| Eligibility |
Inclusion Criteria - Subjects must have undergone a prior ASCT for MM and have progressed
within 365 days of stem cell infusion. Patients who underwent syngeneic transplant (i.e.,
transplant from an identical twin donor) rather than autologous transplant are eligible and
syngeneic transplant will be considered equivalent to ASCT for the purposes of these
inclusion/exclusion criteria. Progression will be defined according to IMWG criteria for
progressive disease143 (Table 4).
Subjects who have undergone two prior ASCTs as part of a planned tandem ASCT consolidation
regimen are eligible.
Patients in whom first progression is identified between days 366 and 450 (inclusive) after
ASCT will be eligible if progression is identified on their first evaluation for
progression in this window and if they had not been evaluated between days 270 and 365 for
progression. This clause is to account for practice patterns in which patients otherwise
doing well are monitored infrequently (every 3-6 months) for relapse after they recover
from their first ASCT. This will allow infrequently monitored patients to be included if
progression is identified on their "12 month follow-up evaluation" if this appointment
happens to be scheduled just outside the 365-day post-ASCT window. N.B.: There is no
requirement that patients must enroll within 365 days of prior ASCT, and patients may be
treated with other agents, including experimental agents, following relapse/progression
after prior ASCT before enrollment on this study.
- Subjects must have received as part of their initial therapy for MM, prior to first
ASCT, a regimen containing either bortezomib or lenalidomide.
- Subjects must have a confirmed diagnosis of active MM prior to first ASCT as defined
by the IMWG criteria143, with the exception that patients treated for active MM on
account of recurrent, complicated infections as the only clinical manifestation or on
account of progressive smoldering MM with imminent clinical complications may be
included.
Subjects must have signed written, informed consent. Subjects must be = 18 and <70 years of
age. Subjects must have an anticipated survival of >100 days after high-dose melphalan.
-Subjects must have adequate vital organ function as defined by the following criteria:
Serum creatinine = 2.5 or estimated creatinine clearance =30 ml/min and not
dialysis-dependent.
Absolute neutrophil count =1000/µl and platelet count =50,000/µl. SGOT = 3x the upper limit
of normal and total bilirubin = 2.0 mg/dl (except for patients in whom hyperbilirubinemia
is attributed to Gilbert's syndrome).
Left ventricular ejection fraction (LVEF) = 45% Adequate pulmonary function with FEV1, FVC,
TLC, DLCO (after appropriate adjustment for lung volume and hemoglobin concentration) =40%
of predicted values.
Toxicities from prior therapies must have recovered to grade =2 according to the CTC 4.0
criteria or to the subject's prior baseline.
- Subjects must have an ECOG performance status of 0-2, unless a higher performance
status is due solely to bone pain.
- Subjects must be willing to comply with the requirements of the RevAssist program if
maintenance lenalidomide is planned.
- Subjects must have measurable disease on study entry. Measurable disease may include
quantifiable or detectable levels of serum or urine paraprotein. For patients with
minimally secretory disease or non-secretory myeloma on study entry, serum free lambda
or kappa light chain levels or the serum free light chain ratio may be measured and
used for disease monitoring if abnormal. Likewise, for patients with IgA MM in which
serum protein electrophoresis is deemed unreliable due to co-migration of normal serum
proteins with the paraprotein, elevated total serum IgA levels may be considered
measurable disease.
- Subjects must have stored in usable condition for second ASCT, as judged by the
principal investigator, =3x106 CD34+ cells per kg of body weight (either autologous or
syngeneic) stored in at least two bags such that after administration of the minimum
dose of 2 x 106 CD34+ cells/kg required on this protocol that a separate aliquot of at
least 1 x 106 CD34+ cells/kg remains for rescue infusion in the event of graft
failure. Patients with inadequate stem cells stored may still sign consent and undergo
a mobilization/collection procedure either before or after apheresis for T cell
harvest. If this is required and is undertaken prior to apheresis for T cell harvest,
two weeks must elapse between the last day of stem cell collection and apheresis for T
cell harvest.
Table 5 IMWG Criteria for Progression
One or more of the following criteria must be met:
Increase of =25% from baseline in Serum M-component (the absolute increase must be =0.5
g/dl) (if baseline M-component is =5 g/dl, increases of =1 g/dl are sufficient to define
progression) and/or Urine M-component (the absolute increase must be X200 mg/24 h ) and/or
The difference between involved and uninvolved FLC levels (only in patients without
measurable serum and urine M-protein levels) (the absolute increase must be >10 mg/dl).
Bone marrow plasma cell percentage (the absolute % must be =10%) For cases of IgA MM in
which SPEPs are unavailable or are deemed unreliable due to migration of the paraprotein in
the beta region, total IgA levels may be used to assess progression and response to
therapy.
Definite development of new bone lesions or soft tissue plasmacytomas or definite increase
in the size of existing bone lesions or soft tissue plasmacytomas.
Development of hypercalcemia (corrected serum calcium >11.5 mg/dl or 2.65 mmol/l) that can
be attributed solely to the plasma cell proliferative disorder IMWG Criteria for Diagnosis
of Multiple Myeloma Presence of an M-component in serum and/or urine plus clonal plasma
cells in the bone marrow and/or a documented clonal plasmacytoma. In patients with no
detectable M-component, an abnormal serum FLC ratio on the serum FLC assay can substitute
and satisfy this criterion. For patients, with no serum or urine M-component and normal
serum FLC ratio, the baseline bone marrow must have =10% clonal plasma cells; these
patients are referred to as having 'non-secretory myeloma'. Patients with biopsy-proven
amyloidosis and/or systemic light chain deposition disease (LCDD) should be classified as
'myeloma with documented amyloidosis' or 'myeloma with documented LCDD,' respectively if
they have =30% plasma cells and/or myeloma-related bone disease.
PLUS one or more of the following, which must be attributable to the underlying plasma cell
disorder:
Calcium elevation (>11.5 mg/dl) Renal insufficiency (creatinine >2 mg/dl) Anemia
(hemoglobin <10 g/dl or at 2 g/dl below normal) Bone disease (lytic lesions or osteopenia)
Exclusion Criteria
Subjects must not:
- Be pregnant or lactating.
- Have inadequate venous access for or contraindications to leukapheresis.
- Have any active and uncontrolled infection.
- Have active or chronic hepatitis B [detectable hepatitis B surface antigen (HBsAg)],
hepatitis C [positive serology (HCV Ab)], or HIV infection.
- Any uncontrolled medical disorder that would preclude participation as outlined.
- Have undergone allogeneic stem cell transplantation.
- Have received prior gene therapy or gene-modified cellular immunotherapy. Subject may
have received, however, non-gene-modified autologous T-cells with their first ASCT in
association with an anti-myeloma vaccine (e.g., hTERT or MAGEA3) or vaccination
against infectious agents (e.g., influenza or pneumococcus) as was performed on our
previous studies.
- Have undergone two prior ASCTs if the second ASCT was a salvage ASCT (defined as a
second ASCT performed upon progression following first ASCT) rather than a second ASCT
as part of a tandem ASCT consolidation regimen.
- Have auto-immune disease (including connective tissue disease, uveitis, sarcoidosis,
inflammatory bowel disease, or multiple sclerosis) that is active and severe in the
judgment of the principal investigator, or have a history of autoimmune disease that
has required prolonged immunosuppressive therapy in the judgment of the principal
investigator.
- Have active central nervous system disease, including CNS involvement by malignancy or
evidence of blood in the CNS such as subdural hematoma. If a subject has any
neurological abnormality on examination, a baseline brain MRI is required to exclude
structural disease and/or intracranial bleeding. Patients with clinically significant
intracranial lesions should be excluded. Patients with common age-related changes that
are not clinically significant (i.e. moderate small vessel ischemic changes) do not
need to be excluded.
- Have a Class III/IV cardiovascular disability according to the New York Heart
Association Classification
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