A NOTCH3-CXCL12-driven myeloma-tumor niche signaling axis promotes chemoresistance in multiple myeloma.

Multiple myeloma (MM) remains incurable due to disease relapse and drug resistance. Notch signals from the tumor microenvironment (TME) confer chemoresistance, but the cellular and molecular mechanisms are not entirely understood. Using clinical and transcriptomic datasets, we found that NOTCH3 is upregulated in CD138+ cells from newly diagnosed MM (NDMM) patients compared to healthy individuals and increased in progression/relapsed MM (PRMM) patients. Further, NDMM patients with high NOTCH3 expression exhibited worse responses to bortezomib (BOR)-based therapies. Cells of the TME, including osteocytes, upregulated NOTCH3 in MM cells and protected them from apoptosis induced by BOR. NOTCH3 activation (NOTCH3OE) in MM cells decreased BOR anti-MM efficacy and its ability to improve survival in in vivo myeloma models. Molecular analyses revealed that NDMM and PRMM patients with high NOTCH3 exhibit CXCL12 upregulation. TME cells upregulated CXCL12 and activated the CXCR4 pathway in MM cells in a NOTCH3-dependent manner. Moreover, genetic or pharmacologic inhibition of CXCL12 in NOTCH3OE MM cells restored sensitivity to BOR regimes in vitro and in human bones bearing NOTCH3OE MM tumors cultured ex vivo. Our clinical and preclinical data unravel a novel NOTCH3-CXCL12 pro-survival signaling axis in the TME and suggest that osteocytes transmit chemoresistance signals to MM cells.

Three years of maintenance with VRD in multiple myeloma: results of total therapy IIIB with a 15-year follow-up.

ABSTRACT: The total therapy (TT) IIIB phase 2 study incorporated bortezomib into tandem melphalan-based hematopoietic stem cell transplantation with dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide for induction/consolidation and bortezomib, lenalidomide, and dexamethasone (VRD) for maintenance in patients with newly diagnosed multiple myeloma (MM). This updated analysis presents a 15.4-year median follow-up. Of 177 patients, 21% patients had gene expression profile (GEP)-defined high-risk MM. 15-year progression free survival (PFS) was 27.9%. Median PFS was better in GEP-defined low-risk patients at 7.8 years and in International Staging System stage 1 patients at 8.7 years. Overall, median OS was 9.1 years, and 15-year overall survival (OS) was 35.9%. GEP-defined low-risk patients' median OS was 11.2 years, and that of GEP-defined high-risk patients was 2.8 years. There was no difference in OS between TT IIIB and TT IIIA. This study includes the longest follow-up of patients treated with maintenance VRD reported to date. In patients with GEP-defined low-risk, nearly half and one-third of patients without ongoing treatment showed no signs of progression at 10 and 15 years, respectively. One-third of patients survived more than 15 years, but 3 years of VRD maintenance did not improve outcomes for patients with GEP-defined high-risk MM. The study was registered on www.clinicaltrials.gov as #NCT00572169.

Risk of infections associated with the use of bispecific antibodies in multiple myeloma: a pooled analysis.

The use of bispecific antibodies (BsAbs) in the treatment of relapsed/refractory multiple myeloma (MM) is showing early promising overall response rates in heavily pretreated patients. Infectious complications related to the use of BsAbs are not well described. We conducted a pooled analysis that included all single-agent BsAbs used in MM with no prior use of different BsAbs. A total of 1185 patients with MM were treated with a BsAb in the studied period (71.6% of the patients treated with an agent targeting B-cell maturation antigen (BCMA). Pooled median follow-up was short at 6.1 months (7.5 vs 5.2 months for BCMA vs non-BCMA BsAbs, respectively). Adverse events of interest included all grade neutropenia in 38.6%, all grade infections in 50% (n = 542/1083), all grade cytokine release syndrome in 59.6% (n = 706/1185), grade III/IV neutropenia in 34.8% (n = 372/1068), grade III/IV infections in 24.5% (n = 272/1110), grade III/IV pneumonia in 10% (n = 52.4/506), and grade III/IV coronavirus disease 2019 in 11.4% (n = 45.4/395) of the patients. Non-BCMA-targeted BsAbs were associated with lower grade III/IV neutropenia (25.3% vs 39.2%) and lower grade III/IV infections (11.9% vs 30%) when compared with BCMA-targeted BsAbs. Hypogammaglobulinemia was reported in 4 studies, with a prevalence of 75.3% (n = 256/340) of the patients, with IV immunoglobulin used in 48% (n = 123/256) of them. Death was reported in 110 patients, of which 28 (25.5%) were reported to be secondary to infections. Certain precautions should be used when using BsAbs to mitigate the risk and/or identify and treat infections promptly.

Characterizing the role of the immune microenvironment in multiple myeloma progression at a single-cell level.

Early alterations within the bone marrow microenvironment that contribute to the progression of multiple myeloma (MM) from its precursor stages could be the key to identifying novel therapeutic approaches. However, the intrinsic variability in cellular populations between patients and the differences in sample processing and analysis methods have made it difficult to identify consistent changes between data sets. Here, we used single-cell RNA sequencing of bone marrow cells from precursor stages, monoclonal gammopathy of unknown significance, smoldering MM, and newly diagnosed MM and analyzed our data in combination with a previously published data set that used a similar patient population and sample processing. Despite the vast interpatient heterogeneity, some alterations were consistently observed in both data sets. We identified changes in immune cell populations as the disease progressed, which were characterized by a substantial decrease in memory and naïve CD4 T cells, and an increase in CD8+ effector T cells and T-regulatory cells. These alterations were further accompanied by an enrichment of nonclonal memory B cells and an increase in CD14 and CD16 monocytes in MM compared with its precursor stages. These results provide crucial information on the immune changes associated with the progression to clinical MM and can help to develop immune-based strategies for patient stratification and early therapeutic intervention.

Clinical implications of loss of bone marrow minimal residual disease negativity in multiple myeloma.

Multiple myeloma (MM) patients frequently attain a bone marrow (BM) minimal residual disease (MRD) negativity status in response to treatment. We identified 568 patients who achieved BM MRD negativity following autologous stem cell transplantation (ASCT) and maintenance combination therapy with an immunomodulatory agent and a proteasome inhibitor. BM MRD was evaluated by next-generation flow cytometry (sensitivity of 10-5 cells) at 3- to 6-month intervals. With a median follow-up of 9.9 years from diagnosis (range, 0.4-30.9), 61% of patients maintained MRD negativity, whereas 39% experienced MRD conversion at a median of 6.3 years (range, 1.4-25). The highest risk of MRD conversion occurred within the first 5 years after treatment and was observed more often in patients with abnormal metaphase cytogenetic abnormalities (95% vs 84%; P = .001). MRD conversion was associated with a high risk of relapse and preceded it by a median of 1.0 years (range, 0-4.9). However, 27% of MRD conversion-positive patients had not yet experienced a clinical relapse, with a median follow-up of 9.3 years (range, 2.2-21.2). Landmark analyses using time from ASCT revealed patients with MRD conversion during the first 3 years had an inferior overall and progression-free survival compared with patients with sustained MRD negativity. MRD conversion correctly predicted relapse in 70%, demonstrating the utility of serial BM MRD assessment to complement standard laboratory and imaging to make informed salvage therapy decisions.