Daratumumab – Hope for Myeloma Patients, a Challenge for Clinical Laboratories

Jelı́nek, Tomáš; Kořístka, Martin; Čermáková, Z; Hájek, Roman

doi:10.14735/amko201713

Cited by 5 publications

(2 citation statements)

References 28 publications

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“…Interference s imunofixací může vést k nesprávnému podhodnocení kompletní remise u pacientů s IgGκ MM: v těchto případech může být terapeutická protilátka hodnocena jako reziduální množství pacientova paraproteinu [45]. Anti--CD38 mAbs způsobují komplikace i ve flowcytometrickém stanovení MRD -několika mechanizmy může vést k falešně negativnímu vyhodnocení MRD stavu [46,47]. Při použití anti-CD38 mAbs je obecně doporučeno užívání antivirotik (acyklovir, valacyklovir) v rámci prevence reaktivace pásového oparu (Varicella-zoster virus -VZV), a to po celou dobu léčby a 3 měsíce po jejím ukončení.…”

Section: Komplikace Spojené S Podáním Anti-cd38 Mabsunclassified

CD38 targeted treatment for multiple myeloma

Jelı́nek¹,

Mihályová²,

Hájek³

2018

Vnitr Lek

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SouhrnAntigen CD38 je uniformně a vysoce exprimován na plazmatických buňkách a stal se tak ideálním cílem pro léčbu mnohočetného myelomu (MM) pomocí anti-CD38 cílených monoklonálních protilátek (mAbs). Nejdále ve vývoji je daratumumab, nicméně podobně slibných výsledků dosahuje i isatuximab, který cílí na zcela jiný epitop molekuly CD38. Anti-CD38 mAbs mají pleiotropní mechanizmus účinku, který je popisován i u jiných mAbs, nicméně zásadním, novým a specifickým mechanizmem je tzv. imunomodulační efekt díky depleci CD38 + imunosupresivních buněčných populací. Monoterapie anti-CD38 mAbs vede k odpovědím u asi 30 % silně předléčených MM pacientů. Jelikož je toxicita těchto látek minimální a mají odlišný mechanizmus účinku, jsou ideálním partnerem do kombinační léčby s běžně užívanými antimyelomovými léky. Daratumumab je schválen jako součást již 3 režimů u relabovaných pacientů s MM a jeho kombinace s lenalidomidem a dexametazonem je v současné době považována za nejlepší možnou léčbu relapsu nemoci, při níž bylo dosaženo bezprecedentního prodloužení mediánu doby bez progrese (Progression Free Survival -PFS), celkové léčebné odpovědi, i kvality odpovědí. Anti-CD38 mAbs se postupně posouvají i do léčby první linie. Stejně tak jsou s úspěchem zkoušeny u dalších plazmocelulárních dyskrazií (AL-amyloidóza), dalších hematologických malignit (akutní lymfoblastická leukemie -ALL, akutní myeloidní leukemie -AML, chronická lymfocytární leukemie -CLL), a dokonce u solidních nádorů či autoimunitních onemocnění. Léčba pomocí anti-CD38 mAbs znamená podobnou revoluci pro pacienty s MM, jako zavedení anti-CD20 mAbs u nemocných s CLL či non-hodgkinskými lymfomy a zcela jistě je velkou nadějí do budoucna směřující k možnosti vyléčení alespoň části nemocných s MM. Klíčová slova: akutní myeloidní leukemie -CD38 -daratumumab -isatuximab -mnohočetný myelom CD38 targeted treatment for multiple myeloma Summary CD38 antigen is highly and uniformly expressed on plasma cells and thus represents an ideal target for the treatment of multiple myeloma (MM) with anti-CD38 monoclonal antibodies (mAbs). Daratumumab is the most advanced anti-CD38 mAb in the clinical development with approval in several indications, nevertheless isatuximab that targets completely different epitope of CD38 molecule is also very promising drug. Anti-CD38 possess pleiotropic mechanism of action that have been described also in other mAbs, but quite specific, novel and very important seems to be the immunomodulatory effect provided by depletion of several CD38 + immunosuppressive immune cell populations. CD38-targeted mAbs induce partial response or better in approximately 30 % of heavily pre-treated myeloma patients as monotherapy. Based on their favourable toxicity profile and distinct mechanism of action, anti-CD38 mAbs represents very attractive partner to back-bone anti-myeloma drugs. Indeed, daratumumab is already approved as a part of three distinct combination regimens in relapsed setting. The combination of daratumumab with lenalidomide and dexamethasone is cons...

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Section: Komplikace Spojené S Podáním Anti-cd38 Mabsunclassified

CD38 targeted treatment for multiple myeloma

Jelı́nek¹,

Mihályová²,

Hájek³

2018

Vnitr Lek

Self Cite

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“…Multiple myeloma (MM) is the second most common hematological malignancy [1] characterized by clonal proliferation of plasma cells (PCs) in the bone marrow (BM), presence of monoclonal immunoglobulin in serum and/or urine and CRAB (hypercalcemia, renal failure, anemia, bone lesions) features [2]. In recent years, survival of MM patients has dramatically improved with the introduction of new drugs, including proteasome inhibitors, monoclonal antibodies, immunomodulatory drugs and CAR-T cells [3][4][5][6]. However, MM still remains an incurable disease, and poor prognosis of patients is commonly associated with an aggressive and mostly resistant entity called extramedullary disease (EMD) [7], which may be found at the time of MM diagnosis (primary EMD) or during the relapse (secondary EMD).…”

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Proteomic analysis of the bone marrow microenvironment in extramedullary multiple myeloma patients

Gregorová

Vychytilova-Faltejskova

Kramarova

et al. 2022

neo

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Multiple myeloma (MM) is a heterogeneous hematological malignancy characterized by the uncontrolled clonal proliferation of bone marrow (BM) plasma cells. The poor prognosis of patients is associated with the presence of extramedullary disease (EMD). Previously, different mechanisms involved in the colonization of BM niches by MM cells and their escape during EMD have been described. Thus, we aimed to investigate the expression of selected cytokines in the BM plasma of MM patients as well as EMD patients to reveal novel molecules involved in EMD pathogenesis.Expression of 120 different cytokines was measured in BM plasma of 13 MM and 11 EMD patients using Proteome Profiler Antibody Arrays. The correlation between statistically significant cytokines and clinicopathological parameters of patients was determined using the Spearman correlation analysis. Finally, protein-protein interactions were analyzed, and GO and KEGG pathways enrichment analysis was performed. In total, 27 cytokines were found to be differently expressed between MM and EMD patients. After the Benjamini Hochberg correction for multiple testing, the statistical significance of two cytokines downregulated in EMD (EGF, BDNF) and six cytokines upregulated in EMD (NAP-2, ADIPOQ, CRP, MIG, BAFF, and THBS1) was maintained.Correlation analysis proved a significant association between the expression of these molecules and selected clinical-pathological features of MM/EMD patients. Protein association network analysis revealed important protein-protein interactions between THBS1/EGF, MIG/NAP-2, THBS1/NAP-2, EGF/NAP-2, and ADIPOQ/CRP. Finally, identified cytokines were proved to be significantly involved in focal adhesion, PI3K/AKT, and MAPK signaling pathways, and regulation of cell development, localization, proliferation, migration, differentiation, immune system processes, and stress response. Obtained results confirm the key function of the BM microenvironment in the pathogenesis of MM and indicate the essential role of numerous cytokines in the disease progression and EMD development. However, the exact mechanisms need to be further clarified.

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Update on PD-1/PD-L1 Inhibitors in Multiple Myeloma

2018

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The treatment of cancer, especially of various types of solid tumors, has been revolutionized by the blockade of the PD-1/PD-L1 pathway by immune checkpoint inhibitors. Their success amongst hematologic malignancies, however, has been limited so far to the treatment of classic Hodgkin's lymphoma, which portrays a typical overexpression of PD-1 ligands (PD-L1, PD-L2) as a consequence of changes in chromosome 9p24.1. Their current application in multiple myeloma (MM) is rather uncertain, as discordant results have been reported by distinct research groups concerning especially the expression of PD-1/PD-L1 molecules on malignant plasma cells or on the responsible immune effector cell populations, respectively. In MM it seems that an approach based on combination treatment might be appropriate as unsatisfactory results have been yielded by monotherapy with PD-1/PD-L1 inhibitors. Immunomodulatory drugs, which are the current cornerstone of MM treatment, are the most logical partners as they possess many possibly synergistic effects. Nevertheless, the initially optimistic results have become disappointing due to the excessive and unpredictable toxicity of the combination of pembrolizumab with lenalidomide or pomalidomide. The FDA has suspended or put on hold several phase 3 trials in relapsed as well as in newly diagnosed myeloma patients. There are also other potentially synergistic and promising combinations, such as the anti-CD38 monoclonal antibody daratumumab, irradiation, etc. Not only the effective partner but also the correct timing of the initiation of the PD-1/PD-L1 inhibitors treatment seems to be of utmost importance. These strategies are currently being examined in various stages of myeloma such as during consolidation post autologous stem cell transplantation, targeting minimal residual disease or even in high risk smoldering myeloma.

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Daratumumab – Hope for Myeloma Patients, a Challenge for Clinical Laboratories

Cited by 5 publications

References 28 publications

CD38 targeted treatment for multiple myeloma

CD38 targeted treatment for multiple myeloma

Proteomic analysis of the bone marrow microenvironment in extramedullary multiple myeloma patients

Update on PD-1/PD-L1 Inhibitors in Multiple Myeloma

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