A Phase I Study Of Thymoglobulin In Patients With Relapsed Or Refractory Multiple Myeloma
Increasingly, upregulation of antiapoptotic proteins have been implicated in the
pathogenesis and in the development of chemotherapy resistance in multiple myeloma.
Therapeutic interventions that target the apoptotic pathway in myeloma are attractive
targets to treat resistant disease. Dexamethasone triggers apoptosis via the release of
Smac (second mitochondria-derived activator of caspase) leading to the activation of
caspase-9 and caspase-3.37 The proteasome inhibitor bortezomib blocks signal transduction
pathways mediated by NF-κB including the regulation of antiapoptotic genes such as TRAF1 and
2 (TNF receptor-associated factors) and cIAP (cellular inhibitor of apoptosis) and BCLXL.
Two independent investigators have established the activity of thymoglobulin in multiple
myeloma cells from cell lines and patients.38,39 Thymoglobulin has been shown to induce
apoptosis via distinct mechanisms in multiple myeloma cells.40 This action appears to be
mediated by interactions with surface markers including CD80, CD38, CD40 and CD45. This
appears to stimulate apoptosis via cathepsin and caspase pathways.39 By targeting
different aspects of the apoptotic process, Thymoglobulin may provide a mechanism to
overcome drug resistance in multiple myeloma.
Normal bone marrow B-cells, activated B cells and plasma cells have been shown to undergo
apoptosis in a concentration dependent manner with rATG. The rATG has been shown to bind to
B cells and this binding competitively inhibits several B cell specific monoclonal
antibodies. The apoptosis can be inhibited by specific pathway inhibitors to caspases,
cathepsin B and lysosomal cysteine proteases, indicating that each of these pathways is
stimulated by thymoglobulin exposure. 18
Thymoglobulin at high concentrations binds complement resulting in direct cell lysis of
lymphocytes.22 Anti-thymocyte globulins induce B cell apoptosis and do so preferentially to
myelomonocytic and T-cell lines.41,42 Both myeloma cell lines and primary myeloma cells
from patient bone marrow aspirates undergo apoptosis after exposure to thymoglobulin, as
might be expected based on the apoptotic affect on B-cell lineages.38 Additionally both
sets of cells undergo opsonization when complement is added in vitro. This demonstrates
that thymoglobulin can induce myeloma cell kill by a number of methods and thus would be
less susceptible to tumor resistance. The thymoglobulin binding sites have been assessed by
competitive binding with monoclonal antibodies. Thymoglobulin binds competitively and
specifically to IgG, HLA-ABC, HLA-DR, CD16, CD32, CD64, CD19, CD20, CD27, CD30, CD38, CD40,
CD52, CD80, CD95, CD126, and CD138. Only IgG, CD16, CD64, and CD80 are not competitively
bound. The apoptosis in primary cells can be inhibited by blocking the caspase, cathepsin
D, or cathepsin B & D pathways. Zand et al also compared apoptotic response for five
different lots of thymoglobulin. All lots apoptotic curves were overlapping over the range
of 1-120 mcg/ml, demonstrating that very little lot to lot variation exists.43 This would
be expected since each lot is derived from the combined sera of multiple immunized rabbits
and thus individual differences in response for each rabbit would be mitigated. This may
not be the case with lots of ATGAM each derived from a single horse. Each lot of
thymoglobulin is already depleted of antibodies to red blood cells, has viruses inactivated
and is tested for lymphocytotoxicity prior to release. The consistency demonstrated by Zand
et al is consistent with the lack of observed variation in potency noticed in the greater
than 20 years of clinical experience with this medication.
Together, these data provide a rational for the clinical use of Thymoglobulin in multiple
myeloma. As a result, we propose a dose escalation, phase I, open-label study of
Thymoglobulin in patients with relapsed or refractory multiple myeloma.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine the maximum tolerated dose and dose limiting toxicity of thymoglobulin in multiple myeloma patients.
End of cycle 1 (DLT) and approximately 16 months after start of treatment (MTD)
Ravi Vij, M.D.
Washington Universtiy in St. Louis
United States: Food and Drug Administration
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