To determine the maximum tolerated dose and dose limiting toxicity of thymoglobulin in
multiple myeloma patients.
To determine the overall response rate (CR+PR) of patients with relapsed or refractory
multiple myeloma treated with Thymoglobulin.
To determine the time to response, duration of response, and time to progression and overall
survival of patients treated with Thymoglobulin.
To determine the safety and tolerability of Thymoglobulin in these patients.
To assess the changes in lymphocyte apoptosis and apoptotic signaling in treated patients.
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.
1. Multiple myeloma diagnosed by standard criteria.
2. Measurable levels of monoclonal protein in serum (> 0.5 g/dL) or urine (> 0.2 g/24
3. At least 2 prior therapies for multiple myeloma with documented evidence of
progression on the most recent treatment.
4. Age 18 years or older.
5. ECOG performance status <= 2.
6. Acceptable organ and marrow function as defined below:
- Hemoglobin > 8 gm/dL
- Absolute neutrophil count > 1,000/mm3
- Platelets > 50,000/mm3
- Total bilirubin < 2.5 X institutional upper limit of normal
- AST, ALT < 2.5 X institutional upper limit of normal
- Creatinine < 1.5 X institutional upper limit of normal
- Normal cardiac function as determined by standard institutional methods
7. Women of child bearing potential must agree to use adequate contraception prior to
study entry and for the duration of study.
8. Ability to understand and the willingness to sign a written informed consent
9. Must have demonstrated resistance to steroids equivalent to >160mg/month of
dexamethasone, 1g/month of prednisone, or 800mg/month of solumedrol, to insure the
effects seen are from thymoglobulin and not the concomitant steroids.
1. Receiving any other investigational agents.
2. Receiving concurrent steroids with a dose equivalent of dexamethasone of > 200
mg/month, 1.25g/month of prednisone, or 1g/month of solumedrol.
3. Pregnant or nursing.
4. Active systemic infection considered opportunistic, life threatening or clinically
significant at the time of treatment.
5. Severe concurrent disease, including severe insulin-dependent diabetes, uncontrolled
hypertension, transient ischemic attacks, uncontrolled symptomatic coronary artery
disease, or symptomatic CNS involvement or psychiatric illness/social situations that
would limit compliance with study requirements.
6. History of other malignancy except for basal cell or squamous cell carcinoma of the
skin or carcinoma in situ of the cervix or breast unless the subject has been off
treatment and free from disease for > 3 years.
7. Weight of <100 kg to avoid exceeding maximum allowed steroid dose.