Haematologica 2003 - Supplements

esponse (50% or greater reduction in M protein) was seen in 32
patients yielding a response rate of 64% (95% CI 49-77%). If
minor responses are included (25-49% reduction in M protein),
the overall response rate increased to 92%. Similar results were
seen in an independent trial of thalidomide plus dexamethasone
in newly diagnosed patients conducted at M. D. Anderson Cancer
Center. Based on these results, a randomized controlled trial
comparing dexamethasone versus thalidomide plus
dexamethasone was initiated by the Eastern Cooperative
Oncology Group, the results of which will define the role of this
combination as upfront, pre-transplant induction therapy for
myeloma.
Given the incurability of myeloma and the leukemogenic
potential of alkylating agents, the current standard of care is to
delay therapy until symptomatic disease occurs. However,
patients with asymptomatic myeloma are at high risk of
progression to symptomatic disease, with a median time to
progression of approximately 1-2 years. With the advent of
effective non-cytotoxic biologic agents, the time is right to
challenge this paradigm of myeloma therapy with carefully
conducted clinical trials. We hypothesized that early therapy with
thalidomide may be effective in delaying progression from
asymptomatic to symptomatic multiple myeloma. Therefore, we
conducted a phase II trial at the Mayo Clinic to determine the
response rate and time to progression with thalidomide therapy in
patients with smoldering and indolent (asymptomatic; early
stage) multiple myeloma. Thirty-one patients with smoldering or
indolent multiple myeloma were studied at the Mayo Clinic. Two
patients were deemed ineligible because they were found to have
received prior therapy for myeloma and were excluded from
analyses except for toxicity. Thalidomide was initiated at a dose
of 200 mg/day, and escalated as tolerated to a maximum of 800
mg/day. However, the dose of thalidomide was adjusted to as low
as 50 mg per day, as needed, to minimize toxicity.
Of the twenty-nine eligible patients, ten (34%) had a partial
response to therapy with at least 50% or greater reduction in
serum and urine monoclonal (M) protein. When minor responses
(25-49% decrease in M protein) were included, the response rate
was 66%. Three patients had progressive disease while on
therapy. Kaplan-Meier estimates of progression free survival are
80% at 1 year and 63% at 2 years. Major grade 3-4 toxicities
included 2 patients with somnolence and 1 patient each with
neuropathy, deep vein thrombosis, hearing loss, weakness, sinus
bradycardia, and edema. Mild grade 1-2 neuropathy, sedation,
and constipation were seen in 87%, 87% and 74% of patients, but
these were generally amenable to appropriate dose reductions.
Because of the lack of a control arm and the toxicities of early
therapy, we presently do not recommend thalidomide for
asymptomatic myeloma outside the setting of an approved
clinical trial until randomized studies can be conducted. A phase
III trial comparing zoledronic acid versus thalidomide plus
zoledronic acid is due to open at the Mayo Clinic shortly, the
results of which will shed light on the role of thalidomide as
initial therapy for early stage myeloma.
DOXIL, VINCRISTINE, DECADRON AND THALIDOMIDE
(DVD-T) FOR NEWLY DIAGNOSED, AND
RELAPSED/REFRACTORY MULTIPLE MYELOMA;
RESPONSE TO THERAPY, AND SUPPORTIVE CARE
ISSUES
Mohamad A Hussein, MD
The Cleveland Clinic Myeloma Research Program. The Cleveland
Clinic Taussig Cancer Center, Cleveland, Ohio, USA
DVd is an effective and well tolerated regimen in newly
diagnosed MM patients resulting in an over all response rate of
90%, however only 10% of the patients achieve complete
remission. In relapsed/refractory group of myeloma patients, only
22% and 5% achieve 50% & 90% reduction in the M-Protein
respectively. Patients achieving >90% decrease in the M-Protein
on DVd had a durable response. Thal/Dex in a similar group of
patients results in 60% overall response with rare cases achieving
90% reduction in the M-protein. Thalidomide modulates integrins
thus interrupting the myeloma cell-stroma interaction results in
the malignant cell becoming sensitized to therapy as well as a
significant decrease in the supportive cytokine environment. We
evaluated the role of Thalidomide in combination with DVd with
the objectives is to enhance the quality of response in the newly
diagnosed patients, i.e., complete remission, and near complete
remission rate, and in the relapsed refractory group enhance the
response rate as well as the quality of response, in addition to
assessing the tolerability of the combination. In both groups the
regimen was administered as follows. On day 1 Doxil was given
at 40 mg/ m2 IVPB; Vincristine at 2 mg IVP & reduced dose
decadron at 40 mg PO daily X 4 days. Thalidomide was started at
50 mg a day, to be increased by 50 mg a day q week to maximum
tolerated dose and not to exceed 400 mg a day. DVd was
repeated q4 W, for a minimum of 6 cycles & 2 cycles after best
response. Patients achieving a plateau phase were maintained on
prednisone 50 mg qod & the maximal tolerated dose of
Thalidomide until disease progression. All patients were screened
for vitamin B12 and folate deficiency, and were allowed to use
erythropoietin and bisphosphonate therapy for anemia, and bony
disease respectively. Response was assessed according to SWOG
criteria. However, for (CR) we required in addition to the
standard SWOG criteria, the BM to show polyclonal PC’s by
immune staining. Following an increased incidence of
neutropenia, infections, oral herpes simplex, increased incidence
of neuropathy & Deep venous Thrombosis (DVT’s) in the first
group of patients; the protocol was amended to initiate all patients
on prophylactic amoxicillin 250mg BID, acyclovir 400 mg BID
until completion of chemotherapy, GM-CSF or G-CSF if the total
WBC was less than 5000/µL on day 1, & Aspirin 81mg daily.
The vincristine dose reduction algorhythm was further modified
to be more aggressive in response to grades 1 and 2 neuropathy.
35 newly diagnosed, and 50 relapsed/refractory myeloma patients
are currently enrolled. 70 patients (25 newly and 45
relapsed/refractory) will be reported for response, and 71 for
toxicity. All patients enrolled had progressive disease, and none
of the relapsed/refractory group was non-responder/nonprogressor.
Patients’ demographics and prognosticators are
outlined in table 1.
Table 1
Newly diagnosed Relapsed/refractory
Age 60 63
PS < 3 < 3
β2 2.9 6.6
Albumin 3.8 3.2
S4