Multiple myeloma future or investigational therapies: Difference between revisions

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Latest revision as of 00:49, 20 August 2018

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Vidit Bhargava, M.B.B.S [2] Shyam Patel [3]

Overview

Chimeric antigen receptor T (CAR-T) cell therapy is actively under study for the treatment of relapsed and refractory multiple myeloma. This form of cell-based therapy employs one's own T lymphocytes, which are engineered to be tumor-specific. The antigen of interest for multiple myeloma CAR-T therapy is B cell maturation antigen (BCMA). Other investigational therapies include lymphoma-like polychemotherapy regimen and Bruton's tyrosine kinase inhibitor CC-292.

Future or Investigational Therapies

Chimeric antigen receptor T (CAR-T) cell therapy

Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings. CAR-T therapy is currently being explored for the treatment of multiple myeloma. This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses. The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population. The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.^[1] A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene. The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."^[1] CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies." In multiple myeloma, the specific tumor antigen against which CAR-T cells are engineered is B cell maturation antigen, or BCMA. Studies on the safety and efficacy are still pending, but the pre-clinical validation has already been completed.^[2]

Other investigational therapies

Lymphoma-like polychemotherapy: The regimen "Dexa-BEAM" (including dexamethasone, carmustine, cytarabine, etoposide and melphalan) in treating advanced and extramedullary multiple myeloma has been studied. It showed improved survival when used as a bridge to stem cell transplantation.^[3]

CC-292: The novel Bruton's tyrosine kinase inhibitor CC-292 in combination with the proteasome inhibitor carfilzomib has been studied for the treatment of multiple myeloma.^[4]

References

↑ ^1.0 ^1.1 Makita S, Yoshimura K, Tobinai K (2017). "Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma". Cancer Sci. 108 (6): 1109–1118. doi:10.1111/cas.13239. PMC 5480083. PMID 28301076.
↑ Bu DX, Singh R, Choi EE, Ruella M, Nunez-Cruz S, Mansfield KG; et al. (2018). "Pre-clinical validation of B cell maturation antigen (BCMA) as a target for T cell immunotherapy of multiple myeloma". Oncotarget. 9 (40): 25764–25780. doi:10.18632/oncotarget.25359. PMC 5995247. PMID 29899820.
↑ Rasche, L.; Strifler, S.; Duell, J.; Rosenwald, A.; Buck, A.; Maeder, U.; Einsele, H.; Knop, S. (2014). "The lymphoma-like polychemotherapy regimen Dexa-BEAM in advanced and extramedullary multiple myeloma". Ann Hematol. doi:10.1007/s00277-014-2023-2. PMID 24526137. Unknown parameter |month= ignored (help)
↑ Eda, H.; Santo, L.; Cirstea, DD.; Yee, A.; Scullen, TA.; Nemani, N.; Mishima, Y.; Waterman, PR.; Arastu-Kapur, S. (2014). "A novel Bruton's tyrosine kinase inhibitor CC-292 in combination with the proteasome inhibitor carfilzomib impacts the bone microenvironment in a multiple myeloma model with resultant anti-myeloma activity". Leukemia. doi:10.1038/leu.2014.69. PMID 24518207. Unknown parameter |month= ignored (help)

Template:WikiDoc Sources

[pmid28301076-1] 1.0 ^1.1 Makita S, Yoshimura K, Tobinai K (2017). "Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma". Cancer Sci. 108 (6): 1109–1118. doi:10.1111/cas.13239. PMC 5480083. PMID 28301076.

[pmid29899820-2] Bu DX, Singh R, Choi EE, Ruella M, Nunez-Cruz S, Mansfield KG; et al. (2018). "Pre-clinical validation of B cell maturation antigen (BCMA) as a target for T cell immunotherapy of multiple myeloma". Oncotarget. 9 (40): 25764–25780. doi:10.18632/oncotarget.25359. PMC 5995247. PMID 29899820.

[Rasche-2014-3] Rasche, L.; Strifler, S.; Duell, J.; Rosenwald, A.; Buck, A.; Maeder, U.; Einsele, H.; Knop, S. (2014). "The lymphoma-like polychemotherapy regimen Dexa-BEAM in advanced and extramedullary multiple myeloma". Ann Hematol. doi:10.1007/s00277-014-2023-2. PMID 24526137. Unknown parameter |month= ignored (help)

[Eda-2014-4] Eda, H.; Santo, L.; Cirstea, DD.; Yee, A.; Scullen, TA.; Nemani, N.; Mishima, Y.; Waterman, PR.; Arastu-Kapur, S. (2014). "A novel Bruton's tyrosine kinase inhibitor CC-292 in combination with the proteasome inhibitor carfilzomib impacts the bone microenvironment in a multiple myeloma model with resultant anti-myeloma activity". Leukemia. doi:10.1038/leu.2014.69. PMID 24518207. Unknown parameter |month= ignored (help)

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@@ Line 1: / Line 1: @@
 {{Multiple myeloma}}
-{{CMG}} {{VB}}
+{{CMG}} {{AE}}{{VB}} {{shyam}}
-*Lymphoma-like polychemotherapy regimen "Dexa-BEAM" (including [[dexamethasone]], [[carmustine]], [[cytarabine]], [[etoposide]] and [[melphalan]]) in treating advanced and extramedullary multiple myeloma has been studied by Rasche L etal. It showed improved survival, when used as a bridge to [[stem cell transplantation]].<ref name="Rasche-2014">{{Cite journal  | last1 = Rasche | first1 = L. | last2 = Strifler | first2 = S. | last3 = Duell | first3 = J. | last4 = Rosenwald | first4 = A. | last5 = Buck | first5 = A. | last6 = Maeder | first6 = U. | last7 = Einsele | first7 = H. | last8 = Knop | first8 = S. | title = The lymphoma-like polychemotherapy regimen Dexa-BEAM in advanced and extramedullary multiple myeloma. | journal = Ann Hematol | volume =  | issue =  | pages =  | month = Feb | year = 2014 | doi = 10.1007/s00277-014-2023-2 | PMID = 24526137 }}</ref>
+==Overview==
+Chimeric antigen receptor T (CAR-T) cell therapy is actively under study for the treatment of relapsed and refractory multiple myeloma. This form of cell-based therapy employs one's own T lymphocytes, which are engineered to be tumor-specific. The antigen of interest for multiple myeloma CAR-T therapy is B cell maturation antigen (BCMA). Other investigational therapies include lymphoma-like polychemotherapy regimen and Bruton's tyrosine kinase inhibitor CC-292.
-*[[Carfilzomib]] is a new proteasome inhibitor that selectively and irreversibly binds to its target, resulting in sustained inhibition. It thus has a better response as compared to [[bortezomib]] along with a favorable safety profile. Clinical trials have been approved and under process to study the effects of the drug. The prospect of its combination with several other agents such as immunomodulators, alkylating agents, glucocorticoids, histone deacetylase inhibitors and kinesin spindle protein inhibitors also holds promise.<ref name="Moreau-2014">{{Cite journal  | last1 = Moreau | first1 = P. | title = The emerging role of carfilzomib combination therapy in the management of multiple myeloma. | journal = Expert Rev Hematol | volume =  | issue =  | pages =  | month = Feb | year = 2014 | doi = 10.1586/17474086.2014.873699 | PMID = 24521249 }}</ref>
+==Future or Investigational Therapies==
+===Chimeric antigen receptor T (CAR-T) cell therapy===
+Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings. CAR-T therapy is currently being explored for the treatment of multiple myeloma. This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses. The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population. The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076  }} </ref> A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene. The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076  }} </ref> CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies." In multiple myeloma, the specific tumor antigen against which CAR-T cells are engineered is B cell maturation antigen, or BCMA. Studies on the safety and efficacy are still pending, but the pre-clinical validation has already been completed.<ref name="pmid29899820">{{cite journal| author=Bu DX, Singh R, Choi EE, Ruella M, Nunez-Cruz S, Mansfield KG et al.| title=Pre-clinical validation of B cell maturation antigen (BCMA) as a target for T cell immunotherapy of multiple myeloma. | journal=Oncotarget | year= 2018 | volume= 9 | issue= 40 | pages= 25764-25780 | pmid=29899820 | doi=10.18632/oncotarget.25359 | pmc=5995247 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29899820  }} </ref>
+===Other investigational therapies===
+*'''Lymphoma-like polychemotherapy''': The regimen "Dexa-BEAM" (including [[dexamethasone]], [[carmustine]], [[cytarabine]], [[etoposide]] and [[melphalan]]) in treating advanced and extramedullary multiple myeloma has been studied. It showed improved survival when used as a bridge to [[stem cell transplantation]].<ref name="Rasche-2014">{{Cite journal  | last1 = Rasche | first1 = L. | last2 = Strifler | first2 = S. | last3 = Duell | first3 = J. | last4 = Rosenwald | first4 = A. | last5 = Buck | first5 = A. | last6 = Maeder | first6 = U. | last7 = Einsele | first7 = H. | last8 = Knop | first8 = S. | title = The lymphoma-like polychemotherapy regimen Dexa-BEAM in advanced and extramedullary multiple myeloma. | journal = Ann Hematol | volume =  | issue =  | pages =  | month = Feb | year = 2014 | doi = 10.1007/s00277-014-2023-2 | PMID = 24526137 }}</ref>
-*Eda etal is studying a novel Bruton's tyrosine kinase inhibitor CC-292 in combination with the proteasome inhibitor carfilzomib and its rols as anti-myeloma combiantion therpay.<ref name="Eda-2014">{{Cite journal  | last1 = Eda | first1 = H. | last2 = Santo | first2 = L. | last3 = Cirstea | first3 = DD. | last4 = Yee | first4 = A. | last5 = Scullen | first5 = TA. | last6 = Nemani | first6 = N. | last7 = Mishima | first7 = Y. | last8 = Waterman | first8 = PR. | last9 = Arastu-Kapur | first9 = S. | title = A novel Bruton's tyrosine kinase inhibitor CC-292 in combination with the proteasome inhibitor carfilzomib impacts the bone microenvironment in a multiple myeloma model with resultant anti-myeloma activity. | journal = Leukemia | volume =  | issue =  | pages =  | month = Feb | year = 2014 | doi = 10.1038/leu.2014.69 | PMID = 24518207 }}</ref>
+*'''CC-292''': The novel Bruton's tyrosine kinase inhibitor CC-292 in combination with the proteasome inhibitor carfilzomib has been studied for the treatment of multiple myeloma.<ref name="Eda-2014">{{Cite journal  | last1 = Eda | first1 = H. | last2 = Santo | first2 = L. | last3 = Cirstea | first3 = DD. | last4 = Yee | first4 = A. | last5 = Scullen | first5 = TA. | last6 = Nemani | first6 = N. | last7 = Mishima | first7 = Y. | last8 = Waterman | first8 = PR. | last9 = Arastu-Kapur | first9 = S. | title = A novel Bruton's tyrosine kinase inhibitor CC-292 in combination with the proteasome inhibitor carfilzomib impacts the bone microenvironment in a multiple myeloma model with resultant anti-myeloma activity. | journal = Leukemia | volume =  | issue =  | pages =  | month = Feb | year = 2014 | doi = 10.1038/leu.2014.69 | PMID = 24518207 }}</ref>
-*In one of the trials, the effect of thymoquinone (TQ), a bioactive constituent of black seed oil is combination with bortezomib is being studied. The results are promising  and show that TQ can enhance the anticancer activity of bortezomib in vitro and in vivo and may have a substantial potential in the treatment of MM.<ref name="Siveen-2014">{{Cite journal  | last1 = Siveen | first1 = KS. | last2 = Mustafa | first2 = N. | last3 = Li | first3 = F. | last4 = Kannaiyan | first4 = R. | last5 = Ahn | first5 = KS. | last6 = Kumar | first6 = AP. | last7 = Chng | first7 = WJ. | last8 = Sethi | first8 = G. | title = Thymoquinone overcomes chemoresistance and enhances the anticancer effects of bortezomib through abrogation of NF-κB regulated gene products in multiple myeloma xenograft mouse model. | journal = Oncotarget | volume =  | issue =  | pages =  | month = Dec | year = 2014 | doi =  | PMID = 24504138 }}</ref>
-*Use of [[pomalidomide]] in relapsed and refractory multiple myeloma is also being considered. The proposed starting dose of pomalidomide is 4 mg given on days 1-21 of each 28-day cycle, while dexamethasone is administered at a dose of 40 mg weekly. The report can be read by clicking [[http://www.ncbi.nlm.nih.gov/pubmed/24496300|here]].<ref name="Dimopoulos-2014">{{Cite journal  | last1 = Dimopoulos | first1 = MA. | last2 = Leleu | first2 = X. | last3 = Palumbo | first3 = A. | last4 = Moreau | first4 = P. | last5 = Delforge | first5 = M. | last6 = Cavo | first6 = M. | last7 = Ludwig | first7 = H. | last8 = Morgan | first8 = GJ. | last9 = Davies | first9 = FE. | title = Expert panel consensus statement on the optimal use of pomalidomide in relapsed and refractory multiple myeloma. | journal = Leukemia | volume =  | issue =  | pages =  | month = Feb | year = 2014 | doi = 10.1038/leu.2014.60 | PMID = 24496300 }}</ref>
-*[[Ibrutinib]] (Imbruvica™) is a small molecule, first-in-class, once-daily, orally available, Bruton's tyrosine kinase inhibitor that is under development for the treatment of B cell malignancies, including chronic lymphocytic leukaemia (CLL), mantle cell lymphoma (MCL) and diffuse large B cell lymphoma (DLBCL), as well as multiple myeloma (MM), follicular lymphoma (FL) and Waldenstrom's macroglobulinemia (WM).<ref name="Cameron-2014">{{Cite journal  | last1 = Cameron | first1 = F. | last2 = Sanford | first2 = M. | title = Ibrutinib: first global approval. | journal = Drugs | volume = 74 | issue = 2 | pages = 263-71 | month = Feb | year = 2014 | doi = 10.1007/s40265-014-0178-8 | PMID = 24464309 }}</ref>
-*A series of degrasyn like compounds (T5165804 and CP2005) are being studied and have showed higher efficacy against tumor cells and can be used as potential carcinoma therapy in the future.<ref name="Peng-2014">{{Cite journal  | last1 = Peng | first1 = Z. | last2 = Maxwell | first2 = DS. | last3 = Sun | first3 = D. | last4 = Bhanu Prasad | first4 = BA. | last5 = Schuber | first5 = PT. | last6 = Pal | first6 = A. | last7 = Ying | first7 = Y. | last8 = Han | first8 = D. | last9 = Gao | first9 = L. | title = Degrasyn-like symmetrical compounds: Possible therapeutic agents for multiple myeloma (MM-I). | journal = Bioorg Med Chem | volume = 22 | issue = 4 | pages = 1450-8 | month = Feb | year = 2014 | doi = 10.1016/j.bmc.2013.12.048 | PMID = 24457091 }}</ref>
 == References ==
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