B01: STROMAL CELL-NEUTROPHIL INTERACTIONS PROMOTE A PRO-TUMOR ENVIRONMENT IN MULTIPLE MYELOMA
M de Jong1; C Fokkema1; T van Heusden1; N Papazian1; S Tahri1; Z Kellermayer1; P Vermeulen1; M van Duin1; P van de Woestijne2; A Broijl1; P Sonneveld1; T Cupedo1
1Dept. of Hematology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands; 2Dept. of Cardiothoracic Surgery, Erasmus MC, Rotterdam, the Netherlands
Cancer development and progression are accompanied by alterations in the local microenvironment. In multiple myeloma (MM), interactions between myeloma cells and their niche are considered critical for disease pathobiology. Recently, we showed that the MM bone marrow (BM) is characterized by inflammatory mesenchymal stromal cells (iMSCs) that transcribe MM survival factors such as IL6, as well as myeloid cell modulation factors such as CCL2, ANXA1, C3 and chemokines that bind CXCR1 and 2. As myeloid cells have been implicated in the pathophysiology of various malignancies, we hypothesized that iMSCs attract and influence myeloid populations in the MM BM. Using flow cytometry, we observed increased expression of CXCR1/2 on CD15+ neutrophils in MM compared to those of controls. In addition, BM neutrophils in MM were activated, as evidenced by a switch to the active form of CD11b and the shedding of CD62L. As these findings suggested possible neutrophil – iMSC interactions, we set out to identify MM-associated alterations in neutrophils by scRNA sequencing of the full BM granulocytic lineage (n = 6 MM, and 4 controls). Immature and mature neutrophils in MM had increased transcription of genes encoding receptors for iMSC-derived signals, including IL6R, FPR and C3AR1. Moreover, we confirmed the activated state of neutrophils through elevated transcription of OSM, SLPI, and IL1B. These data suggest a contribution of iMSCs to neutrophil activation. This was confirmed by coculture of iMSCs and naïve neutrophils, which lead to shedding of neutrophilic CD62L. Further analysis of our transcriptional data revealed that a subpopulation of activated MM neutrophils expressed interferon (IFN)-response genes, including IFIT1, IFIT2 and ISG15. Importantly, by analyzing single cell immune datasets of MM bone marrow, we observed IFN-responsive neutrophils to be the only hematopoietic population transcribing TNFSF13B, encoding the MM-survival factor BAFF. Stimulation of naïve neutrophils with IFNγ or IFNβ induced TNFSF13Btranscription, but did not lead to BAFF secretion. This led us to hypothesize that BAFF release by activated neutrophils might be regulated by the inflammatory stromal environment. To test this hypothesis we cultured IFNγ-stimulated neutrophils in the presence of either non inflammatory MSCs or IL1β-activated iMSCs. Whilst the presence of iMSCs could induce BAFF release by neutrophils, non-inflammatory MSCs did not have this effect. Together these data suggest that stromal – immune interactions in MM are driving a tumor-supportive environment by inducing local release of plasma cell survival factors.
B03: SKELETAL-RELATED EVENTS AND ABNORMAL MRI PATTERN AT DIAGNOSIS ARE ASSOCIATED WITH INFERIOR OVERALL SURVIVAL IN PATIENTS WITH NEWLY DIAGNOSED MULTIPLE MYELOMA
Evangelos Terpos1; Nikolaos Kanellias1; Ioannis Ntanasis-Stathopoulos1; Maria Gavriatopoulou1; Efstathios Kastritis1; Vassilis Koutoulidis2; Despina Fotiou1; Magdalini Migkou1; Evangelos Eleutherakis-Papaiakovou1; Panagiotis Malandrakis1; Tina Bagratuni1; Maria Roussou1; Lia A Moulopoulos2; Meletios A Dimopoulos1
1,2National and Kapodistrian University of Athens School of Medicine, Athens, Greece
Introduction: Skeletal related events (SREs) remain a devastating consequence of multiple myeloma bone disease (MMBD). The presence of osteolytic disease increases the risk of SREs, which include pathologic fractures, spinal cord compression (SCC) and need for surgery or radiotherapy to bone.
Methods: In this context, we conducted this single-center, prospective, observational study to determine the incidence of SREs among MM patients who received treatment with novel agents during first-line therapy (NDMM) and explore possible correlations with disease characteristics, imaging finding and patient prognosis.
Results: Overall, data from 370 patients with NDMM according to the International Myeloma Working Group criteria are included in the present analysis. 200 (54%) were males, whereas 99% were Caucasian. The median age at diagnosis was 65 (range 31-92). One third (n=120) had an ECOG performance status (PS) of 0, 27% (n=100) a PS of 1, 8% (n=30) a PS of 2 and 32% (n=120) a PS of 3-4. One third were ISS stage 1 (34%), one third were ISS stage 2 (35%) and another third were ISS stage 3 (31%). 214 patients (58%) had IgG myeloma subtype, 90 patients had IgA (24%) and 62 patients had light-chain myeloma (17%). At diagnosis, the patients were evaluated for the presence of MMBD with at least one of the following imaging modalities: whole body X-rays (WBXR), whole body low dose computed tomography (WBLDCT) and magnetic resonance imaging (MRI). Based on the WBXR, 73 patients (20%) had no osteolytic lesions, 48 patients (13%) had 1 to 3 lytic lesions and 223 patients (60%) had more than 3 lytic lesions at diagnosis. According to WBLDCT, only 12 (3%) patients had no osteolytic lesions, whereas 7 (2%) patients had 1 to 3 lytic lesions and 76 (20%) had more than 3 lytic lesions (data available for 95 patients). Based on MRI findings, 58 patients (16%) had normal MRI pattern, 151 (40%) had focal MRI pattern, 139 (38%) patients had diffuse MRI pattern and 22 (6%) had variegated MRI pattern at diagnosis. Regarding treatment regimens at first line, 161 patients received IMiD– based regimens, 152 patients received PI-based treatments, 24 patients received PI and IMiD-based regimens, whereas 33 patients received therapy based on alkylating agents. SREs were observed in 183 patients at diagnosis: 154 (154/370 42%) patients presented with pathological fractures (110 with vertebral fractures, 29 with rib fractures and 15 with fractures of the long bones; 6 patients had both vertebral and 14 long bone or rib fractures), while 11 (11/370 3%) needed radiotherapy, 9 (9/370 2%) surgery to bone and 9 (9/370 2%) patients presented with spinal cord compression. The incidence of SREs at diagnosis was higher in patients with osteolytic lesions. Among patients with SREs at Diagnosis, 92.4% showed new SREs during the disease course with WBLDCT. Among those without SREs at diagnosis, 72.2% showed new SREs with WBLDCT. Importantly, patients with normal MRI pattern, who did not present with SREs at diagnosis, had statistically significant improved median overall survival in comparison with patients who had abnormal MRI pattern or presence of SREs at diagnosis (9.2 vs 6.5 years, p=0.048).
Conclusion: Approximately one half of NDMM patients presented with SREs at diagnosis. The presence of SRE or abnormal MRI pattern was associated with inferior survival. SREs lead to functional impairment and increased mortality rates; therefore early detection and prompt management is essential.
B04: COMBINATION OF SUBCUTANEOUS TECLISTAMAB WITH DARATUMUMAB IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM): RESULTS FROM A PHASE 1B MULTICOHORT STUDY
P Rodriguez-Otero1; B Dholaria2; E Askari3; D Reece4; N van de Donk5; A Chari6; H Goldschmidt7; A Krishnan8; T Martin9; M Mateos10; D Morillo3; C Rodriguez11; L Rosinol12; J San-Miguel1; A Balari13; R Wäsch14; K Weisel15; R Verona16; S Lin16; T Prior16; M Wade16; B Weiss16; J Goldberg17; A Oriol18; P Hari19
1Clínica Universidad de Navarra, Navarra (ES); 2Vanderbilt University Medical Center, Nashville (USA); 3Hospital Universitario Fundación Jiménez Díaz, Madrid (ES); 4Princess Margaret Cancer Centre, Toronto (CA); 5Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam (NL); 6Mount Sinai School of Medicine, New York (USA); 7University Hospital Heidelberg, Internal Medicine and National Center for Tumor Diseases (NCT), Heidelberg (DE); 8City of Hope Comprehensive Cancer Center, Duarte (USA); 9University of California, San Francisco, San Francisco (USA); 10University Hospital of Salamanca/IBSAL/CIC/CIBERONC, Salamanca (ES); 11Wake Forest University School of Medicine, Winston-Salem (USA); 12Institute of Hematology and Oncology, IDIBAPS Hospital Clínic University of Barcelona, Barcelona (ES); 13Institut Català d’Oncologia – Hospitalet, IDIBELL, University of Barcelona, Barcelona (ES); 14Freiburg University Medical Center, Freiburg (DE); 15University Medical Center Hamburg-Eppendorf, Hamburg (DE); 16Janssen Research & Development, Spring House (USA); 17Janssen Research & Development, Raritan (USA); 18Institut Català d’Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Barcelona (ES); 19Medical College of Wisconsin, Milwaukee (USA).
In the phase 1 MajesTEC-1 trial, teclistamab (Tec), a B-cell maturation antigen × CD3 T cell redirecting bispecific antibody, showed an overall response rate of 65% at 6.1-month follow-up. Daratumumab (Dara) is a monoclonal antibody that targets CD38 and is approved for the treatment of MM. In MM cell lines, the lytic activity of Tec was enhanced by pretreatment and combination treatment with Dara; thus, the combination of both agents may improve efficacy in RRMM by targeting discrete yet complementary antigens. We present data on patients (pts) with RRMM who received Tec + Dara in the phase 1b TRIMM-2 study (NCT04108195).
Eligible pts were ≥18 years of age, had a MM diagnosis, and received ≥3 prior lines of therapy (LOT; including a proteasome inhibitor [PI] and immunomodulatory drug [IMiD]) or were double refractory to a PI and IMiD. Receipt of anti-CD38 therapy ≤90 days was not allowed. The primary objectives were to identify the RP2D for the Tec + Dara combination and to assess safety of the combination. This analysis focuses on subcutaneous (SC) cohorts in the study. Responses were assessed by IMWG criteria and adverse events (AEs) by CTCAE v5.0 (cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS] were graded per ASTCT guidelines).
33 pts received SC Tec + Dara in different dosing cohorts: Dara 1800 mg + Tec 1500 μg/kg weekly (n=21), + Tec 3000 μg/kg weekly (n=5), + Tec 300 mg biweekly starting Cycle 3 Day 1 (C3D1; Tec 150 mg weekly in C1–C2; n=2), and + Tec 3000 μg/kg biweekly (n=5). 9 pts in the Dara 1800 mg + Tec 1500 μg/kg weekly cohort switched to Tec 3000 μg/kg biweekly dosing after C3D1. As of Jun 22, 2021, median follow-up across the cohorts was 3.6 months (range 0.1–10.4). Median age was 67 years (range 51–78) and 57.6% were female. Median number of prior LOT was 5 (range 2–16); 69.7% were triple-class exposed (prior Dara in all 69.7%) and 60.6% were penta-drug exposed. The most common AE was CRS (54.5%; all grade 1/2); median time to onset was 2 days (range 1–6), and median duration was 2 days (range 1–7). Other AEs (≥30%) were neutropenia (36.4%; all grade 3/4), thrombocytopenia (36.4%; grade 3/4 33.3%), anemia (36.4%; grade 3/4 24.2%), diarrhea (36.4%; grade 3/4 3.0%), nausea (30.3%; all grade 1/2), and pyrexia (30.3%; all grade 1/2). Overall, 66.7% of pts had grade 3/4 AEs. Infections occurred in 51.5% of pts (grade ≥3 24.2%). No ICANS events were reported. One pt in the Dara 1800 mg + Tec 3000 μg/kg weekly cohort died from treatment-unrelated bacterial pneumonia during C1, and 1 pt in the Dara 1800 mg + Tec 1500 μg/kg weekly cohort died from progressive disease. Responses are shown in the Table. Across the cohorts, median time to first response was 1.0 month (range 0–1.9). Median duration of response was not reached. Tec + Dara treatment led to proinflammatory cytokine production and T cell activation. The Tec pharmacokinetic profile was similar to that reported in the MajesTEC-1 study.
The combination of Tec + Dara had a manageable safety profile and showed preliminary efficacy in pretreated pts with MM. These findings warrant further investigation, and the randomized phase 3 MajesTEC-3 study will evaluate Tec + Dara vs Dara, pomalidomide, and dexamethasone or Dara, bortezomib, and dexamethasone in pts with RRMM.
B05: RESULTS FROM A META-ANALYSIS OF CILTACABTAGENE AUTOLEUCEL COMPARED TO PHYSICIAN’S CHOICE OF TREATMENT IN PATIENTS WITH RELAPSED OR REFRACTORY MULTIPLE MYELOMA
F Gay1; JG Berdeja2; V De Stefano3; P Hari4; B Hooper5; A Haltner5; S Kumar6; T Martin7; M-V Mateos8; P Moreau9; E Rosta5; IA Samjoo10; SZ Usmani11; K Weisel12; CC Jackson13; Y Olyslager14; JM Schecter13; M Vogel15; A Garrett16; S Lee16; T Nesheiwat16; L Pacaud16; C Zhou16; S Valluri15; LJ Costa17; Y Lin6
1Division of Hematology, University of Torino, Torino (IT); 2Sarah Cannon Research Institute, Nashville (USA); 3Section of Hematology, Department of Radiological and Hematological Sciences, Catholic University, Fondazione Policlinico A Gemelli, IRCCS, Roma (IT); 4Medical College of Wisconsin, Milwaukee (USA); 5EVERSANA, Sydney (CA); 6Mayo Clinic, Rochester (USA); 7UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco (USA); 8Institute of Cancer Molecular and Cellular Biology, University Hospital of Salamanca, Salamanca (ES); 9Clinical Hematology, University Hospital Hotel-Dieu, Nantes (FR); 10EVERSANA, Burlington (CA); 11Levine Cancer Institute-Atrium Health, Charlotte (USA); 12University Medical Center Hamburg-Eppendorf, Hamburg (DE); 13Janssen R&D, Raritan (USA); 14Janssen Pharmaceutica NV, Beerse (BE); 15Janssen Global Services, LLC, Raritan (USA); 16Legend Biotech USA, Piscataway (USA); 17University of Alabama at Birmingham, Birmingham (USA)
Introduction: The CARTITUDE-1 trial (NCT03548207) is evaluating ciltacabtagene autoleucel (cilta-cel), a novel chimeric antigen receptor T-cell therapy, in patients with relapsed/refractory multiple myeloma (RRMM) who are triple-class exposed to immunomodulatory drugs, proteasome inhibitors, and an anti-CD38 monoclonal antibody. Indirect treatment comparisons (ITCs) have been previously conducted between cilta-cel and physician’s choice of treatment (PCT) as no clear standard of care exists for patients with triple-class exposed RRMM and no direct head-to-head trials were performed to evaluate cilta-cel and other relevant treatments.
Objective: To perform meta-analyses to derive single summary effect estimates for overall survival (OS) and progression-free survival (PFS) using pooled ITCs that evaluated cilta-cel versus PCT in patients with triple-class exposed RRMM.
Methods: ITCs comparing the effectiveness of cilta-cel versus PCT on OS and PFS were included in this analysis. The data cut-off date for CARTITUDE-1 was February 2021, and data for PCT were based on the following sources: (i) Flatiron, a largely US community-based MM registry; (ii) long-term follow-up data from POLLUX (NCT02076009), CASTOR (NCT02136134), and EQUULEUS (NCT01998971), three global RRMM daratumumab randomized clinical trials; (iii) MAMMOTH, a retrospective study based in the US; and (iv) a representative German patient registry maintained by OncologyInformationService. The PCT group for each ITC comprised patients who fulfilled key eligibility criteria for the CARTITUDE-1 trial and was made comparable to CARTITUDE-1 using inverse probability of treatment weighting, resulting in ITCs that were appropriate for meta-analysis. The meta-analysis used a robust variance estimator to account for the use of CARTITUDE-1 in each pairwise ITC. The main meta-analyses included all patients treated with cilta-cel in CARTITUDE-1 compared with PCT. Sensitivity analyses considered ITC effect estimates based on all patients enrolled in CARTITUDE-1. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) are reported for pooled summary effect estimates.
Results: Based on available data, the main meta-analyses included four ITCs for OS and three ITCs for PFS. Significant improvement in OS (HR: 0.21, 95% CI: 0.13–0.34) and PFS (HR: 0.20, 95% CI: 0.07–0.63) was observed with cilta-cel versus PCT (Figure). Results of the main meta-analyses were confirmed with sensitivity analyses that included all enrolled patients.
Conclusions: Cilta-cel demonstrated a significant OS and PFS advantage versus PCT in the meta-analyses, highlighting its potential as an effective treatment in patients with triple-class exposed RRMM.
B06: SUBCUTANEOUS TALQUETAMAB IN COMBINATION WITH DARATUMUMAB IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM): PHASE 1B RESULTS
M Mateos1; P Hari2; N Bahlis3; A Chari4; NWCJ van de Donk5; B Dholaria6; AL Garfall7; H Goldschmidt8; KM Kortüm9; A Krishnan10; T Martin11; D Morillo12; A Oriol13; D Reece14; C Rodriguez15; P Rodríguez-Otero16; JF San-Miguel16; SZ Usmani17; R Verona18; SXW Lin18; TJ Prior18; M Wade18; B Weiss18; JD Goldberg19; E Askari12
1University Hospital of Salamanca/IBSAL/CIC/CIBERONC, Salamanca (ES); 2Medical College of Wisconsin, Milwaukee (USA); 3Arnie Charbonneau Cancer Institute, University of Calgary, Calgary (CA); 4Mount Sinai School of Medicine, New York (USA); 5Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam (NL); 6Vanderbilt University Medical Center, Nashville (USA); 7Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia (USA); 8University Hospital Heidelberg, Internal Medicine and National Center for Tumor Diseases (NCT), Heidelberg (DE); 9University Hospital of Würzburg, Würzburg (DE); 10City of Hope Comprehensive Cancer Center, Duarte (USA); 11University of California, San Francisco, San Francisco (USA); 12Hospital Universitario Fundación Jiménez Díaz, Madrid (ES); 13Institut Català d’Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Badalona (ES); 14Princess Margaret Cancer Centre, Toronto (CA); 15Wake Forest University School of Medicine, Winston-Salem (USA); 16Clínica Universidad de Navarra, Navarra (ES); 17Levine Cancer Institute/Atrium Health, Charlotte (USA); 18Janssen Research & Development, Spring House (USA); 19Janssen Research & Development, Raritan (USA)
MM remains incurable with most patients (pts) relapsing or becoming refractory to standard therapies, highlighting the need for novel agents. Talquetamab (Tal) is a bispecific antibody that binds to G protein-coupled receptor family C group 5 member D (GPRC5D), a receptor highly expressed on plasma cells with limited expression in healthy tissue, and CD3 to redirect T cells to GPRC5D-expressing MM cells. In the phase 1 MonumenTAL-1 study, an overall response rate of 70% at median 6.3-month follow-up was observed at the recommended phase 2 dose (RP2D) of Tal in pts with RRMM. Daratumumab (Dara) is a monoclonal antibody that targets CD38 and is approved for treatment of MM. In preclinical studies, Dara enhanced Tal-mediated lysis of MM cells, suggesting the potential to increase clinical activity in pts with RRMM when the agents are combined. We report initial findings for pts with RRMM who received Tal + Dara in the phase 1b multicohort TRIMM-2 study (NCT04108195).
Eligible pts (≥18 years) had MM and received ≥3 prior lines of therapy (LOT; including a proteasome inhibitor [PI] and immunomodulatory drug [IMiD]) or were double refractory to a PI and an IMiD. Pts who received anti-CD38 therapy ≤90 days were excluded. The primary objectives were to identify the RP2D of Tal in combination with Dara and to characterize the safety at the RP2D. Responses were assessed by IMWG criteria. Adverse events (AEs) were graded per CTCAE v5.0 (cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS] graded per ASTCT guidelines).
As of Jul 23, 2021, 23 pts received SC Tal + Dara in separate cohorts: Dara 1800 mg + Tal 400 μg/kg weekly (n=8), + Tal 400 μg/kg biweekly (n=5), and + Tal 800 μg/kg biweekly (n=10). Median follow-up across the cohorts was 2.9 months (range 0.3–11.2). Median age was 68 years (range 44–81), and 52.2% of pts were male. Pts had a median of 6 prior LOT (range 3–18); 82.6% were triple-class exposed (82.6% had prior Dara and 8.7% had prior isatuximab) and 73.9% were penta-drug exposed. Most frequently reported AEs (≥30%) were dysgeusia (52.2%; all grade 1/2), neutropenia (39.1%; grade 3/4 30.4%), thrombocytopenia (39.1%; grade 3/4 21.7%), anemia (34.8%; grade 3/4 21.7%), CRS (34.8%; all grade 1/2), and skin exfoliation (30.4%; all grade 1/2). Grade 3/4 AEs were reported in 78.3%. Median time to CRS onset was 2.5 days (range 2–4), and median duration was 2 days (range 1–3). Infections occurred in 34.8% of pts (grade 3/4 17.4%). Skin disorders were reported in 65.2% of pts (grade 3/4 13.0%), including nail disorders in 17.4% (all grade 1/2). Two ICANS events were reported (grade 1 [concurrent with CRS] and grade 3); both resolved and did not recur. One pt in the Dara 1800 mg + Tal 400 μg/kg biweekly cohort died from disease progression. Responses are shown in the Table. The median time to first response across the cohorts was 1.0 month (range 0.9–2.4), and median duration of response was not reached. Tal pharmacokinetics was similar to that reported in the MonumenTAL-1 study. Proinflammatory cytokine production and T cell activation were observed after Tal + Dara treatment.
The combination of Tal with Dara was well tolerated, with a safety profile comparable to the monotherapies. The combination showed promising efficacy in pts with RRMM, supporting further clinical development of Tal + Dara combination therapy.
B07: SAFETY AND EFFICACY OF CILTACABTAGENE AUTOLEUCEL, A CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPY DIRECTED AGAINST B-CELL MATURATION ANTIGEN IN PATIENTS WITH MULTIPLE MYELOMA AND EARLY RELAPSE AFTER INITIAL THERAPY: CARTITUDE-2 RESULTS
NWCJ van de Donk1; M Delforge2; M Agha3; AD Cohen4; YC Cohen5; J Hillengass6; S Anguille7; T Kerre8; W Roeloffzen9; JM Schecter10; KC De Braganca10; H Varsos10; L Wang10; M Vogel11; E Zudaire12; C Corsale10; M Akram13; D Geng13; T Nesheiwat13; L Pacaud13; P Sonneveld14; S Zweegman1
1Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam (NL); 2University Hospitals (UZ) Leuven, Leuven (BE); 3UPMC Hillman Cancer Center, Pittsburgh (USA); 4Abramson Cancer Center, University of Pennsylvania, Philadelphia (USA); 5Tel-Aviv Sourasky (Ichilov) Medical Center, and Sackler School of Medicine, Tel Aviv University, Tel Aviv (IL); 6Roswell Park Comprehensive Cancer Center, Buffalo (USA); 7Vaccine and Infectious Disease Institute, University of Antwerp, Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Edegem (BE); 8University Hospital Ghent, Ghent (BE); 9University Medical Center Groningen, Groningen (NL); 10Janssen R&D, Raritan (USA); 11Janssen Global Services, LLC, Raritan (USA); 12Janssen R&D, Spring House (USA); 13Legend Biotech USA, Piscataway (USA); 14Erasmus MC University and Medical Center, Rotterdam (NL)
Introduction: CARTITUDE-2 (NCT04133636) is a phase 2, multicohort study evaluating the safety and efficacy of ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T-cell (CAR-T) therapy with two B-cell maturation antigen (BCMA)-targeting single-domain antibodies, in patients with multiple myeloma (MM) in various disease settings.
Objective: To present the first results from cohort B of CARTITUDE-2, which enrolled patients following early relapse after initial therapy that included a proteasome inhibitor (PI) and immunomodulatory drugs (IMiDs).
Methods: Eligible cohort B patients had MM, received 1 prior line of therapy (PI and IMiD required), had disease progression ≤12 months after autologous stem cell transplantation (ASCT) or frontline therapy, and were naive to CAR-T or anti-BCMA therapies. A single cilta-cel infusion (target dose: 0.75×106 CAR+ viable T cells/kg) was given 5–7 days after initiation of lymphodepletion (300 mg/m2 cyclophosphamide and 30 mg/m2 fludarabine daily for 3 days). The primary objective was minimal residual disease (MRD) negativity at 10-5. Adverse events were graded by Common Terminology Criteria for Adverse Events version 5.0 (cytokine release syndrome [CRS]) and immune effector cell associated neurotoxicity syndrome (ICANS) using American Society for Transplantation and Cellular Therapy (ASTCT) criteria.
Results: As of April 15, 2021, 18 patients (median age: 57.0 years [range: 44–67]; 78% men) received cilta-cel. Median follow-up was 4.7 months (range: 0.6–13.5), and median time from diagnosis to enrollment was 1.1 years (range: 0.5–1.9). Two (11.1%) patients had high cytogenetic risk and 5 (27.8%) had bone marrow plasma cells >30%; 14 (77.8%) patients had prior ASCT, and 15 (83.3%) were refractory to their prior therapy. Overall response rate was 88.9% (95% CI: 65.3–98.6) with ≥complete response (CR) achieved by 27.8% (95% CI: 9.7–53.5) and ≥very good partial response (VGPR) achieved by 66.7% (95% CI: 41.0–86.7). Median time to first response was 0.9 months (range: 0.9–2.6), median time to best response was 1.4 months (range: 0.9–11.8), and median time to ≥CR was 1.8 months (range: 0.9–11.6). Of 13 patients with ≥3 months follow-up, 5 (38%) achieved ≥CR. All MRD-evaluable patients (n=9) were MRD negative at 10-5 (Figure). Hematologic treatment emergent adverse events (TEAEs) in ≥20% of patients were neutropenia (88.9%), thrombocytopenia (61.1%), anemia (50.0%), leukopenia (27.8%), and lymphopenia (22.2%). CRS occurred in 15 (83.3%) patients (1 grade 4); median time to onset was 8 days (range: 5–11), and median duration was 4 days (range: 1–7). One patient had ICANS (grade 1). One patient experienced movement and neurocognitive TEAEs (grade 3) on Day 38 post cilta-cel infusion. No deaths were reported post cilta-cel infusion.
Conclusions: In patients who experienced early clinical relapse or treatment failure to initial therapy, a single cilta-cel infusion resulted in early and deep responses with a manageable safety profile. Responses continue to deepen, and follow-up is ongoing. These findings support the investigation of cilta-cel in earlier lines of therapy and incorporation into potentially curative frontline regimens.
B08: A THIRD BNT162B2 DOSE INDUCES ANTIBODY RESPONSES AGAINST SARS-COV-2 EVEN IN PREVIOUSLY NON-RESPONDERS WITH MULTIPLE MYELOMA
E Terpos1; M Gavriatopoulou1; I Ntanasis-Stathopoulos1; A Briasoulis1; S Gumeni2; P Malandrakis1; E-D Papanagnou2; M Migkou1; N Kanellias1; E Kastritis1; I P Trougakos2; M A Dimopoulos1
1Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece, Athens (GR); 2Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece, Athens (GR)
Introduction: Recent data indicate that COVID-19 vaccination leads to a less intense humoral response in patients with multiple myeloma (MM) primarily in those without prior exposure to SARS-CoV-2, as reflected by a lower production of neutralizing antibodies (NAbs), compared with healthy controls. A third BNT162b2 dose in adults aged 60 years and older was associated with significantly increased IgG titers after 10 to 19 days, with no major adverse toxicity.
Methods: In this context, we prospectively evaluated the development of NAbs against SARS-CoV-2 (ELISA, cPass™ SARS-CoV-2 NAbs Detection Kit; GenScript, Piscataway, NJ, USA) in patients with MM at 30 days post vaccination with a third dose of the mRNA BNT162b2 vaccine (NCT04743388). Serum samples were collected on the date of the booster dose (just before vaccination) and 4 weeks after.
Results: The study population included 167 consecutive MM patients (58% males; median age: 68 years, IQR: 60-75 years) who were vaccinated with the booster BNT162b2 dose between September/October 2021, at the same vaccination center. All patients had been fully vaccinated with the two-dose BNT162b2. At the time of vaccination, the vast majority (93.4%) of patients were receiving anti-myeloma treatment.
The booster dose significantly improved the humoral response in MM patients. More specifically, the median (IQR) of NAbs titer reached 96.7% (52.6-97.8%) as compared with 27.1% (13.9%-65.8%) before the third dose (p<0.001). Overall, 114 (68%) patients had less than 50% NAb activity before the third dose. Among them, 75 (65.8%) patients increased their NAb titer to at least 50% after the third dose. Interestingly, the patients who had achieved a NAbs titer of ≥50% at one month after the second vaccine dose were more likely to achieve a NAbs titer of ≥50% at one month after the third dose, as compared with those who had inferior antibody responses after the second dose (p=0.001).
Fifty-seven (34%) patients had not developed a sufficient humoral response following the second vaccination (NAbs titer <30%). All of them presented with low NAbs titers before the third dose (median 14.5% (IQR 7.2%-23.3%)). The third vaccine dose boosted the median antibody response to 38.8% (IQR 15.6%-92.3%, p<0.001). At one month after the booster dose, 32/57 (56%) patients showed a NAbs titer above the positivity threshold (≥30%) and 26/57 (45.6%) showed a NAbs titer of ≥50%.
In the multivariate analysis, only the presence of a NAbs titer ≥30% at one month after the second dose (Odds Ratio (OR) 9.5, 95% Confidence Interval (CI): 3.3-27.6) and the treatment with anti-BCMA agents (OR 0.03, 95%CI: 0.003-0.27) emerged as significant predictive factors for a NAb titer ≥50% at one month following the third dose. None of patients who were under anti-BCMA therapy achieved a NAbs titer of ≥30% one month after the booster dose.
Conclusion: Our study demonstrated that a third BNT162b2 dose in patients with MM optimized the humoral response against SARS-CoV-2, as depicted by the significant increase in NAbs at one month post the booster dose. Importantly, ~46% of patients with suboptimal NAbs responses at one month following the two-dose BNT162b2 vaccination showed NAbs titers over 50% at one month after the booster dose. Taking also into consideration the defective immunity in patients with MM and the current COVID-19 outbreaks, self-protection measures, such as mask wearing and social distancing, remain particularly important.