Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BioDrugs
Published in: BioDrugs 2/2016

01-04-2016 | Review Article

Management of Multiple Myeloma with Second-Generation Antibody-Drug Conjugates

Authors: Pawel Robak, Tadeusz Robak

Published in: BioDrugs | Issue 2/2016

Login to get access

Abstract

The antibody–drug conjugate (ADC) is a combination of a cytotoxic agent and monoclonal antibodies (mAbs) through a stable specialized chemical linker. After ADC binds to the target antigen, the conjugate is internalized and toxin is released, leading to the death of a target cell. Lorvotuzumab mertansine, indatuximab ravtansine, and milatuzumab–doxorubicin are currently under clinical development for use in multiple myeloma (MM). Preliminary data from recent studies indicate that these agents induce responses in patients with relapsed and/or refractory MM and have an acceptable safety profile.
Literature
1.
2.
3.
4.
Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341:1565–71.CrossRefPubMed
5.
Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352:2487–98.CrossRefPubMed
6.
Richardson PG, Blood E, Mitsiades CS, et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006;108:3458–64.CrossRefPubMedPubMedCentral
7.
Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120:2817–25.CrossRefPubMedPubMedCentral
8.
Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia. 2010;24:1934–9.CrossRefPubMedPubMedCentral
9.
Anderson KC. The 39th David A. Karnofsky Lecture: bench-to-bedside translation of targeted therapies in multiple myeloma. J Clin Oncol. 2012;30:445–52.CrossRefPubMedPubMedCentral
10.
Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373:621–31.CrossRefPubMed
11.
Lonial S, Vij R, Harousseau JL, et al. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J Clin Oncol. 2012;30:1953–9.CrossRefPubMed
12.
Lonial S, Dimopoulos MA, Palumbo A, et al. ELOQUENT-2: a phase III, randomized, open-label study of lenalidomide (Len)/dexamethasone (dex) with/without elotuzumab (Elo) in patients (pts) with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2015;33 Suppl:8508 [abstract].
13.
Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015;373:1207–19.CrossRefPubMed
14.
Sherbenou DW, Behrens CR, Su Y, Wolf JL, Martin TG 3rd, Liu B. The development of potential antibody-based therapies for myeloma. Blood Rev. 2015;29:81–91.CrossRefPubMedPubMedCentral
15.
Lutz RJ, Whiteman KR. Antibody-maytansinoid conjugates for the treatment of myeloma. mAbs. 2009;1:548–51.
16.
Berdeja JG. Lorvotuzumab mertansine: antibody-drug-conjugate for CD56+ multiple myeloma. Front Biosci (Landmark Ed). 2014;19:163–70.CrossRefPubMed
17.
Tassone P, Gozzini A, Goldmacher V, et al. In vitro and in vivo activity of the maytansinoid immunoconjugate huN901-N2′-deacetyl-N2′-(3-mercapto-1-oxopropyl)-maytansine against CD56+ multiple myeloma cells. Cancer Res. 2004;64:4629–36.CrossRefPubMed
18.
19.
Ishitsuka K, Jimi S, Goldmacher VS, et al. Targeting CD56 by the maytansinoid immunoconjugate IMGN901 (huN901-DM1): a potential therapeutic modality implication against natural killer/T cell malignancy. Br J Haematol. 2008;141:129–31.CrossRefPubMed
20.
Bataille R, Jego G, Robillard N, et al. The phenotype of normal, reactive and malignant plasma cells. Identification of “many and multiple myelomas” and of new targets for myeloma therapy. Haematologica. 2006;91:1234–40.PubMed
21.
Chanan-Khan A, Wolf J, Garcia J, et al. Efficacy analysis from a phase I study of lorvotuzumab mertansine (IMGN901) used as monotherapy in patients with heavily pre-treated CD56-positive multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2010;116:819;1962 [abstract].
22.
Berdeja JG, Hernandez-Ilizaliturri F,Chanan-Khan A, et al. Phase I study of lorvotuzumab mertansine (LM, IMGN901) in combination with lenalidomide (Len) and dexamethasone (Dex) in patients with CD56-positive relapsed or relapsed/refractory multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts). 2012;120:728 [abstract].
23.
Lopus M, Oroudjev E, Wilson L, et al. Maytansine and cellular metabolites of antibody-maytansinoid conjugates strongly suppress microtubule dynamics by binding to microtubules. Mol Cancer Ther. 2010;9(10):2689–99.CrossRefPubMedPubMedCentral
24.
25.
Ikeda H, Hideshima T, Fulciniti M, et al. The monoclonal antibody nBT062 conjugated to cytotoxic maytansinoids has selective cytotoxicity against CD138-positive multiple myeloma cells in vitro and in vivo. Clin Cancer Res. 2009;15:4028–37.CrossRefPubMed
26.
Tassone P, Goldmacher VS, Neri P, et al. Cytotoxic activity of the maytansinoid immunoconjugate B-B4-DM1 against CD138+ multiple myeloma cells. Blood. 2004;104:3688–96.CrossRefPubMed
27.
Jagannath S, Chanan-Khan A, Heffner LT, et al. BT062, an antibody-drug conjugate directed against CD138, shows clinical activity in patients with relapsed or relapsed/refractory multiple myeloma. Blood. 2011;118:305 [abstract].
28.
Heffner LT, Jagannath S, Zimmerman TM, et al. BT062, an antibody-drug conjugate directed against CD138, given weekly for 3 weeks in each 4 week cycle: safety and further evidence of clinical activity. Blood (ASH Annual Meeting Abstracts). 2012;120:4042 [abstract].
29.
Kelly KR, Chanan-Khan A, Somlo G, et al. Indatuximab ravtansine (BT062) in combination with lenalidomide and low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma: clinical activity in len/dex-refractory patients. Blood (ASH Annual Meeting Abstracts). 2013;122:758 [abstract].
30.
Kelly KR, Chanan-Khan A, Heffner LT, et al. Indatuximab ravtansine (BT062) in combination with lenalidomide and low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma: clinical activity in patients already exposed to lenalidomide and bortezomib [abstract]. Blood (ASH Annual Meeting Abstracts). 2014;124(21):4736 [abstract].
31.
Sapra P, Stein R, Pickett JQ, et al. Anti-CD74 antibody-doxorubicin conjugate, IMMU-110, in a human multiple myeloma xenograft and in monkeys. Clin Cancer Res. 2005;11:5257–64.CrossRefPubMed
32.
Stein R, Griffiths GL, Cardillo T, et al. Therapeutic activity of a new antibody-drug immunoconjugate, IMMU-110, in preclinical studies targeted against multiple myeloma. J Clin Oncol. 2004;22 Suppl:6535 [abstract].
33.
Stein R, Mattes MJ, Cardillo T, et al. CD74: a new candidate target for the immunotherapy of B-cell neoplasms. Clin Cancer Res. 2007;13:5556s–63s.CrossRefPubMed
34.
Govindan SV, Cardillo TM, Sharkey RM, et al. Milatuzumab-SN-38 conjugates for the treatment of CD74+ cancers. Mol Cancer Ther. 2013;12:968–78.CrossRefPubMed
35.
Kaufman JL, Niesvizky R, Stadtmauer EA, et al. Phase I, multicentre, dose-escalation trial of monotherapy with milatuzumab (humanized anti-CD74 monoclonal antibody) in relapsed or refractory multiple myeloma. Br J Haematol. 2013;163:478–86.CrossRefPubMed
36.
37.
Elkins K, Zheng B, Go M, et al. FcRL5 as a target of antibody–drug conjugates for the treatment of multiple myeloma. Mol Cancer Ther. 2012;11:2222–32.CrossRefPubMed
38.
Ise T, Nagata S, Kreitman RJ, Wilson WH, Wayne AS, Stetler-Stevenson M, et al. Elevation of soluble CD307 (IRTA2/FcRH5) protein in the blood and expression on malignant cells of patients with multiple myeloma, chronic lymphocytic leukemia, and mantle cell lymphoma. Leukemia. 2007;21:169–74.CrossRefPubMed
39.
Tai Y-T, Mayes PA, Acharya C, et al. Novel afucosylated anti-B cell maturation antigen-monomethyl auristatin F antibody– drug conjugate (GSK2857916) induces potent and selective anti-multiple myeloma activity. Blood. 2014;123:3128–38.CrossRefPubMedPubMedCentral
Metadata
Title
Management of Multiple Myeloma with Second-Generation Antibody-Drug Conjugates
Authors
Pawel Robak
Tadeusz Robak
Publication date
01-04-2016
Publisher
Springer International Publishing
Published in
BioDrugs / Issue 2/2016
Print ISSN: 1173-8804
Electronic ISSN: 1179-190X
DOI
https://doi.org/10.1007/s40259-016-0165-6

Other articles of this Issue 2/2016

BioDrugs 2/2016 Go to the issue

Original Research Article

Combination Therapy with AKT3 and PI3KCA siRNA Enhances the Antitumor Effect of Temozolomide and Carmustine in T98G Glioblastoma Multiforme Cells

Leading Article

Targeting Nonsense Mutations in Diseases with Translational Read-Through-Inducing Drugs (TRIDs)

Original Research Article

Expression and Purification of Neurotrophin-Elastin-Like Peptide Fusion Proteins for Neural Regeneration

Systematic Review

The Challenge of Treating Early-Stage Rheumatoid Arthritis: The Contribution of Mixed Treatment Comparison to Choosing Appropriate Biologic Agents

Adis Drug Evaluation

Tbo-Filgrastim: A Review in Neutropenic Conditions

Review Article

Anti-EGFR Therapy for Metastatic Colorectal Cancer in the Era of Extended RAS Gene Mutational Analysis