The changing landscape of relapsed and/or refractory multiple myeloma (MM): fundamentals and controversies

Hernández‐Rivas, José‐Ángel; Ríos-Tamayo, Rafael; Encinas, Cristina; Alonso, Rafael; Lahuerta, Juan José

doi:10.1186/s40364-021-00344-2

Cited by 23 publications

(9 citation statements)

References 176 publications

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“…This high rate of refractoriness with few lines of treatment reflects that the drug’s mechanism of action is changed early in Spain. This finding, similar to that observed in other real-world experiences with BM [ 18 , 22 ], can be justified by the availability of several generations of new anti-MM drugs in the front-line setting [ 28 ]. Earlier use of these new drugs promotes the achievement of relapsed/refractory status after primary refractoriness or early relapse after first-line treatment [ 28 ].…”

Section: Discussionsupporting

confidence: 84%

“…Earlier use of these new drugs promotes the achievement of relapsed/refractory status after primary refractoriness or early relapse after first-line treatment [ 28 ]. This clinical situation will likely increase, decreasing the number of patients with very late relapse after a long course of treatment (e.g., chemotherapy or autologous stem cell transplantation [ASCT] as first-line treatment) [ 28 ], such as those included in other real-world experiences with 7–8 prior lines before BM [ 12 , 21 ].…”

Section: Discussionmentioning

confidence: 99%

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Real-World Outcomes of Belantamab Mafodotin for Relapsed/Refractory Multiple Myeloma (RRMM): Preliminary Results of a Spanish Expanded Access Program (EAP)

et al. 2022

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Introduction Belantamab mafodotin (BM) is a new anti-BCMA antibody–drug conjugate, recently approved for triple-class relapsed and refractory multiple myeloma (RRMM). We assessed real-world outcomes with BM in patients under the Spanish Expanded Access Program (EAP). Methods We conducted an observational, retrospective, multicenter study including RRMM patients who received ≥ 1 dose of BM (Nov 2019 to Jun 2021). The primary endpoint was overall response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and incidence of treatment-emergent adverse events (TEAEs). Results Thirty-three patients were included with a median of 70 years of age (range, 46–79 years). Median time from diagnosis was 71 months (range, 10–858 months). Median prior lines was 5 (range, 3–8 lines); 90% of patients were triple-/quad-/penta-refractory; 48% showed high-risk cytogenetics. Median BM doses was 3 (range 1–16 doses), with a median follow-up of 11 months (6–15 months). ORR was 42.2% (≥ VGPR, 18.2%). Median PFS was 3 months (95% CI 0.92–5.08) in the overall population, and 11 months (HR 0.26; 95% CI 0.10–0.68) for patients who achieved ≥ PR. PFS was not significantly different according to age, cytogenetic risk, and prior therapy lines. OS was 424 days (95% CI 107–740). Non-hematological TEAEs (57.6% of patients; 30.3% ≥ G3) included keratopathy (51.5%; 21.2% ≥ G3) and patient-reported vision-related symptoms (45.5%). Keratopathy was resolved in 70.6% of patients. G3 hematological TEAEs was 18.2%, thrombocytopenia (21.2%). Dose reductions due to TEAEs: 30.3%; delays: 36.4%. Treatment discontinuation causes: progression (54.5%), toxicity (non-ocular; 6%/ocular; 6% /ocular + non-ocular toxicity; 3%), death (6%), and patient’s decision (3%). Conclusions BM showed relevant anti-myeloma activity in RRMM with a manageable safety profile. These results corroborate those observed in the BM pivotal trial.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Real-World Outcomes of Belantamab Mafodotin for Relapsed/Refractory Multiple Myeloma (RRMM): Preliminary Results of a Spanish Expanded Access Program (EAP)

et al. 2022

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“…In particular, while there is broad consensus on SOC therapy for MM, there is greater uncertainty for choosing drugs for relapsed refractory MM patients. (4,(49)(50)(51) In this regard, mmSYGNAL could be developed further into a predictive tool for discovering and tailoring existing and new therapies to the unique biological characteristics of a patient's disease. Our discovery that FDA-approved anticancer therapies (in particular SOC and investigational MM drugs) were enriched within risk-associated programs lends credibility to this strategy.…”

Section: Discussionmentioning

confidence: 99%

Individualized dynamic risk assessment for multiple myeloma

Murie,

Turkarslan,

Patel

et al. 2024

Preprint

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Background. Individualized treatment decisions for patients with multiple myeloma (MM) requires accurate risk stratification that takes into account patient-specific consequences of genetic abnormalities and tumor microenvironment on disease outcome and therapy responsiveness. Methods. Previously, SYstems Genetic Network AnaLysis (SYGNAL) of multi-omics tumor profiles from 881 MM patients generated the mmSYGNAL network, which uncovered different causal and mechanistic drivers of genetic programs associated with disease progression across MM subtypes. Here, we have trained a machine learning (ML) algorithm on activities of mmSYGNAL programs within individual patient tumor samples to develop a risk classification scheme for MM that significantly outperformed cytogenetics, International Staging System, and multi-gene biomarker panels in predicting risk of PFS across four independent patient cohorts. Results. We demonstrate that, unlike other tests, mmSYGNAL can accurately predict disease progression risk at primary diagnosis, pre- and post-transplant and even after multiple relapses, making it useful for individualized dynamic risk assessment throughout the disease trajectory. Conclusion. mmSYGNAL provides improved individualized risk stratification that accounts for a patient's distinct set of genetic abnormalities and can monitor risk longitudinally as each patient's disease characteristics change.

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“…Novel therapies for multiple myeloma (MM), such as proteasomal inhibitors, immunomodulatory drugs, and CAR-T cell therapy, have improved palliation and response rates, providing a longer disease-free period; however, MM inevitably progresses in the vast majority of patients [ 1 ]. Cancer stem cells (CSCs), also known as tumor initiating cells, are believed to be the root cause of tumor recurrence for most if not all malignancies, including MM [ 2 ].…”

Section: To the Editormentioning

confidence: 99%

A novel E-cadherin/SOX9 axis regulates cancer stem cells in multiple myeloma by activating Akt and MAPK pathways

et al. 2022

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Cancer stem cells (CSCs) have been identified in multiple myeloma (MM) and are widely regarded as a key driver of MM initiation and progression. E-cadherin, in addition to its established role as a marker for epithelial-mesenchymal transition, also plays critical roles in controlling the aggressive behaviors of various tumor cells. Here, we show that depletion of E-cadherin in MM cells remarkably inhibited cell proliferation and cell cycle progression, in part through the decreased prosurvival CD138 and Bcl-2 and the inactivated Akt and MAPK pathways. CSC features, including the ability of the cells to form clonogenic colonies indicative of self-renewal and side population, were greatly suppressed upon the depletion of E-cadherin and subsequent loss of SOX9 stem-cell factor. We further provide evidence that SOX9 is a downstream target of E-cadherin-mediated CSC growth and self-renewal—ectopic re-expression of SOX9 in E-cadherin-depleted cells rescued its inhibitory effects on CSC-like properties and survival signaling. Collectively, our findings unveil a novel regulatory mechanism of MM CSCs via the E-cadherin/SOX9 axis, which could be important in understanding the long-term cell survival and outgrowth that leads to relapsed/refractory MM.

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The changing landscape of relapsed and/or refractory multiple myeloma (MM): fundamentals and controversies

Cited by 23 publications

References 176 publications

Real-World Outcomes of Belantamab Mafodotin for Relapsed/Refractory Multiple Myeloma (RRMM): Preliminary Results of a Spanish Expanded Access Program (EAP)

Real-World Outcomes of Belantamab Mafodotin for Relapsed/Refractory Multiple Myeloma (RRMM): Preliminary Results of a Spanish Expanded Access Program (EAP)

Individualized dynamic risk assessment for multiple myeloma

A novel E-cadherin/SOX9 axis regulates cancer stem cells in multiple myeloma by activating Akt and MAPK pathways

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