negatively associated with CR/sCR, whereas high vector copy number in drug product was positively associated with CR/sCR (OR: 1.290, P=0.0287). Multivariate analysis of CR/sCR identified IgG heavy chain versus other heavy chain types (OR: 0.100, P<0.0001), high sBCMA (OR: 0.637, P=0.0110), and elevated prothrombin time-international normalized test (PT-INR) (OR: 0.005, P=0.0365) as negative correlates of CR/sCR, and high vector copy number in drug product (OR: 1.486, P=0.0168) as a positive correlate of CR/sCR. Descriptive analysis demonstrated lower median (range) sBCMA levels at baseline in pts with CR/sCR (191 ng/mL [11–909]) versus non-CR/sCR (340 ng/mL [19–2735]); across both groups, sBCMA levels had increased from screening (CR/sCR, 161 ng/mL [27–689]; non-CR/sCR, 302 ng/mL [24–1490]).
Conclusions: In this subanalysis of KarMMa, multivariate analysis identified IgG, sBCMA, and PT-INR as negative correlates of CR/sCR, and vector copy number in drug product a positive correlate. As sBCMA is a tumor burden indicator and can affect BCMA-targeted therapies (Cowan et al. ASH 2019. Abstract 204), selecting pts with lower tumor burden and controlling tumor burden during manufacturing or bridging therapy may aid in achieving CR/sCR with ide-cel.
Previously presented and published: Shah N, et al. ASH 2021, Blood 2021; 138:1739.
Study support: 2seventy bio, formerly bluebird bio, and Celgene, a Bristol-Myers Squibb Company.
P21: SUBSEQUENT ANTI-MYELOMA THERAPY AFTER IDECABTAGENE VICLEUCEL (IDE-CEL, BB2121) TREATMENT IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA FROM THE KARMMA STUDY
P Rodríguez-Otero1; J San-Miguel1; LD Anderson, Jr2; S Lonial3; A Truppel-Hartmann4; J Sanford5; E Rowe5; TB Campbell5; N Munshi6
1Clínica Universidad de Navarra, Pamplona (Spain); 2University of Texas Southwestern, Dallas (USA); 3Emory School of Medicine, Atlanta (USA); 42seventybio, Cambridge (USA); 5Bristol Myers Squibb, Princeton (USA); 6Dana-Farber Cancer Institute, Boston (USA).
Introduction: Ide-cel, a novel B-cell maturation antigen (BCMA)-directed CAR T cell therapy, showed frequent, deep, and durable responses in triple-class-exposed patients (pts) with RRMM in the phase 2 KarMMa study (NCT03361748; Munshi et al. N Engl J Med 2021). The difference between median progression-free survival (PFS; 8.6 mo) and overall survival (OS; 24.8 mo; Anderson et al. ASCO 2021; poster 8016) prompted analyses examining additional outcomes for pts enrolled in KarMMa, including time to second disease progression (PFS2), type and duration of subsequent anti-myeloma therapy (sAMT), and OS in pts who received sAMT.
Methods: Pts with MM, ≥ 3 prior lines of therapy (including an immunomodulatory agent, proteasome inhibitor [PI], and anti-CD38 antibody), and disease refractory to their last regimen per IMWG criteria received ide-cel infusion (target dose range 150–450 x 106 CAR+ T cells) after lymphodepletion (fludarabine 30 mg/m2/day + cyclophosphamide 300 mg/m2/day for 3 days). After ide-cel treatment, pts who relapsed could receive sAMT immediately or following ide-cel re-treatment (R-ide-cel).
Results: At a median follow-up of 24.8 mo among surviving pts, 104/128 (81%) pts who received ide-cel had progressive disease or had died. After ide-cel treatment, 68 pts received sAMT alone or with R-ide-cel (11/68 received subsequent anti-BCMA therapy). Fifty-two pts did not receive sAMT or R-ide-cel; of these, 33 relapsed after, or did not respond to, ide-cel and did not receive sAMT; and 19 were not included in this analysis because they were continuing in remission at time of analysis (n = 18) or discontinued without progressive disease or death (n = 1). Eight patients received R-ide-cel alone and were excluded from the analysis. Baseline demographics and clinical characteristics of pts receiving sAMT, anti-BCMA, and no sAMT/R-ide-cel were similar; however, more pts with no sAMT/R-ide-cel had revised International Staging System stage III disease compared with pts who had sAMT or anti-BCMA therapy (33%, 9%, 9%, respectively). The most frequent sAMT classes were corticosteroids (n = 58) and PIs (n = 47); the most frequent sAMT agents were dexamethasone (n = 56) and carfilzomib (n = 32). Anti-BCMA agents included belantamab mafodotin (GSK2857916; n = 10) and teclistamab (JNJ64007957; n = 1). In pts who received sAMT, median PFS and OS after ide-cel were 6.1 and 24.8 mo (Table). Median duration of first sAMT was 44 d and duration of all sAMT was 215 d, with a PFS2 of 13.6 mo (inclusive of time on ide-cel). Among pts who received anti-BCMA therapy, median PFS and OS to ide-cel were 12.1 and 31.0 mo; median duration of first sAMT was 48 d and PFS2 was 15.5 mo.
Conclusions: In this descriptive subgroup analysis of the KarMMa trial, the majority of patients who relapsed after ide-cel were able to receive sAMT successfully with a PFS2 intermediate between PFS to initial ide-cel and OS. The PFS2 in this subgroup supports that disease control can be achieved by sequencing of sAMT after relapse from anti-BCMA CAR T therapy. Various classes of anti-myeloma drugs were used as sAMT. Studies are ongoing to define tumor phenotypes prior to and after ide-cel that may correlate with these clinical observations.
Previously presented and published: Rodríguez-Otero P, et al. ASH 2021, Blood 2021;138:2743.
Study support: 2seventy bio, formerly bluebird bio, and Celgene, a Bristol-Myers Squibb Company.
P23: RELAPSED/REFRACTORY MULTIPLE MYELOMA PATIENTS. A MULTICENTER RETROSPECTIVE ANALYSIS OF ELIGIBILITY CRITERIA FOR CAR-T CELL THERAPY.
F Fazio1; A Di Rocco1; T Za2; V Tomarchio3; A Rago4; A Piciocchi5; T Caravita di Toritto4; O Annibali2; V De Stefano2; R Foà1; M Martelli1; MT Petrucci1
1Hematology, Department of Translational and Precision Medicine, Azienda Ospedaliera Policlinico Umberto I, Sapienza University of Rome; 2Section of Hematology, Department of Radiological and Hematological Sciences, Catholic University, Fondazione Policlinico A. Gemelli, IRCCS; Rome; 3Unit of Hematology, Stem Cell Transplantation, University Campus Bio Medico, Rome; 4UOSD Ematologia ASL Roma, Rome; 5Italian Group For Adult Hematologic Diseases (GIMEMA), Rome
The overall survival (OS) of multiple myeloma (MM) patients (pts) has improved over the last years due to the introduction of several novel drugs, such as proteosome inhibitors (PI), immunomodulatory drugs (IMiDs) and anti-CD38 monoclonal antibodies (moAb). The majority of pts continues to relapse, and MM remains an incurable disease. No standard of care has been established for relapsed/refractory (RR) MM pts who have been exposed to the main anti-myeloma drugs. These pts have a limited number of treatment options and represent an unmet medical need. The outcome of pts failing standard of care regimens is poor, with a median progression free survival (PFS) of 3-4 months (mo) and OS of 8-9 mo. Immunotherapy represents the emerging therapeutic strategy for this subset of pts. Chimeric antigen receptor (CAR)-modified T cells are a promising new therapy approach for triple refractory RRMM. Specific CAR-T targets are being studied, but BCMA-directed CAR-T cells have so far provided the most convincing evidence of activity, with one product (idecabtagene vicleucel) recently approved by FDA and EMA.
The primary endpoint of this study was to define the clinical characteristics and outcome of a cohort of RRMM pts potentially eligible to CAR-T cell treatment according to the KarMMa trial criteria. Secondary endpoints were aimed at defining specific factors influencing CAR-T cell therapy eligibility and at identifying a real-life estimate of RRMM pts truly eligible for CAR-T cells.
This is a cohort analysis on RRMM pts managed between January 2018 and July 2021 at 4 Italian Centers of the Multiple Myeloma Lazio Group. At the time of data collection, 47 RRMM pts had underwent at least 3 prior therapy regimens; they had received a previous PI, IMiDs and a moAb and were considered refractory to the last regimen. The clinical characteristics are listed in Table 1. Median age was 68 years, 27 pts were >65 years; 27 were male. Of 47 pts, 33 were ECOG 0-1; 21 pts were ISS III. The majority of pts, 28, had undergone an autologous stem cell transplantation; 31 pts had received 3 prior lines of therapy and 16 >3 prior lines of therapy. Thirty-seven were triple-refractory and 8 were penta-refractory. Based on the KarMMa trial criteria, 22 pts would be defined as eligible and 25 not eligible for CAR-T cell therapy. Specifically, 14 pts were not eligible because of an ECOG 3-2, 24 had an organ dysfunction such as impaired renal function, anemia and thrombocytopenia. Of the 25 pts considered ineligible for CAR-T cell therapy, 17 presented ≥2 ineligibility criteria.
After a median follow-up of 34.7 mo (0-53.8), the median OS for the entire cohort was 21.7 mo. The median OS was 30.7 mo in eligible pts vs 16.2 mo in non-eligible pts (p=0.002). The median PFS of the entire cohort was 7.7 mo and the median PFS was 7.8 mo in eligible pts vs 6.5 mo (p=0.513) in non-eligible pts. Despite the limits of a retrospective study and a limited cohort, our real-life data shows that heavily treated pts with RRMM are less likely to be eligible for CAR-T cell therapy.
Considering the emergent role of quadruplet combined approaches for first-line therapy and given the therapeutic relevance of CAR-T cells for the management of RRMM pts previously exposed to PI, IMiDs and moAb, our data could help to better define pts who could benefit from CAR-T cells under the current indications, while waiting for an extension of this approach to earlier disease stages.
P06: UPDATED RESULTS FROM THE PHASE 1/2 MAJESTEC-1 STUDY OF TECLISTAMAB, A B-CELL MATURATION ANTIGEN X CD3 BISPECIFIC ANTIBODY, IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA
R Popat1; S Usmani2; A Garfall3; N van de Donk4; H Nahi5; J San-Miguel6; A Oriol7; A Nooka8; T Martin9; L Rosinol10; A Chari11; L Karlin12; L Benboubker13; M Mateos14; N Bahlis15; P Moreau16; B Besemer17; J Martínez-López18; S Sidana19; L Pei20; D Trancucci20; R Verona21; S Girgis21; Y Olyslager22; M Jaffe20; C Uhlar21; T Stephenson21; R Van Rampelbergh22; A Banerjee21; J Goldberg20; R Kobos20; A Krishnan23
1University College London Hospitals, NHS Foundation Trust; 2Levine Cancer Institute/Atrium Health; 3Abramson Cancer Center, University of Pennsylvania; 4Amsterdam University Medical Center, Vrije Universiteit Amsterdam; 5Karolinska University Hospital at Huddinge; 6Clínica Universidad de Navarra, CIMA, CIBERONC, IDISNA; 7Institut Català d’Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol; 8Winship Cancer Institute, Emory University; 9University of California, San Francisco; 10Hospital Clínic, IDIBAPS, University of Barcelona; 11Mount Sinai School of Medicine; 12Service d’Hématologie Clinique, Centre Hospitalier Lyon Sud; 13Service d’Hématologie et Thérapie Cellulaire, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire; 14University Hospital of Salamanca/IBSAL/CIC/CIBERONC; 15Arnie Charbonneau Cancer Institute, University of Calgary; 16Hematology Clinic, University Hospital Hôtel-Dieu; 17Department of Hematology, Oncology and Immunology, University of Tuebingen; 18Haematological Malignancies Clinical Research Unit, Hospital 12 de Octubre Universidad Complutense, CNIO, CIBERONC; 19Stanford University School of Medicine; 20Janssen Research & Development; 21Janssen Research & Development; 22Janssen Research & Development; 23City of Hope Comprehensive Cancer Center
Teclistamab (JNJ-64007957) is a bispecific antibody that binds to both B-cell maturation antigen (BCMA) and CD3 receptors to induce T cell-mediated cytotoxicity of BCMA-expressing myeloma cells. Results from phase 1 of the MajesTEC-1 study, an ongoing phase 1/2 study in heavily-pretreated relapsed/refractory multiple myeloma (RRMM; NCT03145181), showed a tolerable safety profile at the recommended phase 2 dose (RP2D) and encouraging efficacy. Here we report initial data from the phase 2 portion of MajesTEC-1 (NCT04557098) as well as updated results from phase 1.
Patients (pts; ≥18 y) had MM per International Myeloma Working Group (IMWG) criteria, measurable disease, and were exposed to a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. In phase 1, pts were relapsed, refractory, or intolerant to established therapies. In phase 2, pts received ≥3 prior lines of therapy (LOT). The primary objectives were to identify the RP2D and to characterize safety and tolerability of teclistamab at the RP2D in phase 1, and to evaluate the efficacy at the RP2D (primary endpoint: ORR) in phase 2. The RP2D was weekly subcutaneous teclistamab 1500 μg/kg following step-up doses of 60 and 300 μg/kg. Responses were assessed by the investigator per IMWG criteria. Adverse events (AEs) were graded per CTCAE v4.03. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT criteria.
As of June 14, 2021, 159 pts (median age 64.0 y [range 33–84]; 15% ≥75 y; 59% male) were treated at the RP2D (phase 1: 40 pts; phase 2: 119 pts). Pts received a median of 5 prior LOT (range 2–15); 100% were triple-class exposed, 69% were penta-drug exposed, 77% were triple-class refractory, and 29% were penta-drug refractory.
In 159 pts, the most common nonhematologic AEs at the RP2D were CRS (any grade: 67%; grade 3 occurred in 1 pt, no grade 4 or 5), injection site erythema (23%; all grade 1/2), and fatigue (22%; grade 3/4: 2%). Of the hematologic AEs, most common were neutropenia (53%; grade 3/4: 45%), anemia (41%; grade 3/4: 27%), and thrombocytopenia (33%; grade 3/4: 18%). Four pts (2.5%) developed ICANS (all grade 1/2; all resolved). No new safety signals were identified in phase 2. Phase 2 pharmacokinetic and pharmacodynamic data supported those reported in phase 1. At the RP2D, teclistamab exposure was sustained across the dosing interval and exceeded target exposure levels. Across both phases, induction of proinflammatory cytokines and T cell activation were observed at the RP2D.
Phase 2 efficacy data are immature. At 8.2-mo median follow-up (range 1.2–15.2), responses in the phase 1 pts at the RP2D (n=40) were consistent with previous reports (ORR: 65% [95% CI 48–79]; ≥VGPR: 60% [95% CI 43–75]; ≥complete response: 40% [95% CI 25–57]). Responses deepened over time, and with longer follow-up of responders compared with previously presented data (median follow-up of 9.5 mo vs 7.1 mo), remained durable (Figure). 85% (22/26) of responders are continuing on treatment, including 1 pt with 15.2 mo of follow-up. Median duration of response (DOR) was not reached, with 6-month DOR rate of 90% [95% CI 63–97].
The safety of teclistamab is supported by data from 159 pts treated at the RP2D. Teclistamab continues to show deep and durable responses with a manageable safety profile in heavily-pretreated pts with RRMM.
P10: TALQUETAMAB, A G PROTEIN-COUPLED RECEPTOR FAMILY C GROUP 5 MEMBER D X CD3 BISPECIFIC ANTIBODY, IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM): UPDATED PHASE 1 RESULTS FROM MONUMENTAL-1
N. W. C. J van de Donk1*; M C Minnema2; J G Berdeja3; A Oriol4; A Krishnan5; P Rodríguez-Otero6; E Askari7; M Mateos8; L. J Costa9; R Verona10; J Ma10; S Girgis10; S Yang10; B. W Hilder10; J Russell10; J. D Goldberg11; A Chari12
1Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam (NL); 2University Medical Center Utrecht, Utrecht (NL); 3Sarah Cannon Research Institute and Tennessee Oncology, Nashville (USA); 4Institut Català d’Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Badalona (ES); 5City of Hope Comprehensive Cancer Center, Duarte (USA); 6Clínica Universidad de Navarra, Navarra (ES); 7Hospital Universitario Fundación Jiménez Díaz, Madrid (ES); 8University Hospital of Salamanca/IBSAL/CIC/CIBERONC, Salamanca (ES); 9University of Alabama at Birmingham, Birmingham (USA); 10Janssen Research & Development, Spring House (USA); 11Janssen Research & Development, Raritan (USA); 12Mount Sinai School of Medicine, New York (USA)
G protein-coupled receptor family C group 5 member D (GPRC5D) has limited expression in healthy human tissue but is highly expressed in malignant plasma cells, making it a promising target for immunotherapy approaches for MM. Talquetamab (JNJ-64407564) is a first-in-class bispecific antibody that binds to both GPRC5D and CD3 receptors to redirect T cells to kill MM cells. Updated and new results of talquetamab at the recommended phase 2 doses (RP2Ds) are reported (NCT03399799).
Eligible patients had RRMM or were intolerant to standard therapies. Patients who were previously treated with B-cell maturation antigen (BCMA)-directed therapies were eligible. This analysis focuses on patients who received talquetamab subcutaneously (SC; range: 5.0–800 μg/kg) weekly (QW) or biweekly (Q2W) with step-up dosing. The primary objectives were to identify the RP2D (part 1) and assess talquetamab safety and tolerability at the RP2Ds (part 2). Adverse events (AEs) were graded by CTCAE v4.03; cytokine release syndrome (CRS) was graded per Lee et al 2014 criteria. Responses were investigator-assessed per IMWG criteria.
As of July 19, 2021, 95 patients had received SC talquetamab. The original RP2D was 405 μg/kg SC talquetamab QW with step-up doses, and a second RP2D of 800 μg/kg SC talquetamab Q2W with step-up doses was also identified.
30 patients received 405 μg/kg QW (median 61.5 years [range 46–80]; 63% male; 100% triple-class exposed; 80% penta-drug exposed; 77% triple-class refractory, 20% penta-drug refractory; 30% prior BCMA-directed therapy; median follow-up [mF/U]: 7.5 mo [range 0.9–15.2]). 23 patients received 800 μg/kg Q2W (median 60.0 years [range 47–84]; 48% male; 96% triple-class exposed; 70% penta-drug exposed; 65% triple-class refractory, 22% penta-drug refractory; 17% prior BCMA-directed therapy; mF/U: 3.7 mo [range 0.0–12.0]).
No treatment discontinuations due to AEs were reported at either RP2Ds. Most common AEs at the 405 μg/kg QW were CRS (73%; 1 grade 3 CRS), neutropenia (67%; grade 3/4: 60%), and dysgeusia (60%; grade 2: 29%). Skin-related AEs occurred in 77% of patients and were all grade 1/2 (nail disorders: 30%). Infections occurred in 37% of patients (1 grade 3 COVID-19 pneumonia). Most common AEs at 800 μg/kg Q2W were CRS (78%; all grade 1/2), dry mouth (44%; all grade 1/2), and neutropenia (44%; grade 3/4: 35%). Skin-related AEs occurred in 65% of patients with grade 3 events in 13% (nail disorders: 17%). Infections occurred in 13% of patients (1 grade 3 pneumococcal sepsis).
In 30 response-evaluable patients treated at 405 μg/kg QW, the overall response rate (ORR) was 70% (very good partial response or better [≥VGPR]: 57%). In 17 response-evaluable patients treated at 800 μg/kg Q2W, the ORR was 71% (≥VGPR: 53%). Responses were durable and deepened over time with both RP2Ds (Figure). Median duration of response (DOR) was not reached at either RP2D; 6-month DOR rate was 67% (95% CI: 41–84) at 405 μg/kg QW. Serum trough levels of talquetamab were comparable at both RP2Ds. Pharmacodynamic data at both RP2Ds showed peripheral T cell activation and induction of cytokines.
SC talquetamab is well tolerated and highly effective at both RP2Ds. Preliminary data suggest that less frequent, higher doses of SC talquetamab do not negatively impact the safety profile. Further evaluation of talquetamab as monotherapy (phase 2; NCT04634552) and in combination with other therapies in patients with RRMM is underway.
Monoclonal Antibodies & BCM-AB Drug Conjugates
P04: DARATUMUMAB PLUS BORTEZOMIB AND DEXAMETHASONE VERSUS BORTEZOMIB AND DEXAMETHASONE ALONE IN PATIENTS WITH PREVIOUSLY TREATED MULTIPLE MYELOMA: OVERALL SURVIVAL RESULTS FROM THE PHASE 3 CASTOR TRIAL
P Sonneveld1; A Chanan-Khan2; K Weisel3; AK Nooka4; T Masszi5; M Beksac6; I Spicka7; V Hungria8; M Munder9; MV Mateos10; TM Mark11; MD Levin12; T Ahmadi13; X Qin14; W Garvin Mayo15; X Gai16; J Carey14; R Carson14; A Spencer17
1Erasmus MC Cancer Institute, Rotterdam, The Netherlands; 2Mayo Clinic Florida, Jacksonville, FL, USA; 3Department of Oncology, Hematology and Bone Marrow Transplantation With Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 4Winship Cancer Institute, Emory University, Atlanta, GA, USA; 5Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary; 6Ankara University, Ankara, Turkey; 7Clinical Department of Haematology, 1st Medical Department, Charles University, Prague, Czech Republic; 8Clinica São Germano, São Paulo, Brazil; 9Third Department of Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany; 10University Hospital of Salamanca/IBSAL/Cancer Research Center-IBMCC (USAL-CSIC), Salamanca, Spain; 11Department of Medicine, University of Colorado, Aurora, CO, USA; 12Albert Schweitzer Hospital, Dordrecht, The Netherlands; 13Genmab US, Inc., Plainsboro, NJ, USA; 14Janssen Research & Development, LLC, Spring House, PA, USA; 15Janssen Research & Development, LLC, Raritan, NJ, USA; 16Janssen Research & Development, LLC, Beijing, China; 17Malignant Haematology and Stem Cell Transplantation Service, Alfred Health-Monash University, Melbourne, Australia
Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 approved in combination with standard-of-care regimens for pts with newly diagnosed multiple myeloma (NDMM) and as monotherapy and in combination with standard-of-care regimens for pts with relapsed/refractory multiple myeloma (RRMM). In the primary analysis of the phase 3 CASTOR study (median follow-up, 7.4 months), DARA plus bortezomib and dexamethasone (D-Vd) significantly prolonged progression-free survival (PFS) versus bortezomib and dexamethasone (Vd) alone in pts with RRMM, and key secondary endpoints (including time to disease progression, rate of very good partial response or better, overall response rate, and minimal residual disease [MRD]–negativity rate) showed a statistically significant benefit favoring D-Vd. Here, we report final overall survival (OS) and updated MRD-negativity and safety results after ~6 years of follow-up.
Methods: Pts with RRMM and ≥1 prior line of therapy were randomized 1:1 to receive D-Vd or Vd. All pts received up to 8 (21-day) cycles of Vd (V 1.3 mg/m2 SC on Days 1, 4, 8, and 11; d 20 mg PO or IV on Days 1, 2, 4, 5, 8, 9, 11, and 12). Pts in the D-Vd group also received DARA (16 mg/kg IV QW in Cycles 1-3, Q3W in Cycles 4-8, and Q4W thereafter until disease progression or unacceptable toxicity). The primary endpoint was PFS; OS was a secondary endpoint.
Results: In total, 498 pts were randomized (D-Vd, n=251; Vd, n=247). Median (range) age was 64 (30-88) years; pts had received a median (range) of 2 (1-10) prior lines of therapy. At a median (range) follow-up of 72.6 (0.0-79.8) months, the CASTOR study showed a statistically significant and clinically meaningful improvement in OS with D-Vd versus Vd (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.59-0.92; P=0.0075 [crossing the prespecified stopping boundary of P=0.0323]), representing a 26% reduction in the risk of death with D-Vd (Figure). Median OS was 49.6 (95% CI, 42.2-62.3) months with D-Vd versus 38.5 (95% CI, 31.2-46.2) months with Vd. Prespecified subgroup analyses showed an OS improvement with D-Vd versus Vd across most subgroups, including pts aged ≥65 years; pts who had received 1 or 2 prior lines of therapy; pts with International Staging System stage III disease, high-risk cytogenetic abnormalities, or prior bortezomib treatment; and pts who were refractory to their last prior line of therapy. The most pronounced OS benefit of D-Vd was seen in pts with 1 prior line of therapy (HR, 0.56; 95% CI, 0.39-0.80). D-Vd achieved significantly higher rates of MRD negativity (10–5) versus Vd (15.1% vs 1.6%; P<0.0001). The most common (≥10%) grade 3/4 treatment-emergent adverse events (TEAEs; D-Vd/Vd) were thrombocytopenia (46.1%/32.9%), anemia (16.0%/16.0%), neutropenia (13.6%/4.6%), lymphopenia (10.3%/2.5%), and pneumonia (10.7%/10.1%). Rates of discontinuation due to TEAEs were low and similar between treatment groups (D-Vd, 10.7%; Vd, 9.3%). No new safety concerns were identified with extended follow-up.
Conclusion: Treatment with D-Vd significantly prolonged OS compared with Vd alone. These results, together with the OS results observed with DARA in combination with lenalidomide and dexamethasone in the phase 3 POLLUX study, demonstrate for the first time an OS benefit with DARA-containing regimens in RRMM. The greatest OS benefit of D-Vd was observed in pts with 1 prior line of therapy. Our results support early use of D-Vd to maximize pt benefit.
P05: DARATUMUMAB PLUS LENALIDOMIDE AND DEXAMETHASONE VERSUS LENALIDOMIDE AND DEXAMETHASONE ALONE IN PATIENTS WITH PREVIOUSLY TREATED MULTIPLE MYELOMA: OVERALL SURVIVAL RESULTS FROM THE PHASE 3 POLLUX TRIAL
MA Dimopoulos1; A Oriol2; H Nahi3; J San-Miguel4; NJ Bahlis5; SZ Usmani6; N Rabin7; RZ Orlowski8; K Suzuki9; T Plesner10; SS Yoon11; D Ben Yehuda12; PG Richardson13; H Goldschmidt14; D Reece15; T Ahmadi16; X Qin17; W Garvin Mayo18; X Gai19; J Carey17; R Carson17; P Moreau20
1Athens, Greece; 2Barcelona, Spain; 3Stockholm, Sweden; 4Pamplona, Spain; 5Calgary, AB, Canada; 6New York, NY, USA; 7London, United Kingdom; 8Houston, TX, USA; 9Tokyo, Japan; 10Vejle, Denmark; 11Seoul, South Korea; 12Jerusalem, Israel; 13Boston, MA, USA; 14Heidelberg, Germany; 15Toronto, Canada; 16Plainsboro, NJ, USA; 17Spring House, PA, USA; 18Raritan, NJ, USA; 19Beijing, China; 20Nantes, France
(1) National and Kapodistrian University of Athens, (2) Institut Català d’Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, (3) Karolinska Institute, Department of Medicine, Division of Hematology, Karolinska University Hospital at Huddinge, (4) Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IDISNA), CIBER-ONC, (5) Arnie Charbonneau Cancer Research Institute, University of Calgary, (6) Memorial Sloan Kettering Cancer Center, (7) Department of Haematology, University College London Hospitals NHS Trust, (8) Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, (9) Japanese Red Cross Medical Center, Department of Hematology, (10) Vejle Hospital and University of Southern Denmark, (11) Department of Internal Medicine, Seoul National University College of Medicine, (12) Hematology Department, Hadassah Medical Center, Faculty of Medicine, Hebrew University, (13) Dana-Farber Cancer Institute, (14) University Hospital Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), (15) Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, (16) Genmab US, Inc., (17) Janssen Research & Development, LLC, (18) Janssen Research & Development, LLC, (19) Janssen Research & Development, LLC, (20) Hematology, University Hospital Hôtel-Dieu
Introduction: Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 that is approved in combination with standard-of-care regimens for pts with newly diagnosed multiple myeloma (NDMM) and as monotherapy and in combination with standard-of-care regimens for pts with relapsed/refractory multiple myeloma (RRMM). In the primary analysis of the phase 3 POLLUX study (median follow-up, 13.5 months), DARA plus lenalidomide and dexamethasone (D-Rd) provided a significant progression-free survival (PFS) benefit versus lenalidomide and dexamethasone (Rd) alone, and key secondary endpoints (including time to disease progression, rate of very good partial response or better, overall response rate, and minimal residual disease [MRD]–negativity rate) showed a statistically significant benefit favoring D-Rd. Here, we report final overall survival (OS) and updated MRD-negativity and safety results after >6 years of follow-up.
Methods: Pts with RRMM and ≥1 prior line of therapy were randomized 1:1 to receive D-Rd or Rd. All pts received 28-day cycles of Rd (R 25 mg PO on Days 1-21; d 40 mg QW). Pts in the D-Rd group also received DARA (16 mg/kg IV QW in Cycles 1-2, Q2W in Cycles 3-6, and Q4W thereafter). In both groups, pts were treated until disease progression or unacceptable toxicity. The primary endpoint was PFS; OS was a secondary endpoint.
Results: In total, 569 pts were randomized (D-Rd, n=286; Rd, n=283). The median (range) age was 65 (34-89) years; pts had received a median (range) of 1 (1-11) prior lines of therapy. At a median (range) follow-up of 79.7 (0.0-86.5) months, the POLLUX study showed a statistically significant and clinically meaningful improvement in OS with D-Rd versus Rd (hazard ratio, 0.73; 95% confidence interval [CI], 0.58-0.91; P=0.0044 [crossing the prespecified stopping boundary of P<0.0331]), representing a 27% reduction in the risk of death in the D-Rd group (Figure). The median OS was 67.6 (95% CI, 53.1-80.5) months in the D-Rd group versus 51.8 (95% CI, 44.0-60.0) months in the Rd group. Prespecified subgroup analyses showed an OS improvement with D-Rd versus Rd in most subgroups, including pts aged ≥65 years; pts who had received 1, 2, or 3 prior lines of therapy; pts with International Staging System stage III disease; and pts who were refractory to a proteasome inhibitor or to their last prior line of therapy. D-Rd achieved significantly higher rates of MRD negativity (10–5) versus Rd (33.2% vs 6.7%; P<0.0001). The most common (≥10%) grade 3/4 treatment-emergent adverse events (TEAEs; D-Rd/Rd) were neutropenia (57.6%/41.6%), anemia (19.8%/22.4%), pneumonia (17.3%/11.0%), thrombocytopenia (15.5%/15.7%), and diarrhea (10.2%/3.9%). Rates of discontinuation due to TEAEs were comparable between treatment groups (D-Rd, 19.1%; Rd, 16.0 %). There were no new safety concerns identified with extended follow-up.
Conclusion: Treatment with D-Rd significantly prolonged OS compared with Rd alone. These results, together with the OS results observed with DARA in combination with bortezomib and dexamethasone in the phase 3 CASTOR study, demonstrate for the first time an OS benefit with DARA-containing regimens in RRMM. Our results support the use of DARA in pts with RRMM.
P13: CAN PATIENT-REPORTED OCULAR SYMPTOMS GUIDE DOSE MODIFICATIONS IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA RECEIVING BELANTAMAB MAFODOTIN?
R Popat1; A Badros2; S Kumar3; P Rodriguez-Otero4; A Cohen5; S Manier6; P Voorhees7; F Gay8; R Rifkin9; T Martin10; A Chari11; K Weisel12; A Farooq13; B Jeng2; W Chng14; H Lee15; J Berdeja16; V Jadhav17; A Tosolini17*; L Eliason17*; A Palumbo17†; M Dimopoulos18; S Lonial19; S Trudel20; P Richardson21; E Terpos18
1University College London Hospitals, NHS Foundation Trust, London (UK); 2University of Maryland School of Medicine, Baltimore (USA); 3Mayo Clinic, Rochester (USA); 4Clinica Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra, Navarra (Spain); 5Perelman School of Medicine, University of Pennsylvania, Philadelphia (USA); 6Lille University Hospital, Lille (France); 7Levine Cancer Institute - Atrium Health, Charlotte (USA); 8University of Turin, Turin (Italy); 9UC Health, Steamboat Springs (USA); 10University of California San Francisco, San Francisco (USA); 11Mount Sinai, New York (USA); 12University Medical Center of Hamburg-Eppendorf, Hamburg (Germany); 13University of Chicago Medical Center, Chicago (USA); 14National University Cancer Institute of Singapore, Singapore; 15The University of Texas MD Anderson Cancer Center, Houston (USA); 16Sarah Cannon Research Institute, Nashville (USA); 17GlaxoSmithKline, Bengaluru (India), 17*Upper Providence (USA), 17†Zug (Switzerland); 18National and Kapodistrian University of Athens School of Medicine, Athens (Greece); 19Winship Cancer Institute of Emory University, Atlanta (USA); 20Princess Margaret Cancer Centre, Toronto (Canada); 21Dana-Farber Cancer Institute, Boston (USA)
Introduction: Belantamab mafodotin (belamaf) is a B-cell maturation antigen (BCMA)-targeting antibody-drug conjugate approved as a monotherapy for triple-class refractory adult patients with relapsed/refractory multiple myeloma (RRMM). This hypothesis generating post hoc analysis of DREAMM-2 trial (NCT03525678) data examined relationships between corneal exam findings, best-corrected visual acuity (BCVA) changes and direct patient-reported ocular symptoms per the Ocular Surface Disease Index (OSDI) questionnaire. This approach may provide insight into relationships between corneal exam findings, BCVA, ocular symptoms, impact on quality of life to determine if BCVA decline and symptoms can guide dosing. Surrogate marker identification for results from corneal exam findings would help providers determine if dosing adjustments are necessary.
Methods: Snellen chart BCVA assessment and corneal eye exams were performed on all patients receiving belamaf (2.5 mg/kg, q3w) by ECPs at baseline (BL) and before each dose. Corneal exam findings (keratopathy) and BCVA were assessed per protocol-defined criteria. Grade (GR) assessment, relative to BL, was based on the worst finding in the worse eye. Patient-reported ocular symptoms and vision-related functioning, as per the OSDI, were used to evaluate the impact of treatment-related ocular toxicity. The OSDI patient-reported outcome questionnaire assesses eye symptoms/effects on vision-related function and was performed in all patients before each belamaf dose. Items 1–5 address the frequency of eye-related symptoms and items 6–9 address functional limitation frequency. OSDI was considered positive, clinically meaningful and potentially treatment associated when at least one question 1–5 (sensitivity to light, gritty/painful eyes, blurred or poor vision) was reported as experienced “all of the time” and at least one question 6–9 (driving at night, reading, working with PC or watching TV) was reported as experienced “most of the time.”
Results: GR 3–4 (severe) keratopathy was observed 5% of the time in patients not reporting frequent ocular symptoms measured by the OSDI questionnaire (no items 1–9 ≥ “most of the time”). In patients who reported no items 1–5 “all of the time” AND no items 6–9 ≥ “most of the time” (OSDI negative), GR 3–4 keratopathy was observed 6.5% of the time (Table). In patients who reported “no deterioration from BL” for any OSDI eye-related symptoms or functional limitations, GR 3–4 keratopathy was observed ~3%–7% of the time and GR 0–2 (mild) keratopathy ~23%–34% of the time. Similar results were observed in patients with BL BCVA ≤20/30 who reported “no deterioration from BL” for any eye-related adverse events (AEs) or functional limitations (GR 3–4 keratopathy: ~2%–6% of the time; GR 0–2 keratopathy: ~19%–28% of the time); patients with worse BL visual acuity (BCVA >20/30) who reported “no deterioration” for items 1–9 had lower incidence of GR 3–4 (~0%–1%) and GR 0–2 keratopathy (~3%–8%).
Conclusions: These results suggest that hematologists/oncologists may be able to use ocular symptoms and the OSDI tool as potential surrogate markers for eye exam results to help determine whether dosing changes are needed. Validation with other belamaf dose regimens is ongoing.
Funding Source: GSK(205678)
Encore statement: Previously presented as Poster 2746 at the American Society of Hematology Annual Meeting, 11–14 December 2021; submitted with permission and on behalf of the original authors.
P14: DREAMM-9: PHASE I STUDY OF BELANTAMAB MAFODOTIN PLUS STANDARD OF CARE IN PATIENTS WITH TRANSPLANT-INELIGIBLE NEWLY DIAGNOSED MULTIPLE MYELOMA
S Usmani1; A Alonso2; H Quach3; Y Koh4; A Guenther5; CK Min6; X Leleu7; AO Abdallah8; A Oriol9; B Bessemer10; M Garg11; I Sandhu12; K Weisel13; E Ocio San Miguel14; M Cavo15; X Zhou16; M Kaisermann16*; L Mis16†; D Williams16*; A Yeakey16‡; G Ferron-Brady16*; D Figueroa16*; B Kremer16*; I Gupta16*; W Janowski17
1Levine Cancer Institute, Charlotte (USA); 2Hospital Quirón Madrid, Madrid (Spain); 3St Vincent’s Hospital Melbourne, Melbourne (Australia); 4Seoul National University Hospital, Seoul (South Korea); 5Helios Kliniken Schwerin GmbH, Schwerin (Germany); 6The Catholic University of Korea Seoul St. Mary’s Hospital, Seoul (South Korea); 7CHU de Poitiers, Poitiers (France); 8University of Kansas, Kansas City (USA); 9Institut Catala d’Oncologia (ICO) -Hospital Universitari Germans Triasi Pujol (HUGTP), Badalona (Spain); 10University of Tuebingen, Tübingen (Germany); 11Leicester Royal Infirmary, Leicester, (UK); 12University of Alberta, Edmonton (Canada); 13University Medical Center Hamburg-Eppendorf, Hamburg (Germany); 14Hospital Universitario Marqués de Valdecilla (IDIVAL), University of Cantabria, Santander (Spain); 15IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istitutodi Ematologia “Seràgnoli”, Universitàdegli Studi di Bologna, Bologna (Italy); 16GlaxoSmithKline, Waltham (USA), 16†Mississauga (Canada), 16‡Research Triangle Park (USA); 17Calvary Mater Newcastle, Newcastle (Australia).
Background: The bortezomib, lenalidomide, and dexamethasone (VRd) regimen is a SoC for NDMM. Belamaf, a B-cell maturation antigen (BCMA)–targeting antibody-drug conjugate, demonstrated durable responses in patients with relapsed/refractory multiple myeloma. Preclinical studies of belamaf in combination with bortezomib/lenalidomide suggest enhanced antimyeloma activity. We report preliminary findings of belamaf + VRd for patients with TI NDMM.
Materials and Methods: DREAMM-9 (NCT04091126) is an ongoing Phase I, open label, randomized, dose and schedule evaluation trial. Adults with TI NDMM and ECOG status 0–2 are eligible. VRd is administered Q3W until Cycle 8, followed by lenalidomide + dexamethasone (Rd) Q4W. Belamaf + VRd is administered until Cycle 8, and with Rd thereafter. The currently evaluated belamaf dose cohorts are: Cohort 1 (1.9 mg/kg Q3/4W), Cohort 2 (1.4 mg/kg Q6/8W), Cohort 3 (1.9 mg/kg Q6/8W), Cohort 4 (1.0 mg/kg Q3/4W), and Cohort 5 (1.4 mg/kg Q3/4W). Primary endpoint is safety. Secondary endpoints include efficacy, tolerability, and pharmacokinetics (PK).
Results: Overall 36 patients were treated across the 5 cohorts. The median (range) age was 74.0 (63–80) years; 56% patients were male, 17 (47%) had stage 2 disease, 3 (8%) had extramedullary disease, 6 (17%) patients had high risk cytogenetic abnormalities; the median number of belamaf cycles ranged from 1–9. No new safety signals were observed. Across Cohorts 1–5, all patients experienced AEs related to study treatment; 1 patient in Cohort 1 died due to COVID-19 infection. The most common AEs leading to dose modification were thrombocytopenia, neutropenia, and corneal events. Patients in Cohort 2 and 3 had the lowest number of Grade ≥3 corneal events (3 and 2 events, respectively).
All 12 patients in Cohort 1, all 6 in Cohorts 3 and 5, and 5/6 patients in Cohorts 2 and 4 have responded to the treatment; ≥half of patients in each cohort achieved very good partial response or better. As of data cut-off, 3/12 patients in Cohort 1, 2/6 in Cohort 4, and 1/6 patients each in Cohorts 3 and 5 remained in complete response. Belamaf PK profile was similar to that observed in patients with RRMM taking into consideration baseline patients characteristics.
Conclusions: Preliminary data suggest addition of belamaf to VRd did not reveal new safety signals and demonstrates high response rates, albeit with short follow-up. The trial is ongoing to confirm safety and evaluate the efficacy of belamaf + VRd.
Funding: GSK (Study 209664); drug linker technology licensed from Seagen Inc; mAb produced using POTELLIGENT Technology licensed from BioWa.
Encore statement: Previously presented as Poster 2738 at the American Society of Hematology Annual Meeting, 11–14 December 2021; submitted with permission and on behalf of the original authors.
P16: DARATUMUMAB MONOTHERAPY HAS A FAVORABLE EFFECT ON BONE METABOLISM IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA; RESULTS OF THE PHASE 2 REBUILD STUDY
E Terpos1; I Ntanasis-Stathopoulos1; E Kastritis1; E Hatjiharissi2; E Katodritou3; E Eleutherakis-Papaiakovou1; E Verrou3; M Gavriatopoulou1; A Leonidakis4; S Delimpasi5; P Malandrakis1; M-C Kyrtsonis6; M Papaioannou2; A Symeonidis7; MA Dimopoulos1
1Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece; 2First Department of Internal Medicine, Aristotle University of Thessaloniki, School of Medicine, AHEPA University Hospital, Thessaloniki, Greece; 3Department of Hematology, Theagenio Cancer Hospital, Thessaloniki, Greece; 4Health Data Specialists S.A., Athens, Greece; 5Department of Hematology and Bone Marrow Transplantation Unit, Evangelismos Hospital, Athens, Greece; 6First Department of Propedeutic Internal Medicine, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece; 7Hematology Division, Department of Internal Medicine, University of Patras Medical School, Patras, Greece
Introduction: Non-invasive biomarkers of bone metabolism are indicative of bone dynamics during anti-myeloma treatment. Daratumumab (dara) inhibits in vitro osteoclastogenesis and bone resorption. We assessed the impact of dara monotherapy on bone remodeling in patients (pts) with relapsed/refractory multiple myeloma (RRMM).
Methods: REBUILD was a prospective, open-label, phase 2 study conducted in six centers in Greece. Eligible pts were adults with RRMM, who had ≥2 prior lines of therapy including lenalidomide and a proteasome inhibitor (PI). Exclusion criteria included previous treatment with anti-CD38 antibodies, including dara. Pts received intravenous dara according to the usual clinical practice. The primary endpoint was the percent change from baseline in values of bone resorption markers C-terminal cross-linking telopeptide of type 1 collagen (CTX) and tartrate-resistant acid phosphatase isoform 5b (TRACP-5b) after 4 months of dara monotherapy. Secondary endpoints included the change from baseline to 4 months of dara monotherapy in bone formation markers (e.g., bone-specific alkaline phosphatase [bALP], osteocalcin [OC], and procollagen type-I N-propeptide [PINP]), markers of osteoclast regulation (RANKL, osteoprotegerin, dicckopf-1 [DKK-1], sclerostin and C-C motif ligand-3 [CCL3]), progression-free survival (PFS), and overall survival (OS).
Results: The present analysis is based on 33 pts with available data. The pts’ median (range) age was 73.0 (52.0–84.0) years, and most were female (18, 54.5%). Most (16, 48.5%) pts had >10 lytic bone lesions at baseline. Six (18.2%) pts received bisphosphonates along with dara monotherapy. The ORR (Partial Response or better [≥PR]) was 63.6% (CR: 3.0%, VGPR: 21.2%, PR: 39.4%). The CTX median change from baseline to 4 months was 3.9%, with 13 (39.4%) and 11 (33.3%) pts having a ≥20% and ≥30% reduction in CTX levels, respectively. The TRACP-5b levels decreased from baseline to 4 months by a median of 2.6%, with 10 (30.3%) and 6 (18.2%) pts having a ≥20% and ≥30% reduction in TRACP-5b levels, respectively. The median changes from baseline to 4 months in the CTX and TRACP-5b levels for pts with a ≥PR at 4 months were -1.3% and -2.6%, respectively; the respective changes for pts without response (i.e., pts with minimal response, stable disease, disease progression, or no response assessment before death) were 5.3% and -7.2%. The levels of the bone formation markers bALP, OC, and PINP increased from baseline to 4 months, the median changes being 18.4%, 92.6% and 10.2%, respectively. For pts with ≥PR at 4 months, the median changes from baseline to 4 months in bALP, OC, and PINP levels were 25.3%, 146.0% and 15.7%, respectively; the respective changes for pts without response were 18.3%, 15.6% and -7.3%. Other major differences at 4 months included the decrease in DKK-1 by a median of 17.5%, the decrease in CCL3 by 16.0%. The median (95% confidence interval) PFS and OS were 9.3 (6.7–15.3) and 21.2 (11.4–not reached) months, respectively; the respective results in all 57 patients were 4.7 (3.0–7.2) and 10.5 (8.4–18.1) months.
Conclusions: In these highly pre-treated pts with MM, monotherapy with dara showed a positive effect on bone metabolism; OC had a 3-fold increase after 4 months of therapy. The reduction in TRACP-5b and in CCL-3 but not in CTX suggests a mild inhibitory effect on osteoclasts by dara.
P17: DARATUMUMAB (D) PLUS LENALIDOMIDE (R) AND DEXAMETHASONE (D) AS SALVAGE THERAPY FOR PATIENTS WITH REFRACTORY-RELAPSED MULTIPLE MYELOMA (RRMM): INITIAL FOLLOW-UP OF AN ITALIAN MULTICENTER RETROSPECTIVE CLINICAL EXPERIENCE BY “RETE EMATOLOGICA PUGLIESE”
G Mele1; N Cascavilla2; N Di Renzo3; A Guarini4; P Mazza5; L Melillo6; V Pavone7; G Tarantini8; P Curci9; AP Falcone2; C Germano8; A Mele7; G Palazzo5; G Palumbo6; G Reddiconto3; B Rossini4; G Specchia9; P Musto9; D Pastore1
1Haematology, Ospedale A. Perrino, Brindisi; 2Haematology, Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG); 3Haematology, Ospedale V. Fazzi, Lecce; 4Haematology, Ospedale Giovanni Paolo II, Bari; 5Haematology, Ospedale G. Moscati, Taranto; 6Haematology, Ospedali Riuniti, Foggia; 7Haematology, Ospedale Cardinale Panico, Tricase (LE); 8Haematology, Ospedale Monsignor R. Dimiccoli, Barletta (BA); 9Haematology, University of Bari Medical School, Bari.
Introduction: DRd is a combination regimen approved for the treatment of RRMM. We report here a multicenter retrospective analysis of 127 consecutive patients (63 F and 64 M) with symptomatic RRMM, from January 2018 to December of 2020 treated with DRd as salvage therapy, regardless of age, comorbidities, impaired kidney function and reduced bone marrow reservoir. Our cohort represents a patients population closer to real world clinical practice.
Patients: The median age at diagnosis was 66 years (32-83). The median age at the start of DRd was 70.2 years (41-85). The median time to the start of DRd from diagnosis was 3 years (0-19). The median therapy lines received were 1 (1-4). 49 patients (38.6%) had previously undergone single or tandem ASCT. The last treatment received before the D-based regimen was VMP (35%) or VTd (32%). 93 patients (73.2%) had relapsed MM and 34 (26.8%) patients had refractory MM. 80.3% of MM relapsed patients had been previously exposed to only one therapy.
Results: After a median follow-up of 28 months from the start of study treatment, the median number of cycles administered was 12 (1-33). The ORR was 86.5% with CR 30.2%, VGPR 33.6%, PR 22.7%. Surprisingly, an encouraging ORR was observed also in the 13% of L-refractory patients: 75% (CR 25%, VGPR 19%, PR 31%). Median TTR was 1 month (1-7). Best response was achieved at a median number of 5 cycles. Median TTP and median OS were not reached (1-year OS: 85.9%; 2-years OS: 73.7%). Both OS and TTP were significantly affected by “the high-quality response” (p <0.001). TTP was worst for those who had received ≥ 2 prior lines of treatments vs those who had received < 2 lines of treatment (p 0.07), but the “number of prior lines of treatment” is far from the p-value significance threshold. “Baseline disease status” and “age at starting treatment” did not affect either OS or TTP. R was reduced to 15 or 10 mg for haematological toxicities (19%) and non-haematological toxicities (renal failure 6%, gastrointestinal toxicity 6%, skin rash 5%, musculoskeletal toxicity 4%, thrombotic events 3%), while a delay before subsequent course administration was recorded because of neutropenia (18%), infections (15%), diarrhoea (5%) and thrombotic events (2%). 20.6% of patients discontinued treatment because of relapse, and 3.2% for haematological toxicities. After a median follow-up of 12 months from the start of study treatment, grade 3/4 neutropenia (36%) was the most common haematological toxicity. After a median follow-up of 28 months from the start of treatment, grade 3/4 neutropenia (37.7%) continues to be the most common haematological adverse event. As regards non-haematological adverse events, after a median follow-up of 12 months, fatigue (32%) was the most common, while FUO/infections occurred in 15% of patients, skin rash and deep vein thrombosis in 7% of patients. After a median follow-up of 28 months, fatigue (24.8%) and FUO/infections (17.3%) continue to be the most common non-haematological adverse events and diarrhoea occurred in 5.8% of patients.
Conclusion: In our experience, the ORR was lower than what was previously reported in the POLLUX trial (ORR 86.5% vs 93%). The lower ORR observed could be related to a less selected population. In fact, in our survey, no exclusion criteria were applied. In addition, unfortunately, the interference of D with immunofixation and serum protein electrophoresis assays may lead to an underestimation of CR.
P18: DARATUMUMAB (D) PLUS BORTEZOMIB (V) AND DEXAMETHASONE (D) AS SALVAGE THERAPY FOR PATIENTS WITH REFRACTORY/RELAPSED MULTIPLE MYELOMA (RRMM): INITIAL FOLLOW-UP OF AN ITALIAN MULTICENTER RETROSPECTIVE CLINICAL EXPERIENCE BY “RETE EMATOLOGICA PUGLIESE”
G Mele1; N Cascavilla2; N Di Renzo3; A Guarini4; P Mazza5; L Melillo6; V Pavone7; G Tarantini8; P Curci9; AP Falcone2; C Germano8; A Mele7; G Palazzo5; G Palumbo6; G Reddiconto3; B Rossini4; G Specchia9; P Musto9; D Pastore1
1Haematology, Ospedale A. Perrino, Brindisi; 2Haematology, Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo (Foggia); 3Haematology, Ospedale V. Fazzi, Lecce; 4Haematology, Ospedale Giovanni Paolo II°, Bari; 5Haematology, Ospedale G. Moscati, Taranto; 6Haematology, Ospedali Riuniti, Foggia; 7Haematology, Ospedale Cardinale Panico, Tricase (Lecce); 8Haematology, Ospedale Monsignor R. Dimiccoli, Barletta (Bari), ITALY; 9Haematology, University of Bari Medical School, Bari.
Introduction: Real-life reports of experiences with D-based combination therapies in RRMM are very limited. We report herein a multicenter retrospective analysis of 65 consecutive patients (M 59.4%, F 40.6%) with symptomatic RRMM, from January 2018 to December of 2020, treated with DVd as salvage therapy at 9 haematological centers in Puglia.
Patients: The median age at diagnosis was 62.5 years (range 36-81). The median age at the start of DVd from diagnosis was 68.1 years (range 40-81). The median time to the start of DVd from diagnosis was 4 years (range 0-16). The median therapy lines received were 3 (range 1-6). 38 patients (58%) had previously undergone single or tandem ASCT. The patients were previously exposed to V (93%) and carfilzomib (32%), in addition to a prior exposure to IMIDs (Len 78%, Thal 41%, Pom 8%). The last treatment received before the DVd regimen was KRd (29%) or Rd (26%). 52 (80%) patients had relapsed MM, while 13 (20%) patients had refractory MM. 73.9% of MM relapsed patients had been heavily treated.
Results: After a median follow-up of 28 months from the start of study treatment, the median number of cycles administered was 8 (range 1-34). 7% of patients required dose reduction/adjustment (V to 1 mg/m2) for peripheral neuropathies (5%) and thrombocytopenia (2%), respectively, while 25% of patients were shifted to a weekly schedule of V and d for haematological toxicities (14% thrombocytopenia, 11% neutropenia), and 5% for constipation. 55.4% of patients discontinued treatment due to relapse. The ORR was 72.6% (CR 8.1%, VGPR 19.3%, PR 45.2%). Median TTR was 1.5 months (range 1-9). Best response was achieved at a median number of 5 cycles. Median TTP was 10.8 months (95%-CI: 7.1-13.8). Median OS was not reached (1-year OS: 70.2%; 2-years OS: 58.9%). OS was significantly affected both by “the high-quality response” (p <0.001) and “number of prior lines of treatment” (p 0.02), while TTP was significantly affected only by the “high-quality response” (p <0.001). “Baseline disease status” and “age at starting treatment” did not affect either OS or TTP. We evaluated haematological and non-haematological toxicities after a median follow-up of 12 and 28 months. After a median follow-up of 12 months from the start of study treatment, grade 3/4 thrombocytopenia (26%) was the most common haematological toxicity. After a median follow-up of 28 months from the start of treatment, grade 3/4 thrombocytopenia (27.6%) continues to be the most common haematological adverse event. As regards non-haematological adverse events, after a median follow-up of 12 months, FUO/infections (32%) were the most common non-haematological adverse event. After a median follow-up of 28 months, FUO/infections (15%) continue to be the most common non-haematological adverse event, although the incidence rate has reduced by half, and constipation occurred in 7.6% of patients.
Conclusions: The ORR, in our experience, was lower than what was previously reported in the CASTOR trial (ORR 72.6% vs 85%). The following imperative considerations must be pointed out. First, the lower ORR observed in our small experience could be related to a less selected population. Second, the majority of patients 1) were heavily pretreated, 2) had been previously exposed to at least one proteasome inhibitor and 3) had previously undergone continuous treatment with KRd or Rd. Nevertheless, encouraging out-comes were observed, suggesting that patients can benefit from this effective therapy even at advanced lines of therapy.
P20: POLYCENTRIC “REAL LIFE” STUDY OF BELANTAMAB MAFODOTIN FOR RELAPSED/REFRACTORY MULTIPLE MYELOMA
R Iula1; F Trastulli2; R Della Pepa1; A D’Ambrosio1; M Romano1; A Leone1; G Gaeta1; S Palmieri2; S Rocco2; F Pane1; F Ferrara2; L Catalano1
1Hematology - Department of Clinical Medicine and Surgery, Federico II University, Naples (Italy); 2Division of Hematology and Stem Cell Transplantation Program, AORN Cardarelli Hospital, Naples (Italy)
Background: Despite recent therapeutic advances, multiple myeloma (MM) remains an incurable disease.
Particularly poor outcomes were described for “triple-refractory”patients, who are refractory to at least one proteasome inhibitor, immunomodulatory agent and anti-CD38 antibody.
In this setting, we need further therapeutic options, and the DREAMM-2 study has shown interesting responses with Belantamab Mafodotin (BM). However, real-life studies are still lacking.
Methods: We performed a real-life analysis in two Italian centers (AOU Federico II and AORN Cardarelli, both in Naples). Unselected triple refractory patients received BM monotherapy as part of a compassionate use program. Whole sample (WS) included patients who received at least 1 dose of BM; evaluable population (EP) included only patients receiving not less than 2 BM cycles.
Primary endpoint was overall response rate (ORR, i.e rate of patients with partial response -PR- very good partial response -VGPR- or complete response –CR-). Secondary outcomes included median progression free survival (mPFS), median overall survival (mOS), clinical benefit rate (CBR, i.e. rate of patients achieving stable disease -SD- or better), duration of response (DoR), time to response (TTR), time to best response (TTBR) and toxicity.
BM was i.v. infused at the dose of 2.5 mg/kg every 3 weeks until progressive disease (PD) or unacceptable toxicity. Before treatment, 20 mg i.v. dexamethasone and 10 mg i.v. chlorphenamine were administered. Each patient received ice packs on eyes throughout the drug infusion, and anti-infective and eye prophylaxis (corticosteroid and lubricant eye drops) were prescribed at home.
Laboratory assessments were performed at baseline and at day 1 of each cycle. All patients underwent eye examination before the first cycle of BM and as clinically indicated thereafter.
Results: Seventeen patients were treated from June 2020 to December 2021. Median age was 63 years (r.: 51-77); median time from the diagnosis was 7 years (r.: 1-19), and median number of previous lines of therapy was 7 (r.: 4-14).
In the WS (17 patients), median follow-up was 7 months (r.: 0.5-18) and median number of cycles was 3 (r.: 1-18). ORR was 35%, mPFS and mOS were 3 months (r.:0.5-18) and 8 months (r.:1-18), respectively.
In the EP (14/17), ORR was 43% (6/14), including 1 CR (7%) and 5 PR (36%). Two patients (14%) showed SD, with a CBR of 57% (8/14). Among responsive patients (RP), 2 patients received successfully consolidation with a second ASCT; 3 patients are to date still on treatment and 1 patient experienced PD after 3 months of PR. In the EP, mPFS and mOS were 4 months (r.: 1-18) and 11 months (r.:2-18), respectively.
Among RP, DoR, mPFS and mOS were not reached, TTR was 2 months (r.: 2-8) and TTBR was 6 months (r.: 2-8).
Thrombocytopenia (57%) and keratopathy (21%) were the most frequent adverse reactions. Two patients with grade 3 eye toxicity discontinued the therapy and eye damage resolved.
Interpretation: Our analysis confirms the efficacy of BM and compares favorably with DREAMM-2 study (ORR: 43% vs 32%, mPFS: 4 vs 2.8 months, mOS: 11 vs 13.7 months, respectively).
Moreover, we found less corneal toxicities (21% vs 72%), more thrombocytopenia (57% vs 38%) and no infusion-related reactions (0% vs 21%).
In conclusion, BM shows meaningful anti-MM activity and a manageable toxicity profile even outside controlled clinical trials, proving to be an effective novel strategy in advanced MM.
Ixazomib & Iberdomid & Real world data
P07: RESULTS FROM THE CC-220-MM-001 DOSE-EXPANSION PHASE OF IBERDOMIDE PLUS DEXAMETHASONE IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA
N. W. C. J van de Donk1; R Popat2; C Hulin3; S Jagannath4; A Oriol5; P. G Richardson6; T Facon7; K Weisel8; J. T Larsen9; M Minnema10; A Abdallah11; A. Z Badros12; S Knop13; E. A Stadtmauer14; M Chen15; T. V Nguyen15; A Amin15; T Peluso16; S Lonial17
1Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Department of Hematology, Cancer Center Amsterdam, Amsterdam, Netherlands; 2NIHR UCLH Clinical Research Facility, University College London Hospitals NHS Foundation Trust, London, UK; 3Service d’Hématologie Hôpital Haut-Lévêque, CHU Bordeaux, Pessac, France; 4The Mount Sinai Hospital, New York, NY, USA; 5Catalan Institute of Oncology and Josep Carreras Institute, Hospital Germans Trias i Pujol, Badalona, Spain; 6Dana-Farber Cancer Institute, Boston, MA, USA; 7Service des Maladies du Sang, CHRU de Lille - Hôpital Claude Huriez, Lille, France; 8University Medical Center of Hamburg-Eppendorf, Hamburg, Germany; 9Mayo Clinic Arizona, Phoenix, AZ, USA; 10University Medical Center Utrecht, Utrecht, Netherlands; 11University of Kansas Medical Center, Kansas City, KS, USA; 12Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA; 13Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany; 14University of Pennsylvania, Philadelphia, PA, USA; 15Bristol Myers Squibb, Princeton, NJ, USA; 16Celgene International Sàrl, a Bristol-Myers Squibb Company, Boudry, Switzerland; 17Winship Cancer Institute, Emory University, Atlanta, GA, USA
Iberdomide (IBER), a potent oral cereblon E3 ligase modulator (CELMoD®) agent with enhanced tumoricidal and immune-stimulatory effects versus immunomodulatory (IMiD®) agents, has shown marked synergy with dexamethasone (DEX) and other standard myeloma treatments in preclinical models. IBER is being evaluated with various treatment combinations in patients (pts) with relapsed/refractory multiple myeloma (RRMM) in the phase 1/2 study CC-220-MM-001 (NCT02773030). Results from the dose expansion of IBER+DEX in pts with heavily pretreated, triple-class exposed (≥1 IMiD agent, ≥1 proteasome inhibitor [PI], and ≥1 CD38 monoclonal antibody [mAb]) RRMM are reported here.
Key eligibility criteria were: RRMM; ≥3 prior lines of therapy, including lenalidomide, pomalidomide, a PI, a glucocorticoid, and a CD38 mAb; progressive disease (PD) within 60 days of last myeloma therapy; and refractoriness to an IMiD agent, a PI, a glucocorticoid, and a CD38 mAb. Pts who had received prior anti-BCMA therapy were included in a separate cohort. Oral IBER (at the recommended phase 2 dose of 1.6 mg) was given on days (D) 1–21, plus DEX (40 mg; 20 mg if >75 years of age) on D1, 8, 15, and 22 of each 28-day cycle. The primary endpoint was to determine efficacy as overall response rate (ORR). Secondary endpoints included further efficacy and safety assessments; health-related quality of life (HRQoL) was an exploratory endpoint.
As of June 2, 2021, 107 pts had received IBER+DEX with a median age of 64 (44–83) years and a median time since initial diagnosis of 6.9 (1.6–24.5) years; 25.2% and 29.9% of pts had extramedullary plasmacytomas and high-risk cytogenetics, respectively. Median number of prior regimens was 6 (3–23), and prior therapies included autologous stem cell transplantation (78.5%), IMiD agents (100%), PIs (100%), and CD38 mAbs (100%); 99.1% of pts were refractory to last myeloma regimen and 97.2% of pts had triple-class refractory disease. Median follow-up was 7.69 (0.5–17.5) months; median number of cycles received was 4 (1–17), with 12.1% pts continuing treatment and 69.2% pts discontinuing due to PD.
ORR was 26.2%, with 0.9% stringent complete responses, 7.5% very good partial responses, and 17.8% partial responses; clinical benefit rate was 36.4% and disease control rate 79.4%. Median duration of response was 7.0 (4.5–11.3) months, median progression-free survival 3.0 (2.8–3.7) months, and median overall survival 11.2 (9.0–not reached) months. Similar response rates (ORR=25%) were reported among pts who had prior anti-BCMA therapy (N=24).
Overall, 82.2% of pts had grade (Gr) 3/4 treatment-emergent adverse events (TEAEs). Most frequent hematologic Gr 3/4 TEAEs were neutropenia (44.9%; 4.7% febrile neutropenia), anemia (28.0%), thrombocytopenia (21.5%), and leukopenia (20.6%); 27.1% of pts had Gr 3/4 infections with 10.3% reporting Gr 3/4 pneumonia. Occurrence of other Gr 3/4 non-hematologic TEAEs was generally low. IBER dose interruptions and reductions due to TEAEs occurred in 52.3% and 18.7% of pts, respectively; 4.7% of pts discontinued due to TEAEs. No pt discontinued IBER due to neutropenia.
Overall, HRQoL was maintained in these pts.
IBER+DEX showed promising efficacy and a manageable safety profile in pts with heavily pretreated, triple-class refractory RRMM, as well as in pts who had received prior anti-BCMA therapy. These results support further development of IBER in combination regimens in MM, including initiation of phase 3 trials.
P09: ATTRITION RATES IN MULTIPLE MYELOMA UNDER REAL WORLD CONDITIONS – AN ANALYSIS FROM THE AUSTRIAN MYELOMA REGISTRY
MA Benda1,2; H Ulmer3; R Weger4,5; T Winder1; B Hartmann1; Irene Strassl6; Siegfried Sormann8; E Willenbacher4; W Willenbacher4,5
1Feldkirch Academic Teaching Hospital, Internal Medicine II: Oncology, Hematology, Gastroenterology, Infectiology, Feldkirch; 2Private University of the Principality of Liechtenstein, Triesen, Principality of Liechtenstein, Triesen-Liechtenstein; 3Department of Medical Statistics, Informatics and Health Economics, Innsbruck Medical University, Innsbruck; 4Medical University of Innsbruck Internal Medicine V: Haematology & Oncology, Innsbruck; 5syndena, connect to cure, Innsbruck; 6Ordensklinikum Linz Elisabethinen, Internal Medicine I: Hematology with Stem Cell Transplantation, Hemostaseology and Medical Oncology, Linz; 7Medical University of Graz, Internal Medicine, Division of Hematology, Graz
Myleoma (MM) is characterised by frequent disease relapse with the need to introduce further lines of therapy (LoTs). How often all these theoretical options (Dimopoulos et al, 2021) are actually used in “Real World (RW) settings is considered controversial. In recent studies MM patients were found to have attriction rates (ARs) of up to 57% from LoT-1 to LoT-2. (Yong et al, 2016; Fonseca et al, 2020). We aim to assess ARs inside the Austrian Multiple Myeloma Registry and verify treatment patterns in the RW.
Methods: Patients with an index diagnosis made between JAN 2009 and AUG 2021 were eligible. Baseline data and treatment patterns were collected. Attrition was defined as being either deceased, progressive without receiving a further LoT, or being lost to follow up for 5 years or more.
Results: 571 pts. (n) were identified, of whom 57.1% were men. Median age at FD was 72 years (SD 12.7 y) with a median follow-up of 50.8 months (SD 44.1 m). 507 patients (88.1%) received the first LOT. In 1st LoT 43.2 % (n 219) received stem cell transplantation (SCT), 39.4% (n 200) received maintenance therapy (55.9 % of transplanted patients). The most common treatment in both transplanted and non-transplanted patients was VRD with 20.5 %. AR was nearly constant across LoT 1 to 4 pending between 19.9-27 %. Summarized ARs across all LoTs without SCT was 36% (n 98) compared to 27.7% in the SCT cohort (n 65). A further LoT was instituted in 37.7-48.6 % of pts. in LoT 1-4. Treatment duration (DoT) decreased with a mean of 12.4months in LoT-1 (SD 15.8) to 4 months (SD 15.4) in LoT-5. The exception is LoT-2 with a DoT of 18.4 months (SD 22.1). The latter may be explained by the short observation window with many patients in the 1st line not yet completed. The depth of remission decreases with each subsequent LoT, as PD is present in 10.5% of patients after 1st LoT compared to 29.7% of patients in LoT-5. The risk of attrition decreases by 32.1% in SCT pts. (CI95% 0.679: 0.47-0.99; p=0.045), and follow-up time becomes significantly longer at 53.8 months versus 47.2 months (p=0.007). Patients defined as being victims of attrition were significantly older at 75 years (SD 10.52months, p=0.003). Both factors influence each other, since patients with SCT were significantly younger (64 years, p=0.003). Frontline regimens with a PI and DEX alone increased the risk of falling into AR by 80% (95%CI 1.802:1.09-2.99; p=0.022) compared to triplet and quadruplet inductions. This might mirror the difference between fixed duration vs continuous therapies. Maintenance (nearly uniformly with LEN) in frontline regimens reduces the risk of attrition by 51.5% (95%CI 0,485:0.33-0.73; p<0.001).
Conclusions: Overall, our analyses demonstrated ARs significantly lower that than previously reported (Yong et al, 2016; Fonseca et al, 2020). This indicates that issues like drug access and reimbursement might also play major roles with respect to long term results in MM. Our results confirm a negative impact of doublet 1st treatments vs. more intensive ones. The positive impact of SCT on long term prognosis was also confirmed in the RW, in line with multiple clinical trials. The influence of anti-body-based quadruplet inductions cannot be analysed yet but will be assessed in the future. A more detailed breakdown of treatment patterns will be presented.
P11: IXAZOMIB WITH CYCLOPHOSPHAMIDE AND DEXAMETHASONE IN RELAPSED OR REFRACTORY MYELOMA: MUKEIGHT PHASE II RANDOMISED CONTROLLED TRIAL RESULTS
H Auner; S Brown; K Walker; J Kendall; B Dawkins; D Meads; G Morgan; M Kaiser; M Cook; S Roberts; C Parrish; G Cook
The Hugh and Josseline Langmuir Centre for Myeloma Research at Imperial College London, Clinical Trials Research Unit and Leeds Institute of Clinical Trials Research at University of Leeds, Academic Unit of Health Economics at Leeds Institute of Health Sciences at University of Leeds, Perlmutter Cancer Center at NYU Langone Health, The Institute of Cancer Research and The Royal Marsden Hospital NHS Foundation Trust, Centre for Clinical Haematology at Queen Elizabeth Hospital Birmingham; Department of Clinical Haematology at St James’s University Hospital; London, Leeds, New York, Birmingham
In the past two decades, treatment options for multiple myeloma (MM) have increased dramatically. While these developments hold great promise, many of the new treatment approaches will, for the foreseeable future, be inaccessible to large numbers of MM patients globally as they are costly and complex to deliver. The all-oral combination of ixazomib, cyclophosphamide, and dexamethasone (ICD) is well tolerated and effective in newly diagnosed and relapsed/refractory multiple myeloma (RRMM), and it is economically competitive.
We carried out MUKeight, a randomised, controlled, open, parallel group, multi-centre phase II trial in patients with RRMM after prior treatment with thalidomide, lenalidomide, and a proteasome inhibitor (ISRCTN58227268), with the primary objective to test whether ICD has improved clinical activity compared to cyclophosphamide and dexamethasone (CD) in terms of progression-free survival (PFS). Between January 2016 and December 2018, 112 participants were randomised between ICD (n=58) and CD (n=54) in 33 UK centres. Baseline characteristics were generally well balanced between the arms, with a median age of 70 years (range 46-82). In the entire study population, 73.6% (81/112) participants had a Charlson Comorbidity Index score of 0-2. More participants in the ICD arm had ECOG PS 1 or 2 (78.9% vs. 66.0%), and more were classed as frail (80.7% vs. 66.0%) by the modified IMWG frailty score. Overall, patients had a median of 4 (range 1-5+) prior lines of therapy, and median time from diagnosis to trial entry was 6.8 years (range 1.8-21.0). Median PFS in the ICD arm was 5.6 months, compared to 6.7 months with CD (hazard ratio (HR)=1.21, 80% CI 0.9-1.6, p=0.3634). Response rates were not significantly different between ICD and CD, with 24/57 participants (42.1%, 80% CI 33.2-51.5) in the ICD arm, and 21/53 (39.6%, 80% CI 30.5-49.4) in the CD arm, achieving at least PR. Median PFS in the ICD arm was 5.6 months (80% CI 4.1-7.2), compared to 6.7 months (80% CI 4.7-7.3) with CD (hazard ratio (HR)=1.21, 80% CI 0.9-1.6, p=0.3634). Overall survival (OS) was not significantly different between the arms, with a median OS of 14.1 months for ICD compared to 19.1 months for CD (HR=1.52, 80% CI 1.06-2.18, p=0.1346) Dose modifications or omissions, and serious adverse events (SAEs), occurred more often in the ICD arm. Of the 34 patients who discontinued CD due to disease progression, 20 crossed over to and received ICD. Median PFS from day 1 cycle 1 of crossover treatment was 4.6 months (80% CI 4.1-5.0). 5/20 participants (25.0%) achieved at least PR, including 3 VGPRs, with 10/20 (50.0%) participants achieving stable disease as their maximum response.
In summary, the addition of ixazomib to cyclophosphamide and dexamethasone did not improve key outcomes in the comparatively frail, old, and heavily pre-treated RRMM patients enrolled in the MUKeight trial. The results also suggest that the inexpensive and all-oral combination of CD can be associated with satisfactory responses, a finding that is particularly relevant for MM patients who do not have access to costly or complex novel drug combinations, or those with impaired access to healthcare facilities for reasons such as geographical remoteness, frailty, or public health concerns.
P12: TREATMENTS IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA: RETROSPECTIVE CHART REVIEW OF REAL-WORLD OUTCOMES FOR STANDARD OF CARE
M-C Vekemans1; M Delforge2; S Anguille3,4; J Depaus5; N Meuleman6; A Van de Velde4,7; I Vande Broek8; D Strens9; S Van Hoorenbeeck10; EJ Moorkens10; J Diels11; F Ghilotti12; S Dalhuisen13; S Vandervennet10
1Cliniques Universitaires Saint-Luc, Brussels (BE); 2Universitaire Ziekenhuizen Leuven, Leuven (BE); 3Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp (BE); 4Division of Hematology and Center for Cell Therapy & Regenerative Medicine, Antwerp University Hospital, Edegem (BE); 5Department of Haematology, Université catholique de Louvain, CHU UCL Namur, Yvoir (BE); 6Institut Jules Bordet, Université Libre de Bruxelles, Brussels (BE); 7Heilig Hartziekenhuis, Lier (BE); 8AZ Nikolaas, Haematology, Sint-Niklaas (BE); 9Realidad bvba, Grimbergen (BE); 10Janssen-Cilag NV, Beerse (BE); 11Janssen Pharmaceutica NV, Beerse (BE); 12Janssen-Cilag SpA, Cologno Monzese (IT); 13Janssen-Cilag BV, Breda (NL)
Introduction: The prognosis of patients with multiple myeloma has improved considerably with the introduction of immunomodulatory agents (IMiDs), proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (mAbs). However, most patients relapse and require further therapy, with no clear standard of care (SOC). Data on how patients with relapsed/refractory multiple myeloma (RRMM) are treated in clinical practice and outcomes to these treatments in the real-world setting are lacking. This study aimed to evaluate the outcomes of patients with triple-class (IMiD, PI, and anti-CD38 mAb) and triple-line exposed RRMM using real-world data from patients in Belgium.
Methods: This multicenter (7 non-academic and academic Belgian centers), observational study was conducted based on a retrospective chart review of adult patients with RRMM who had received ≥3 lines (IMiD, PI, anti-CD38-directed) of therapies (tri-exposed) and started subsequent treatment from March 2017 through May 2021. In patients meeting eligibility criteria, all treatment lines utilized were considered for analysis (as separate observations for patients who met the eligibility criteria more than once during the follow-up), with date of treatment initiation as specific baseline for each treatment line. Prognostic value with overall survival (OS), progression-free survival (PFS), and time-to-next therapy (TTNT) was evaluated using Cox proportional hazards models.
Results: A total of 112 patients with 237 eligible treatment-lines were included; median follow-up was 16.6 months. In 45% of initiated treatment lines, patients were refractory to 4 or 5 therapies, 62% had ≥5 prior lines, 22% had extramedullary disease; in 48% of observations, time-to-progression (TTP) in prior line was <4 months. After patients were tri-exposed, >50 unique regimens were initiated, with the most common being carfilzomib + dexamethasone (14%), pomalidomide + dexamethasone + chemotherapy (8%), and ixazomib + lenalidomide + dexamethasone (6%). Among included observations, 4% were exposed to anti-BCMA agents. The most frequently initiated therapies were: PI only (19%), PI + IMiD combinations (17%), and regimens that included anti-CD38 antibodies (15%). Median OS was 9.79 months (95% CI: 7.79, 12.22), median PFS was 3.42 months (95% CI: 2.79, 4.27), and median TTNT was 3.61 months (95% CI: 3.09, 4.57). The following factors were prognostic for worse outcomes for OS (Figure) and PFS: higher refractory status (p<0.001), being male (p=0.001), older age (p<0.001), shorter duration of prior lines (p<0.001), shorter TTP in prior line (p=0.025), and higher lactate dehydrogenase levels (p<0.002).
Conclusions: Real-world outcomes (OS, PFS, and TTNT) were poor in tri-exposed patients with RRMM. The wide variety of treatment regimens used in clinical practice confirms the absence of a clear SOC for these patients. These real-world data from patients in Belgium are consistent with those from other countries, underscoring the high unmet medical need for new and effective treatments for patients with RRMM.
P15: EVOLUTION OF MULTIPLE MYELOMA TREATMENT PATTERNS FROM 2015 THROUGH 2019: REAL-WORLD EVIDENCE FROM A EUROPEAN DATABASE STUDY
A Oriol Rocafiguera1; T H Steinmetz2; A Brescianini3; S Gonzalez-McQuire3; N Eugene4; A Abbasi4; S Wetten4; X Leleu5
1Institut Català d’Oncologia, Institut Josep Carreras, Hospital Germans Trias i Pujol - Badalona, Barcelona (ES); 2Oncology Cologne, Center for Hematology and Oncology, Cologne (DE); 3Amgen (Europe) GmbHM, Rotkreuz (CH); 4Amgen Ltd, Uxbridge (UK); 5Hôpital La Milétrie, CHU Poitiers, Poitiers (FR)
Novel treatment options in multiple myeloma (MM) have resulted in a dynamic and heterogeneous treatment landscape.
To describe real-world treatment patterns across five European countries from 2015–2019.
Using the MM Oncology Advantage database (IQVIA Ltd), this retrospective observational study analyzed data on patients receiving an ongoing treatment in any line from July 2015 through December 2019.
Triplets accounted for almost two-thirds of all first-line (1L) therapies overall and 51% of second-line (2L) regimens in 2019, but monotherapy/doublets were still mainly used in third line or later (3L+: 86% in 2015-2016; 62% in 2019) with a gradual increase of triplets during the period.
In 2019, most common 1L therapies were bortezomib (V)-based regimen with no immunomodulatory drug (IMiD) (37%), lenalidomide (R)-based without proteasome inhibitor (PI) (22%), and V and thalidomide (V+T) based (19%) regimens. Since 2015-16, V-based without IMiD, and Chemo±T regimens have decreased, and R-based regimens have increased over time (Table). V-based without IMiD (DE 51%; UK 38%; ES 35%; FR 30%; IT 29%) and R-based only (FR 30%; DE 24%, IT 27%; ES 23%) were most common in all countries in 1L except in UK and IT where V+T was the most common (42% and 35%, respectively).
For 2L in 2019, approximately half of patients were treated with a novel regimen and the remaining received mainly R-based only (34%) or V-based without IMiD (11%). From 2015 to 2019, use of V-based without IMiD and R-based only regimens nearly halved (Table). In 2019, R-based only was common in ES (50%) FR (41%) and IT (35%); daratumumab (D)+R was most common in DE (34%) and V-based without IMiD common in UK (27%).
For 3L+ in 2019, nearly half of patients received a novel regimen. About a third of patients received a pomalidomide (P)-based regimen consistently in 2019 and other years. Since 2015-16, overall use of R-based only, V-based without IMiD, and Chemo±T regimens have decreased from 64% to 18% in 2019 (Table). In 2019, P-based regimens were commonly used across all countries (FR 54%; IT 31%; DE 28%; ES 20%) except the UK where R-based only (37%) and other R regimens (42%) were used in almost all patients.
Since 2015, R use has increased three-fold in 1L accounting for 34% of regimens in 2019. Despite fluctuations in combinations, R use has remained constant at around 70% in 2L and around 35% in 3L+.
Treatment sequence in 616 patients receiving 3L in 2019 was described using 7 treatment classes: IMiD, monoclonal antibody [mAb] only, mAb+IMiD, mAb+PI, PI without IMiD, PI+IMiD, and other. There were 86 different sequence permutations, with the top 10 sequences comprising 58% of patients. Focusing on prior/current IMiD use, 65% didn’t receive an IMiD in 1L (no=400), 26% received T (nt=158) and 10% R (nR=58). Of patients without 1L IMiD (no=400), 81% received R in 2L, and 64% of them had another IMiD in 3L. Among 1L R patients (nR=58), 83% had no IMiD in 2L, of whom 56% received an IMiD in 3L (35% P; 21% R). Re-treatment with R occurred infrequently with 12% of all patients with re-treatment occurring at any time.
In conclusion, the uptake of novel agents since 2017 and the increased use of triplets (including R-based in 1L) continue to drive a changing MM treatment landscape with decreasing use of older combinations and increasing options at all lines of therapy. Differences in access to novel treatments might have influenced further heterogeneity between countries.
P22: A NON-INTERVENTIONAL, PROSPECTIVE, OBSERVATIONAL STUDY OF RELAPSED/REFRACTORY MULTIPLE MYELOMA PATIENTS TREATED WITH IXAZOMIB IN REAL-WORLD SETTINGS IN GREECE; INTERIM RESULTS OF THE ‘OL-ORAL’ STUDY
E Katodritou1; MC Kyrtsonis2; S Delimpasi3; E Spanoudakis4; G Vassilopoulos5; P Zikos6; N Viniou7; G Kaiafa8; M Papathanasiou9; V Pappa10; E Michalis11; I Adamopoulos12; K Kokoviadou13; G Tsirakis14; C Poziopoulos15; E Terpos16
1Department of Hematology, Theagenio anticancer hospital, Thessaloniki (GR); 2First Department of Propaedeutic and Internal Medicine Unit,University of Athens, Laikon General Hospital, Athens (GR); 3Department of Hematology and Bone Marrow Transplantation Unit, Evangelismos Hospital, Athens (GR); 4Department of Hematology, Democritus University of Thrace, Alexandroupoli (GR); 5Department of Hematology, University of Thessaly Medical School, Larissa (GR); 6”Agios Andreas” General Hospital of Patras, Patras (GR); 7First Department of Internal Medicine Unit,University of Athens Laikon General Hospital, Athens (GR); 81st Medical Propaedeutic Department of Internal Medicine,Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki (GR); 9Hematology Department - BMT Unit, G Papanikolaou Hospital, Thessaloniki (GR); 10Second Department of Propaedeutic and Internal Medicine Unit, University of Athens “ATTIKON” University General Hospital of Athens, Athens (GR); 11Department of Clinical Hematology, “G. GENNIMATAS” General Hospital of Athens, Athens (GR); 12Department of Hematology and Thalassemia, Kalamata General Hospital, Kalamata (GR); 13Department of Hematology, Papageorgiou General Hospital, Thessaloniki (GR); 14Department of Hematology, «Agios Georgios” General Hospital of Chania, Chania (GR); 15“METROPOLITAN” Athens Private Hospital, Athens (GR); 16Department of clinical therapeutics, University of Athens, Alexandra General hospital, Athens (GR).
Background: Ixazomib (IXA) combined with lenalidomide (LEN) and dexamethasone (DEX) (IRd) is approved for adults with multiple myeloma (MM) after ≥1 prior therapy. Real world data on IRD use in Greece are limited.
Aims: The objective of this study is to generate data on progression-free (PFS) and overall survival (OS) rates, as well as on medication adherence in IRd-treated MM patients.
Methods: Relapsed/refractory MM patients prescribed IRd for the first time, after 1-3 prior therapies, per the approved label, were eligible to consent and consecutively enrolled. Patients refractory to bortezomib (BOR), pre-treated with IXA, and having received >1 IRd cycles, are excluded. Data were collected by routine assessments, patient self-report, and medical chart review. We present the interim analysis results with cut-off at 24 months after first patient’s enrollment.
Results: Forty eligible patients [57.5% (23/40) males; median (interquartile range, IQR) age: 71.7 (64.8-77.3) years] were enrolled from Sep-2018 to Sep-2020 by 14 hospitals. Prior to IRd, 80.0% (32/40) of patients had received proteasome inhibitors [77.5% BOR; 7.5% carfilzomib], 65.0% (26/40) immunomodulatory drugs (57.5% LEN; 10.0% thalidomide; 2.5% pomalidomide), and 30.0% (12/40) autologous stem cell transplantation. At IRd initiation, the median (IQR) time since MM diagnosis was 3.5 (1.7-5.5) years. Of the patients, 85.0% (34/40) had ECOG PS 0-1, while 55.0% (22/40) had relapsed, 37.5% (15/40) relapsed and refractory, and 7.5% (3/40) refractory MM; 42.5% (17/40) were refractory to LEN.
IRd was initiated as 2nd, 3rd and 4th line in 67.5% (27/40), 22.5% (9/40) and 10.0% (4/40) of patients, respectively, at the recommended dose in 40.0% (16/40); IXA, LEN and DEX were started at a lower dose in 12.5%, 42.5%, and 50% of patients, respectively. Patient characteristics are shown in Table 1. Over a median (IQR) observation period of 6.9 (4.4-15.5) months, a median (IQR) of 7.5 (4.5-12.5) IRd cycles were received. Overall confirmed response rate [≥ partial response (PR)] in the response-evaluable patients was 56.7% (17/30) [61.1% in 2nd and 50% in ≥3rd line]. Mean (SD) time to first documented response ≥ PR was 58.1 (27.0) days. Kaplan-Meier estimated 12-month PFS and OS rates were 58.0% (95% CI: 37.8-73.7) and 82.9% (95% CI: 65.6-92.0) (Figure 1). Adherence to IXA was high (median ratio of capsules taken/prescribed: 1). IRd discontinuation rate was 59.0% (23/39), due to disease progression (12/23), adverse event (AE) (8/23), death (2/23; unrelated to IXA in both cases), and lack of efficacy (1/23). IXA-related AE rate was 42.5% (17/40) [serious AE rate: 17.5% (7/40)].
Conclusions: These results provide preliminary insight on patient and disease characteristics and clinical outcomes in MM patients treated with IRd in 2nd to 4th line in Greek routine settings. The final results are awaited to complement these findings in a larger patient cohort