Medications
Proteasome inhibitors, anti-CD38 monoclonal antibodies, IMiDs, and BCMA-directed therapies including CAR-T. What they target, what the response rates look like.
Comprehensive 2025 review of teclistamab's BCMA x CD3 mechanism, MajesTEC-1 outcomes (63% ORR, 39% at or above CR), and emerging resistance pathways.
Longitudinal MajesTEC-1 analysis identifies BCMA loss and T-cell exhaustion as principal resistance mechanisms to teclistamab.
Epitope mapping confirms isatuximab and daratumumab bind distinct, non-overlapping CD38 epitopes, with potential for sequential use.
Regulatory summary of cilta-cel's approval based on CARTITUDE-1 data showing 97.9% ORR and 82.5% stringent CR rate.
Extended follow-up from MagnetisMM-3 confirms durable responses and tolerability of elranatamab (BCMA x CD3 bispecific) in relapsed/refractory myeloma.
Comprehensive 20-year retrospective of proteasome inhibitor resistance mechanisms (beta-5 subunit mutation, UPR bypass, NF-kB reactivation) and strategies to overcome them.
Phase 1 dose-escalation trial establishing the recommended dose of elranatamab with 64% ORR in triple-class-refractory patients.
Two-year CARTITUDE-1 data show sustained 97.9% ORR and 82.5% stringent CR with single cilta-cel infusion in heavily pretreated patients.
Pivotal KarMMa phase 2 trial (NEJM): ide-cel achieved 73% ORR and 33% complete response, leading to the first CAR-T FDA approval in myeloma.
Original CARTITUDE-1 publication reporting 97% ORR including 67% stringent CR with single cilta-cel infusion.
First-in-human MajesTEC-1 phase 1 data defining the recommended phase 2 dose and early efficacy signal for teclistamab.
Reviews carfilzomib's irreversible epoxyketone mechanism, beta-5 subunit selectivity, and superior response rates vs. bortezomib in relapsed/refractory myeloma.
Canonical Science paper demonstrating that lenalidomide redirects CRL4-CRBN E3 ligase to degrade Ikaros/Aiolos, establishing the IMiD mechanism.
Parallel canonical Science paper independently confirming cereblon/IKZF1/IKZF3 axis as the IMiD molecular target in myeloma.
CAR-T first shows progression-free survival advantage over bispecifics first in a cohort of more than 600 patients with relapsed/refractory myeloma.
Bispecific antibodies showed inferior overall survival versus CAR-T in real-world comparative analysis of the TriNetX global database.
Base-edited universal CAR38-T cells, CD38 knocked out to prevent fratricide; activity against CD38-positive malignancies in xenografts; long-lived plasma cells named as a target.
2026 review: 2 BCMA CAR-T products and 4 bispecifics (3 BCMA, 1 GPRC5D) approved; evaluates sequencing, frontline expansion, and resistance patterns.
Second-generation anti-BCMA CAR construct transduced into NK-92 cells; shows enhanced killing and cytokine secretion against myeloma cell lines vs non-transduced NK-92. Preclinical.
Bortezomib (first approved 2003), carfilzomib (irreversible, beta-5 selective), and ixazomib (first oral): mechanism, resistance patterns, and combination regimens. ER stress accumulation drives plasmocyte apoptosis.
Thalidomide, lenalidomide, and pomalidomide bind cereblon and redirect CRL4CRBN ubiquitin ligase to degrade IKZF1 and IKZF3, transcription factors required for myeloma plasmocyte survival.
Intrinsic and acquired cereblon loss drive lenalidomide resistance; pomalidomide and novel agents used in later lines; maintenance post-transplant extends PFS.
First-in-class humanized IgG1 kappa anti-CD38 monoclonal antibody; US accelerated approval after at least 3 prior lines including a proteasome inhibitor and an IMiD, or double-refractory disease; approximately 30% ORR to 16 mg/kg monotherapy in a phase II trial.
Regular FDA approval November 21, 2016 of daratumumab with lenalidomide and dexamethasone, or bortezomib and dexamethasone, after at least one prior therapy; PFS HR 0.37 (MMY3003) and 0.39 (MMY3004); 2015 accelerated approval based on single-agent response data.
Original mechanism paper (de Weers 2011): daratumumab induces myeloma cell death via complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC); bone marrow stromal cells do not block CDC or ADCC.
Daratumumab depletes CD38-positive regulatory T cells, regulatory B cells, and myeloid-derived suppressor cells, relieving immunosuppression and expanding T cell numbers in treated patients.
Cilta-cel: dual BCMA-binding scFv domains, 4-1BB co-stimulation; ORR 84.6% in CARTITUDE-4; FDA approved 2022; approved for 1 to 2 prior lines 2024.
2026 comparison of ide-cel, cilta-cel, and the two approved GPRC5D-targeted CAR-T therapies; cilta-cel shows highest ORR; toxicity profiles distinct by construct.