Multiple myeloma

Disease ID:1204
Name:Multiple myeloma
Associated with:1 target
5 immuno-relevant ligands
Synonyms
plasma cell myeloma
Description
A myeloma that is located in the plasma cells in bone marrow.
Database Links
Disease Ontology: DOID:9538
OMIM: 254500

Targets

leukocyte immunoglobulin like receptor B1 (CD85j)
Role:  Loss of LILRB1 on malignant plasma cells contributes to immune escape in multiple myeloma.
References:  5

Ligands

Key to terms and symbols Click ligand name to view ligand summary Click column headers to sort
Ligand References Clinical and Disease comments
iberdomide
Immuno Disease Comments: Phase 1/2 clinical candidate for MM- see NCT03161483
Clinical Use: CC-220 is being evaluated in clinical trials for systemic lupus erythematosus (SLE; Phase 2), and for relapsed and refractory multiple myeloma (alone or in combination with (Phase 1/2). | View clinical data
Bioactivity Comments: CC-220 binds cereblon (CRBN) with higher affinity than or [6]. CC-220 displaces a Cy5-conjugated cereblon modulating compound from the binding pocket of CRBN with an IC50 of 60nM. | View biological activity
plerixafor
Immuno Disease Comments: Immunostimulant stem cell mobiliser used in autologous stem cell transplantation.
Clinical Use: Plerixafor is an immunostimulant approved for use as a hematopoietic stem cell mobiliser in the treatment of non-Hodgkin lymphoma and multiple myeloma where autologous stem cell transplantation is necessary. The EMA granted plerixafor orphan status in 2011 as an adjunctive treatment to cytotoxic therapy in acute myeloid leukaemia.

Recent studies have suggested the possibility of plerixafor being repurposed for new indications, including recurrent high-grade glioma and pancreatic cancer. Plerixafor is in Phase I study (in combination with ) for recurrent high-grade glioma (ClinicalTrials.gov identifier NCT01339039). | View clinical data
masitinib
Immuno Disease Comments: EMA orphan drug for MM.
Clinical Use: The European Medicines Agency has granted this drug orphan status for treating pancreatic cancer, and it is in clinical trials for other human cancers. Under the synonym N-(methyl-diazacyclohexyl-methylbenzamide)-azaphenyl-aminothiopyrrole (a.k.a. Masican) the EMA has also granted orphan designation for the treatment of malignant gastrointestinal stromal tumours, mastocytosis and multiple myeloma. A Phase 3 trial of masitinib in combination with in amyotrophic lateral sclerosis (ALS, a.k.a. motor neurone disease, MND) is underway (NCT03127267). Click here to link to ClinicalTrials.gov's listing of masitinib trials. Fourteen Phase 3 trials are registered with ClinicalTrials.gov (as of Jan 2018), but many of these are not active. | View clinical data
Bioactivity Comments: This compound is primarily an inhibitor of type III receptor tyrosine kinases, but has some inhibitory activity at non-receptor tyrosine kinases [3]. | View biological activity
daratumumab
Immuno Disease Comments: Approved therapeutic for MM.
Clinical Use: This monoclonal antibody has been granted orphan drug approval in the EU (EMA 2013) for the treatment of plasma-cell myeloma, a rare form of white blood cell cancer. This antibody is in clinical trial for the treatment of other CD38-positive hematological malignancies including multiple myeloma. Click here to link to ClinicalTrials.gov's listing of daratumumab trials. In November 2015, the US FDA granted accelerated approval for daratumumab as a treatment for multiple myeloma, in patients who have received at least three prior treatments.
Phase III trial NCT02136134 evaluated the addition of daratumumab to and in patients with relapsed or refractory multiple myeloma. Preliminary results suggest this combination is much more effective than the current standard of care (as presented at the 2016 ASCO Annual Meeting, June 3-7, Chicago: Abstract LBA4 and reported in [11]). In November 2016, the US FDA approved the use of daratumumab plus and dexamethasone, or bortezomib and dexamethasone for multiple myeloma patients who have received at least one prior therapy. | View clinical data
Bioactivity Comments: Daratumumab is reported to induce complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) in patient-derived multiple myeloma cells [2].
Peptide sequence analysis of the heavy chain variable region of daratumumab matches a sequence claimed in patent US7829673 [1], and is the heavy chain component of monoclonal −005 described therein. | View biological activity
elotuzumab
Immuno Disease Comments: Approved drug for MM.
Clinical Use: Following evaluation in Phase III clinical trial for MM, which tested various combinations of , or ± elotuzumab [8-9], the US FDA approved the elotuzumab/lenalidomide/dexamethasone combination in late 2015. Use is indicated for MM patients who have received one to three prior therapies.
In the European Union elotuzumab has had orphan drug designation since August 2012, for the treatment of MM. | View clinical data
Bioactivity Comments: The biological activity of elotuzumab has been well characterised [4,7]. We have tagged the primary molecular target, providing data from patent US7709610 [10]. | View biological activity

References

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1. De Weers M, Graus Y, Oprins J, Parren P, Van De Winkel J, Van Vugt M. (2010) Antibodies Against Cd38 For Treatment Of Multiple Myeloma. Patent number: US7829673. Assignee: Genmab A/S. Priority date: 23/03/2005. Publication date: 09/11/2010.

2. de Weers M, Tai YT, van der Veer MS, Bakker JM, Vink T, Jacobs DC, Oomen LA, Peipp M, Valerius T, Slootstra JW et al.. (2011) Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J. Immunol., 186 (3): 1840-8. [PMID:21187443]

3. Dubreuil P, Letard S, Ciufolini M, Gros L, Humbert M, Castéran N, Borge L, Hajem B, Lermet A, Sippl W et al.. (2009) Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. PLoS ONE, 4 (9): e7258. [PMID:19789626]

4. Hsi ED, Steinle R, Balasa B, Szmania S, Draksharapu A, Shum BP, Huseni M, Powers D, Nanisetti A, Zhang Y et al.. (2008) CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin. Cancer Res., 14 (9): 2775-84. [PMID:18451245]

5. Lozano E, Díaz T, Mena MP, Suñe G, Calvo X, Calderón M, Pérez-Amill L, Rodríguez V, Pérez-Galán P, Roué G et al.. (2018) Loss of the Immune Checkpoint CD85j/LILRB1 on Malignant Plasma Cells Contributes to Immune Escape in Multiple Myeloma. J. Immunol., 200 (8): 2581-2591. [PMID:29531171]

6. Matyskiela ME, Zhang W, Man HW, Muller G, Khambatta G, Baculi F, Hickman M, LeBrun L, Pagarigan B, Carmel G et al.. (2018) A Cereblon Modulator (CC-220) with Improved Degradation of Ikaros and Aiolos. J. Med. Chem., 61 (2): 535-542. [PMID:28425720]

7. Tai YT, Dillon M, Song W, Leiba M, Li XF, Burger P, Lee AI, Podar K, Hideshima T, Rice AG et al.. (2008) Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood, 112 (4): 1329-37. [PMID:17906076]

8. van Rhee F, Szmania SM, Dillon M, van Abbema AM, Li X, Stone MK, Garg TK, Shi J, Moreno-Bost AM, Yun R et al.. (2009) Combinatorial efficacy of anti-CS1 monoclonal antibody elotuzumab (HuLuc63) and bortezomib against multiple myeloma. Mol. Cancer Ther., 8 (9): 2616-24. [PMID:19723891]

9. Veillette A, Guo H. (2013) CS1, a SLAM family receptor involved in immune regulation, is a therapeutic target in multiple myeloma. Crit. Rev. Oncol. Hematol., 88 (1): 168-77. [PMID:23731618]

10. Williams M, Tso JY, Landolfi NF, Powers DB, Liu G. (2010) Therapeutic use of anti-CS1 antibodies. Patent number: US7709610. Assignee: Facet Biotech Corporation. Priority date: 28/05/2003. Publication date: 04/05/2010.

11. (2016) A Three-Drug Combo for Multiple Myeloma. Cancer Discov, 6 (11): OF4. [PMID:27630127]