2022年 · 第102卷第30期

Daratumumab is a human IgG kappa monoclonal antibody targeting CD38, which has direct antitumor and immunomodulatory effects. MAIA (NCT02252172) is a randomized, open-label Phase 3 clinical trial. In a preliminary analysis of the MAIA Phase 3 study (median follow-up of 28.0 months) in patients with newly diagnosed multiple myeloma (NDMM) who were not eligible for transplant, daratumumab + lenalidomide/dexamethasone (D-Rd) significantly improved progression-free survival (PFS) and induced deeper responses, including improvement in complete response (CR) and negative minimal residual disease (MRD), compared with lenalidomide/dexamethasone (Rd). After a median follow-up of 36.4 months, the D-Rd regimen continued to show PFS benefit and deeper remission, even in patients over 73 years of age. However, health levels vary greatly in older patients, and subgroup analyses based on frailty will be richer than analyses based on age alone. Therefore, the study used age, per-patient medical history review (CCI), and baseline ECOG PS score to divide patients into three subgroups: healthy, moderate, and frail, which was further simplified to non-frail [396 healthy and moderate subgroup combinations: 196 (53.3%) in the D-Rd group and 200 (54.2%) in the Rd group; 341 in the frailty subgroup, 172 (46.7%) in the D-Rd group, and 169 (45.8%) in the Rd group].

Teclistamab is a T cell redirecting bispecific antibody that targets CD3 expressed on the surface of T cells and B cell maturation antigen (BCMA) expressed on the surface of myeloma cells. In the Phase 1 dose determination part of the study, terituzumab showed good efficacy in patients with relapsed or refractory multiple myeloma.

Multiple myeloma (MM) is a common malignant plasma cell disease that has hitherto been incurable. Malignant plasma cells highly express B cell maturation antigen (BCMA). Based on this, the therapeutic technology of chimeric antigen receptor T cell (CAR-T) targeting BCMA has gradually developed and become more mature. In March 2021, the world's first CAR-T product targeting BCMA was approved for marketing in the United States. The phase II clinical trial of this product achieved an overall response rate (ORR) of up to 73%, of which complete response and above (CR + sCR) accounted for 33%, but the median progression-free survival (mPFS) was only 8.8 months, which hindered the clinical application of BCMA CAR-T. BCMA CAR-T treatment could not effectively eliminate tumor stem cells, which may be one of the main causes of disease recurrence.

The immunomodulator lenalidomide is the main drug in the treatment of multiple myeloma (MM), and the combination with other drugs such as proteasome inhibitors and corticosteroids can induce remission in most patients, however almost all patients will relapse due to acquired drug resistance of multiple myeloma cells. To explore the non-genetic mechanisms of drug resistance, the study included 5 patients with longitudinal bone marrow samples, 4 who progressed during lenalidomide treatment, and 1 who progressed after lenalidomide treatment. Bone marrow samples from 5 patients were collected before treatment and at the time of relapse for tandem mass spectrometry (TMT) -based proteomic and phosphorylated proteomic analysis and RNA sequencing. Through proteomics analysis, the study found that the top 6 upregulated proteins in the relapsed group were TRIP13, RRM1, NCAPD2, NCAPH, MORF4L1, and CKD6 compared with the pre-treatment sample. Phosphorylated proteomics analysis showed that only 15 of 134 significantly changed phosphorylated peptides had protein expression changes, indicating that most of the sites with changed phosphorylation levels did not change their protein expression levels. Through RNA sequencing of 5 pairs of samples, it was found that among the highest upregulated proteins, the mitotic regulatory proteins TRIP13 and NCAPH had the highest Pearson correlation coefficient of RNA/protein expression of 0.84, followed by NCAPD2 (0.67), RRM1 (0.6) and CDK6 (0.39). In MM, the low correlation of protein and RNA implies a high degree of transcriptional and post-translational regulation.