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Despite the astonishing outcomes after chimeric antigen receptor (CAR) T-cell therapy for relapsed refractory multiple myeloma (RRMM), most patients eventually relapse. There are only limited data available on salvage therapies following relapse after BCMA-directed CAR T-cell therapy. Here, we analyzed outcomes of post-CAR T-cell therapy relapse and impact of different salvage strategies in an international cohort of 139 patients (n = 130 ide-cel, n = 9 cilta-cel), receiving talquetamab (n = 28), teclistamab (n = 37), combinations of immunomodulating drugs (IMiDs), proteasome inhibitors (PIs) or CD38 monoclonal antibodies (n = 43), and others (n = 31). The median time to relapse after CAR T-cell therapy was 5 months, 53% had the extramedullary disease (EMD) at relapse, associated with dismal post-relapse outcome (P = 0.005). Overall response and complete response upon salvage therapies were 79% and 39% for talquetamab, 64% and 32% for teclistamab, 30% and 0% for IMiDs/PIs/CD38, and 26% and 3% for others (P < 0.001). Duration of response, as well as median survival, was significantly improved with bispecific antibodies (P < 0.001, respectively). Bispecific antibodies seemed to overcome the poor prognosis associated with early relapse and EMD, and were independent predictors for improved survival in multivariable analysis. In summary, these results suggest bispecific antibodies as the standard of care for relapse after CAR T-cell therapy for RRMM., Competing Interests: Competing interests: Nico Gagelmann: Consulting or Advisory Role: Stemline Therapeutics, MorphoSys Travel, Accommodations, Expenses: Bristol Myers Squibb/Celgene, Janssen. Maximilian Merz: Honoraria: Janssen, BMS GmbH & Co KG, Amgen, AbbVie, Stemline Therapeutics, Takeda, Sanofi, Pfizer Consulting or Advisory Role: Janssen, BMS GmbH & Co KG, Pfizer, Sanofi Research Funding: Janssen, SpringWorks Therapeutics, Roche/Genentech Travel, Accommodations, Expenses: Janssen, Stemline Therapeutics, Pfizer. Hamza Hashmi: Consulting or Advisory Role: Sanofi, Bristol Myers Squibb/Celgene, Janssen Speakers’ Bureau: Janssen, Karyopharm Therapeutics, Amgen. Nausheen Ahmed: Consulting or Advisory Role: Kite/Gilead, BMS Research Funding: Kite/Gilead (Inst). Aina Oliver-Caldés: Travel, Accommodations, Expenses: Janssen. Friedrich Stölzel: Honoraria: Medac, Jazz Pharmaceuticals, Consulting or Advisory Role: Glycostem, Travel, Accommodations, Expenses: SERVIER. Anca-Maria Albici: Honoraria: AbbVie, Travel, Accommodations, Expenses: SERVIER. Natalie Schub: Honoraria: Janssen Oncology, Consulting or Advisory Role: BMS, Travel, Accommodations, Expenses: Kite/Gilead. Soraya Kharboutli: Honoraria: Bristol Myers Squibb GmbH, Travel, Accommodations, Expenses: Janssen, Bristol Myers Squibb, Sobi, Novartis. Fabian Müller: Honoraria: AstraZeneca, Bristol Myers Squibb/Pfizer, Kite/Gilead, Consulting or Advisory Role: Bristol Myers Squibb/Pfizer, Janssen, Kite/Gilead, Kite/Gilead, Novartis, Miltenyi Biomedicine, Research Funding: Kite/Gilead, Travel, Accommodations, Expenses: SOBI, Janssen. Leyla Shune: Consulting or Advisory Role: Janssen Oncology. Faiz Anwer: Consulting or Advisory Role: Janssen, BMS, Speakers’ Bureau: Bristol Myers Squibb Foundation, Research Funding: Celgene (Inst), Acetylon Pharmaceuticals (Inst), Millennium (Inst), Astellas Pharma (Inst), AbbVie (Inst), Janssen (Inst), Bristol Myers Squibb (Inst), Caribou Biosciences (Inst), Caribou Biosciences, Travel, Accommodations, Expenses: Bristol Myers Squibb, Open Payments Link: https://openpaymentsdata.cms.gov/physician/16726 . Vladan Vucinic: Honoraria: Janssen, BMS GmbH & Co KG, Gilead Sciences, Amgen, Consulting or Advisory Role: Gilead Sciences, Janssen, BMS GmbH & Co KG, Amgen, Travel, Accommodations, Expenses: Sobi, Janssen, Gilead Sciences, Amgen. Uwe Platzbecker: Honoraria: Celgene/Jazz, AbbVie, Curis, Geron, Janssen, Consulting or Advisory Role: Celgene/Jazz, Novartis, BMS GmbH & Co KG, Research Funding: Amgen (Inst), Janssen (Inst), Novartis (Inst), BerGenBio (Inst), Celgene (Inst), Curis (Inst), Patents, Royalties, Other Intellectual Property: Part of a patent for a TFR-2 antibody (Rauner et al. Nature Metabolics 2019), Travel, Accommodations, Expenses: Celgene. Francis Ayuk: Honoraria: Bristol Myers Squibb/Celgene, Kite/Gilead, Janssen, Miltenyi Biomedicine, Novartis, Takeda, Mallinckrodt/Therakos, medac pharma, Consulting or Advisory Role: Bristol Myers Squibb/Celgene Research Funding: Mallinckrodt/Therakos. Nicolaus Kröger: Honoraria: Novartis, Celgene (Inst), Sanofi, Jazz Pharmaceuticals (Inst), Kite/Gilead, RIEMSER (Inst), AOP Orphan Pharmaceuticals, BMS GmbH & Co KG, Neovii, Alexion Pharmaceuticals, Takeda, Pierre Fabre Consulting or Advisory Role: Neovii, Sanofi, Jazz Pharmaceuticals, Novartis, Celgene, RIEMSER, Gilead Sciences, Speakers’ Bureau: AOP Orphan Pharmaceuticals, Research Funding: Neovii (Inst), Novartis (Inst), Celgene (Inst), Riemser (Inst), Travel, Accommodations, Expenses: Neovii, Novartis, Gilead Sciences, Jazz Pharmaceuticals, Sanofi, Celgene. Jack Khouri: Honoraria: GPCR Therapeutics, Consulting or Advisory Role: Janssen Oncology. Joseph McGuirk: Honoraria: Kite, a Gilead company, AlloVir, Magenta Therapeutics, Nektar, Sana Biotechnology Consulting or Advisory Role: Kite, a Gilead company, Juno Therapeutics, Allovir, Magenta Therapeutics, EcoR1 Capital, CRISPR therapeutics, Speakers’ Bureau: Kite/Gilead, Research Funding: Novartis (Inst), Fresenius Biotech (Inst), Astellas Pharma (Inst), Bellicum Pharmaceuticals (Inst), Novartis (Inst), Gamida Cell (Inst), Pluristem Therapeutics (Inst), Kite, a Gilead company (Inst), AlloVir (Inst), Travel, Accommodations, Expenses: Kite, a Gilead company, Syncopation Life Sciences, SITC/ACCC. Al-Ola Abdallah: Research Funding: Celgene (Inst), Seagen (Inst), AbbVie (Inst), Bristol Myers Squibb/Medarex (Inst), Sanofi (Inst), GlaxoSmithKline (Inst), Patents, Royalties, Other Intellectual Property: PSA vaccine patent. Carlos Fernández de Larrea: Honoraria: Janssen, BeiGene, Bristol Myers Squibb/Celgene, Pfizer, Amgen, GlaxoSmithKline Consulting or Advisory Role: Janssen, Bristol Myers Squibb/Celgene, Amgen, Pfizer, Sanofi, BeiGene Research Funding: Janssen (Inst), Bristol Myers Squibb/Celgene (Inst), Amgen (Inst), GlaxoSmithKline (Inst) Travel, Accommodations, Expenses: Janssen, Amgen, GlaxoSmithKline, Bristol Myers Squibb/Celgene, BeiGene, Pfizer. No other potential conflicts of interest were reported., (© 2024. The Author(s).)

Establishing a strategy for sequencing of T cell redirecting therapies for relapsed/refractory multiple myeloma (RRMM) is a pressing clinical need. We longitudinally tracked the clinical and immunological impact of bispecific T cell engaging antibodies (BsAb) as bridging therapy (BT) to subsequent BCMA-directed CAR-T cell therapies in 52 RRMM patients. BsAbs were a potent and safe option for BT, achieving the highest overall response rate (100%) to BT compared to chemotherapy, anti-CD38 or anti-SLAMF7 antibody based regimens (46%). We observed early CD4+CAR+ and delayed CD8+CAR+ T cell expansion in patients receiving BsAb as BT. In vitro cytotoxicity of CAR-T cells was comparable amongst BT options. Single-cell analyses revealed increased clonality in the CD4+ and CD8+ T cell compartments in patients with previous exposure to BsAbs at leukapheresis and on day 30 after CAR-T infusion. This study demonstrates the feasibility and efficacy of BT with BsAbs for CAR-T cell therapy in RRMM.

Variants of recombinant staphylokinase (Sak) were investigated by Fourier-transform infrared spectroscopy: Sak (wild type), Sak-M26A, Sak-M26L, and Sak-G34S/R36G/R43H (Sak-B). Estimation of the secondary structure and hydrogen-deuterium exchange experiments revealed the existence of fast-exchanging and strongly solvent-exposed fractions of the helical structures in the two samples Sak and Sak-M26L. These two samples are also thermally less stable with unfolding transition temperatures of 43.7 degrees C (Sak) and 43.5 degrees C (Sak-M26L), respectively. On contrast, Sak-M26A and Sak-G34S/R36G/R43H have a slower hydrogen-deuterium exchange, have a smaller solvent-exposed portion of the helical part, and are more resistant against thermal unfolding; the transition temperatures are 51.7 degrees C and 59.3 degrees C, respectively. The secondary structure analysis was performed by two different approaches, by curve-fitting after band narrowing and by pattern recognition (factor analysis) based upon reference spectra of proteins with known crystal structure. Within the limits of the used methods, we are unable to detect significant differences in the secondary structure of the four variants of Sak. According to the results of the factor analysis, the portions of secondary structure elements were obtained to 16-20% alpha-helix, 28-30% beta-sheet, 23-27% turns, 28-30% irregular (random) and other structure. The sharp differences in the specific plasminogen-activating capacity (Sak, Sak-G34S/R36G/R43H and Sak-M26L are fully active, but Sak-M26A does not form a stable complex with plasminogen) are not reflected in the structural features revealed by the infrared spectra of this study.