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4456 Nivolumab-Based Salvage Therapy to Restore T Cell Fitness in Penta-Refractory Multiple Myeloma with Relapse to Anti-BCMA CAR T Cell Therapy

Program: Oral and Poster Abstracts
Session: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational: Poster III
Hematology Disease Topics & Pathways:
Research, Biological therapies, Translational Research, Plasma Cell Disorders, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Checkpoint Inhibitor, Diseases, Therapies, Lymphoid Malignancies
Monday, December 12, 2022, 6:00 PM-8:00 PM

Johannes M. Waldschmidt, MD1,2, Sankalp Arora, MD3*, Tushara Vijaykumar1*, Noori Sotudeh, PhD4*, Praveen Anand, PhD1*, Hannah Stuart1*, Julia Frede, PhD, MPhil1, Tim Campbell5*, Shari M. Kaiser, PhD5*, Manisha Lamba, PhD5*, Nikhil C Munshi, MD, PhD6, Kenneth C. Anderson, MD1, Andrew J. Yee, MD, PhD7, Birgit Knoechel, MD, PhD4, Jens G. Lohr, MD, PhD1 and Noopur Raje, MD7

1Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
2Department of Hematology, Oncology and Stem Cell Transplantation, University of Freiburg Medical Center, Freiburg, Baden Wurttemberg, Germany
3University of Alabama at Birmingham, Birmingham, AL
4Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA
5Bristol Myers Squibb, Princeton, NJ
6Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
7Massachusetts General Hospital, Boston, MA


Idecabtagene Vicleucel (ide-cel) is the first FDA-approved BCMA-directed CAR T cell therapy for the treatment of relapsed/refractory multiple myeloma (RRMM). Despite remarkable activity of 85% objective response rate and a progression-free survival (PFS) of 11.8 months reported in the CRB-401 trial (NCT02658929), most responses to ide-cel are not durable, and nearly all patients (pts) eventually relapse, even those achieving MRD-negative complete remission (CR). Factors associated with clinical relapse to ide-cel include BCMA loss, lack of CAR T persistence, T-cell exhaustion and PD-1/ PD-L1 impaired T-cell fitness. Here, we report clinical data and correlative findings for 4 pts who were salvaged with a nivolumab (anti-PD1)- based triplet therapy at the time of clinical relapse to first or second ide-cel infusion.


Four pts with penta-refractory RRMM were treated as part of the CRB-401 phase 1 study as previously reported (Raje et al. N Engl J Med. 2019;380:1726-37). All pts received nivolumab along with lenalidomide-dexamethasone (Nivo-Rd) or pomalidomide-dexamethasone (Nivo-Pd) at the time of relapse to ide-cel. CD3+ T cells (n=1,047) were isolated from the peripheral blood of 2 of these pts and full-length single-cell RNA sequencing (scRNA-seq) was conducted before and upon treatment with Nivo-Rd/-Pd. Response rates were assessed as per IMWG criteria.


The median age of pts was 48.5 years (range 37-56). Two out of 4 pts had cytogenetic high-risk MM and all pts were penta-refractory at the time of CRB-401 study inclusion. The median PFS and OS after first ide-cel infusion were 10.4 (range 3.0-13.8) months and 21.5 (range 16.0-34.6) months, respectively. Three pts received a second ide-cel infusion, whereof only 1 pt achieved a partial response (PR) at a PFS of 5.2 months. Two pts each were treated with Nivo-Rd and Nivo-Pd respectively at the time of progression to ide-cel. Responses to anti-PD1- based therapy varied markedly with 1 PR, 1 stable disease (SD) and 2 progressive disease (PD) as per IMWG criteria. The median PFS to nivolumab-based salvage therapy was 3.6 (range 0.4-8.1) months.

Interestingly, pts MM1 and MM2 both had a CR to first ide-cel infusion (PFS 13.8 and 11.9 months, respectively), but while both pts did not respond to second CAR T cell infusion, the benefit from anti-PD1 treatment differed markedly in both pts. MM1 reached a PR and PFS of 105 days. In contrast, MM2 experienced immediate PD and succumbed to his disease 3.0 months later.

Profiling of CD3+ T cells from MM1 and MM2 by scRNA-seq revealed rapid cellular state changes in response to PD1 inhibition. PAGODA2 clustering and t-Stochastic Neighbor Embedding (t-SNE) visualization revealed 3 distinct clusters, segregating to an individual pre-anti-PD1 cluster for MM1 and MM2 each and a shared post-anti-PD1 cluster comprising CD3+ T cells from both pts. The pre-anti-PD1 cluster for MM1 contained CD3+ T-cells with a memory T cell- like phenotype (IL7Rhigh, CD62Lhigh) and decreased expression of markers correlating with T-cell fitness (GNLY, PRF1, NKG7, GZMH, LY6C, KLRG1). This phenotype could be rescued, and T-cell fitness could be restored by Nivo-Pd treatment, potentially contributing to the clinical response observed in MM1. Opposingly, the pre-anti-PD1 cluster for MM2 showed intact T-cell fitness with low expression of T-cell exhaustion markers. No clinical benefit to Nivo-Rd was noted in this pt.


Checkpoint inhibition and IMiD therapy can induce clinical responses at the time of relapse to first or second CAR T infusion. Efficacy however seems to depend on impaired T-cell fitness as premise for PD1 inhibition to re-induce clinical responses in selected pts.

Disclosures: Waldschmidt: Janssen: Consultancy; Takeda: Consultancy; Sanofi: Consultancy. Campbell: Bristol Myers Squibb: Current Employment. Kaiser: Bristol-Myers Squibb: Current Employment. Lamba: Bristol Myers Squibb: Current Employment. Munshi: GSK: Consultancy; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Novartis: Consultancy; Adaptive Biotechnology: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; Legend: Consultancy; Karyopharm: Consultancy; Abbvie: Consultancy; Takeda Oncology: Consultancy. Anderson: Raqia: Other: Scientific founder ; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Dynamic Cell Therapy: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; NextRNA: Other: Scientific founder ; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Other: Scientific founder ; Precision Biosciences: Membership on an entity's Board of Directors or advisory committees; OncoPep: Other: Scientific founder ; Starton: Membership on an entity's Board of Directors or advisory committees; Window: Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees. Yee: Amgen: Consultancy; Adaptive Biotechnologies: Consultancy; Bristol Myers Squibb: Consultancy; GSK: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Oncopeptides: Consultancy; Sanofi: Consultancy; Takeda: Consultancy. Lohr: Bristol Myers Squibb: Other: Research funding outside submitted work. Raje: Massachusetts General Hospita: Current Employment; Two Seventy Bio: Research Funding; Research to Practice: Honoraria; Medscape: Honoraria; Amgen: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria.

OffLabel Disclosure: Checkpoint inhibition at the time of relapse to CAR T cell therapy in multiple myeloma

*signifies non-member of ASH