High-throughput sequencing (HTS) of antibody gene rearrangements is an emerging tool for minimal residual disease (MRD) monitoring in B cell malignancies in which the malignant clone harbors a monoclonal Ig heavy chain (IgH) and/or light chain (κ or λ) rearrangement. This approach has shown promise in B-ALL and CLL, but application of Ig HTS to clinical multiple myeloma (MM) samples has not been demonstrated previously. We conducted HTS of PCR-amplified IgH (VDJ and DJ) and κ/λ (VJ) rearrangements from bone marrow aspirates (BMA) of patients with MM (n=9), MGUS (n=1), and lymphoplasmacytic lymphoma (n=1), and peripheral blood (PB) of a patient with plasma cell leukemia (n=1). In 9/12 samples, an aliquot was enriched for CD138+ cells by immunomagnetic separation and analyzed separately. Dominant clones from enriched and un-enriched aliquots were compared to verify the malignant clonotype sequence. Disease burden in un-enriched samples was also evaluated by microscopy (BMA/PB smear) and ranged from 0 (hemodilute) to 37%. In 11/12 samples, a clearly dominant IgH and/or κ/λ rearrangement (>2.7% of total sequences, range 2.7-99.9%) was identified with clear separation from background frequency (at least 2.7-fold higher frequency than next most common clone). One sample exhibited an oligoclonal repertoire with no clearly dominant sequence. In 9/9 cases with paired CD138-enriched samples, the dominant sequences in the enriched and un-enriched samples were identical, indicating successful identification of the malignant clonal Ig rearrangements in the un-enriched sample. Results were largely consonant with clinical data, though in one IgG-λ MM sample, no dominant, productive λ rearrangement was detected, and in one IgG-κ MM sample, no dominant, productive heavy chain rearrangement was detected. This may be due to mutations at primer-binding sites in these rearrangements. In both cases, alternative clone-tracking sequences were available from the other loci (i.e., IgH in the first case and κ in the second). In 7/12 cases, >1 dominant sequence among the IgH (VDJ and DJ), κ, and λ rearrangements was identified that would be suitable for longitudinally tracking the malignant clone. HTS of Ig heavy and light chain rearrangements can successfully identify the MM clone in clinical specimens, including those with low MM burden. Application of this technique to MRD evaluation in MM warrants further development.
<p>Supplemental tables: (1) Subject characteristics. (2) Cytogenetic profiles and high-risk features. (3) Prior treatment exposures and refractoriness. (4) CAR T cell product characteristics. (5) Products that did not meet target dose. (6) Adverse events of grade 3-4. (7) Cytokine release syndrome and ICANS. (8). Maintenance therapy. Supplemental Figures: (1) Study schematic and subject disposition, (2) Correlates of manufacturing success, (3) Hematopoietic recovery, (4) Post-infusion T cell phenotypes, (5) Correlates of in vivo expansion and manufacturing success, (6) Late post-infusion CAR T cell re-expansion, (7) Soluble BCMA, (8) Late-onset clinical responses, (9) MM cell BCMA expression, (10) Pre- and post-treatment Sox2-specific T cell responses in CART-BCMA monotherapy patients, (11) Pre- and post-treatment Sox2-specific T cell responses in CART-BCMA + huCART19 combination therapy patients, (12) Sustained post-treatment SOX2-specific T-cell responses.</p>
8033 Background: As multiple myeloma (MM) negatively affects patients’ (pts) health-related quality of life (HRQoL), assessment of patient-reported outcomes (PROs) in addition to clinical outcomes is important. Teclistamab (tec; JNJ-64007957) is an off-the-shelf bispecific antibody that redirects CD3+ T cells to mediate T-cell activation and subsequent lysis of BCMA-expressing MM cells. Initial results from the pivotal cohort of the phase 1/2 MajesTEC-1 study demonstrated that tec was well tolerated with encouraging efficacy in pts who received ≥3 prior lines of treatment (LOT; including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody). Here we report PROs from this cohort. Methods: Pts (aged ≥18 years) had documented RRMM (International Myeloma Working Group criteria), progressive/measurable disease, and had previously received ≥3 prior LOT; prior anti-BCMA treatment (tx) was not allowed. Pts received weekly subcutaneous tec at the recommended phase 2 dose (1.5 mg/kg with step-up doses of 0.06 and 0.3 mg/kg). PROs were assessed at screening and every even cycle (cycles 2–8 reported here) using the EORTC QLQ-C30 (range: 0–100; higher scores indicate better global health status [GHS] but greater symptom severity [symptom scales]) and the EuroQol 5-dimensional descriptive system (visual analog scale [VAS] range: 0 [worst imaginable health state] to 100 [best imaginable]). Tx effect was assessed by a mixed-effects model with repeated measures; the proportion of pts with meaningful improvement was defined as a change ≥10 points. Time to worsening was determined using the Kaplan-Meier estimate. Results: A total of 110 pts were included (median follow-up: 7.8 mos). Overall PRO compliance rates were high (baseline [BL]: 85–90%; cycles 2–8: 80–94%). Tec improved overall HRQoL as evidenced by improvements in GHS scores (cycles 2–8) and reduction in pain (-4.2 [cycle 2] to -15.1 [cycle 8]; Table), with no overall change in physical functioning and fatigue. The proportions of pts with meaningful improvements from BL at cycle 8 were GHS: 50%; physical functioning: 35%; pain: 65%; fatigue: 73%; 50% of pts reported meaningful improvement in their overall health (VAS). Median time to improvement from baseline was ̃1.5 months (with nausea/vomiting and fatigue taking longer to improve), while median time to worsening (all symptoms) ranged from 2 months to not estimable. Conclusions: Consistent with clinical outcomes, pts treated with tec reported rapid, clinically meaningful improvements in HRQoL. Clinical trial information: NCT04557098. [Table: see text]
The British Journal of Haematology publishes original research papers in clinical, laboratory and experimental haematology. The Journal also features annotations, reviews, short reports, images in haematology and Letters to the Editor.
Introduction: High dose chemotherapy/autologous stem cell transplantation (ASCT) and CD19-directed chimeric antigen receptor-modified T cells (CART19) are potentially-curative treatment options for patients (pt) diagnosed with relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) and high grade B cell lymphoma (HGBL). Analysis of a large series of pt receiving ASCT and/or CART19 has not been performed and may reveal differences in treatment failure (TF) which could inform efforts to optimize pt selection for these therapies. Methods: Included pt were age ≤75 years who received ASCT and/or CART19 for R/R DLBCL/HGBL at the University of Pennsylvania between 3/1/13 and 3/1/21. All ASCT pt demonstrated either partial or complete metabolic response to salvage immunochemotherapy (IC). Freedom from TF (FFTF) was defined as the interval between receipt of cell infusion and proven/suspected relapse of lymphoma (DLBCL/HGBL for ASCT pt or any lymphoma for CART19 pt) or last follow-up (f/u) in remission. Data were censored on 3/1/23. Results: Characteristics at the time of relapse preceding ASCT or CART19 are listed in the Table. Minimum prior LOT was 1 for ASCT and 2 for CART19 pt. With a median length of f/u of 62.7 months (mo) for ASCT pt and 37.6 mo for CART19 pt, the estimated (est) rate of FFTF at 36 mo were 59% and 24%, respectively. Cox regression analysis of characteristics predictive of TF at 36 mo revealed history of tIL (hazard ratio [HR] 0.23, P = 0.016) for ASCT pt, and history of tIL (HR 0.48, P = 0.004) as well as IPI score ≥3 (HR 2.7, P < 0.001) for CART19 pt. As depicted in the Figure, ASCT pt experienced significantly higher est rates of FFTF at 36 mo if achieving actual FFTF at 3 mo (64% vs. 38%, P = 0.002), 6 mo (76% vs. 52%, P = 0.02), 12 mo (84% vs. 62%, P = 0.03) and 24 mo (95% vs. 78%, P = 0.03) post-infusion as compared to CART19 pt. For characteristics which predict for TF at 36 mo (no history of tIL and IPI score ≥3), the incidence was either similar or significantly lower for CART19 versus ASCT pt who achieved actual FFTF at 3, 6, 12 and 24 mo. Keyword: Aggressive B-cell non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract. D. J. Landsburg Consultant or advisory role: Morphosys, Epizyme, Calithera, ADC Therapeutics, Karyopharm Research funding: Curis, Calithera, Epizyme Educational grants: Novartis S. D. Nasta Research funding: Pharmacyclics, Roche, Rafael, FortySeven J. Svoboda Consultant or advisory role: SEAGEN, Pharmacyclics, Incyte, Genmab, BMS, Atara, Astra Zeneca, Adaptive, ADCT Research funding: TG, SEAGEN, Pharmacyclics, Merck, Incyte, BMS, Astra Zeneca J. N. Gerson Consultant or advisory role: Genentech, Abbvie Research funding: Loxo S. J. Schuster Consultant or advisory role: Novartis, Regeneron, Nordic, Morphosys, MustangBio, Incyte, Genentech/Roche, Janssen, Legend Biotech, Loxo, Acerta, BiGene, Celgene, Nanovecter Research funding: Novartis, Pharmacyclics, Merck, DTRM, Juno Therapeutics, Abbvie, Adaptive Biotechnologies, Incyte, Genentech/Roche, Celgene, TG Therapeutics S. K. Barta Consultant or advisory role: Daiichi Sankyo, Kyowa Kirin, Janssen, Affimed Honoraria: Acrotech, Seagen, Kyowa Kirin E. A. Chong Honoraria: Juno/BMS, Novartis, Beigene, KITE, Tessa A. L. Garfall Consultant or advisory role: Jannsen, GlaxoSmithKline, Bristol-Myers Squibb Research funding: Novartis, Tmunity Therapeutics, Janssen, Crispr Therapeutics E. A. Stadtmauer Research funding: BMS, Celgene, Abbvie, Sorrento N. V. Frey Consultant or advisory role: Sana Biotechnology, Kite Pharma, Syndax Pharmaceuticals Research funding: Research Funding D. L. Porter Consultant or advisory role: Novartis, Kite/Gilead, Incyte, Janssen, Jazz, DeCart, BMS, Bluebird Bio, Angiocrine, Mirror Biologics, Capstan Therapeutics, Instill Bio Research funding: Novartis
B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cells (CART-BCMA) are a promising treatment for relapsed/refractory multiple myeloma (r/rMM). We evaluated the safety and feasibility of bridging radiation (RT) in subjects treated on a phase I trial of CART-BCMA.Twenty-five r/rMM subjects were treated in three cohorts with two doses of CART-BCMA cells ± cyclophosphamide. We retrospectively analyzed toxicity, response, and CART manufacturing data based on RT receipt.Thirteen subjects received no RT <1 year before CART infusion (Group A). Eight subjects received RT <1 year before CART infusion (Group B) with median time from RT to apheresis of 114 days (range 40-301). Four subjects received bridging-RT (Group C) with a median dose of 22 Gy and time from RT to infusion of 25 days (range 18-35). Group C had qualitatively lower rates of grade 4 (G4) hematologic toxicities (25%) versus A (61.5%) and B (62.5%). G3-4 neurotoxicity occurred in 7.7%, 25%, and 25% in Group A, B, and C, respectively. G3-4 cytokine release syndrome was observed in 38.5%, 25%, and 25% in Group A, B, and C, respectively. Partial response or better was observed in 54%, 38%, and 50% of Group A, B, and C, respectively. RT administered <1 year (P = 0.002) and <100 days (P = 0.069) before apheresis was associated with lower in vitro proliferation during manufacturing; however, in vivo CART-BCMA expansion appeared similar across groups.Bridging-RT appeared safe and feasible with CART-BCMA therapy in our r/rMM patients, though larger future studies are needed to draw definitive conclusions.
