Topics:

Myeloma

Myeloma

Abstract #664
A New International Staging System
for Multiple Myeloma From the
International Myeloma Working
Group

From: Greipp PR, San Miguel JF, Durie BG, Loiseau HA,
Fonseca R, Jacobson JL, Rasmussen E, Crowley JJ. A New
International Staging System for Multiple Myeloma From the
International Myeloma Working Group. Blood 2003;102:190a,
abstract 664. Copyright American Society of Hematology, used
with permission.

P. R. Greipp, J. F. San Miguel, B. G. Durie, H. A. Loiseau,
R. Fonseca, J. L. Jacobson, E. Rasmussen, J. J. Crowley
Hematology, Mayo Clinic, Rochester, Minnesota; Hematology,
University of Salamanca, Salamanca, San Vicente, Spain;
Cedars Sinai Comprehensive Cancer Center, Los Angeles,
California; University of Nantes, Nantes, France; Cancer
Research and Biostatistics, Seattle, Washington

Introduction: In 1975, Durie and Salmon (DS)
developed a staging system that has remained, for
over 25 years, the gold standard for stratification
of MM patients. However the system does not
contain B2M, widely recognized as the most useful
prognostic factor. Acceptance of staging systems
utilizing B2M has been impeded by lack of
agreement on the merits of other components.
Similar to what has been done in other malignancies,
an international cooperative effort gathered
data on 11,171 cases from 17 institutions in Asia,
Africa, Europe, and North America; 8,270 received
standard treatment, and 2,901 received
high dose therapy as initial planned treatment.

Results: Median age was 60 years; 61% were
IgG, 24% IgA, 10% light chain only, 3% IgD, and
2% biclonal or other. Median serum M-protein
level was 3.9 g/dL, hemoglobin 10.5 g/dL, platelets
221 x 103/mcL, creatinine 1.1 mg/dL, B2M
3.8 mcg/mL, albumin 3.6 g/dL, and bone marrow
plasma cell percent (PC) 40.0%. 42% had 3 or
more bone lesions, 24.4% had pathologic fractures,
and 33.2% had compression fractures.
Univariate survival analysis. Cutoffs were chosen
by CART analysis. Overall survival of the entire
group was 44 months.

Significant variables predicting survival in order
of hazard ratio (HR) were: B2M ≥3.5 (1.78),
creatinine≥2 (1.76), platelets

Of 3278 Stage II patients, 1057 (32%) were
classified Stage II because of an albumin Abstract #662
Gene Expression Profiling Can
Be Used To Predict EFS in Myeloma
Patients Treated with High Dose
Therapy and Tandem Stem Cell
Transplant

From: Shaughnessy J, Rasmussen E, Zhan F, Barlow W,
Jacobson J, Crowley J, Barlogie B. Gene Expression Profiling
Can Be Used To Predict EFS in Myeloma Patients Treated
With High Dose Therapy and Tandem Stem Cell Transplant.
Blood 2003;102:190a, abstract 662. Copyright American
Society of Hematology, used with permission.

J. Shaughnessy, E. Rasmussen, F. Zhan, W. Barlow,
J. Jacobson, J. Crowley, B. Barlogie
Myeloma Institute for Research and Therapy, University of
Arkansas for Medical Sciences, Little Rock, Arkansas; Cancer
Research and Biostatistics, Seattle, Washington

One of the hopes for global gene expression
profiling is that it will account for the tremendous
variability in survival of multiple myeloma, which
can range from several months to > 10 years after
diagnosis. The presence of cytogenetic abnormalities
(CA) and/or interphase FISH chromosome 13
deletion (FISH13) has emerged as the most powerful
variables predicting for early failure of tandem
auto-transplants in MM, but even these
variables only account for ~15% of this outcome
variability.

Gene expression profiling using Affymetrix
U95Av2 microarrays was performed on cRNA
from CD138-enriched plasma cells from 212 newly
diagnosed multiple myeloma patients registered
to the Total Therapy II protocol. The median
follow-up time was 20 months. There were 34
events representing either disease specific death or
progression/relapse. Cox regression was used to
model disease specific event-free survival (EFS)
using both standard prognostic values and Affymetrix
signal. Gene expression values considered
were based on significance of univariate
association with EFS based on Cox regression
models. The median Signal call was used as a cut
point prior to modeling inclusion. The 100 genes
most significantly associated with EFS based on
the score test were potential variables in multivariate
modeling. Cox regression and stepwise selection
with a 0.05 entry criteria and 0.005 significance
criteria was used to model EFS using gene expression
variables after adjusting for the standard
prognostic variables model. A generalized estimate
of R2 was obtained using the approach
suggested by Cox and Snell (1989).

Using standard prognostic variables only, the
model which best fit disease specific event-free
survival was FISH13 and CA. Adjusting for CA,
patients with FISH13 had an increased risk of
event (HR=2.4, 95% CI=1.1-5.4, p=0.0329). Adjusting
for FISH13, patients with CA had an increased
risk of event (HR=3.9, 95% CI=1.8-8.5,
p=0.0007). Adjusting for CA, FISH13 and other
genes in the model, three genes were significant at
the 0.005 level: 98-026.1, 98-026.2, and 98-026.3.
After adjustment for other model variables, patients
with high 98-026.1 expression had increased
risk of event (HR=25, 95% CI=3.3-195.9,
p=0.0019), patients with high 98-026.2 had decreased
risk of event (HR=0.06, 95% CI=0.008-
0.42,p=0.005), and patients with high 98-026.3
had decreased risk of event (HR=0.15, 95%
CI=0.04-0.54, p=0.0036). After adjusting for these
3 genes and each other, FISH13 patients had an
increased risk of event (HR=2.8, 95% CI=1.2-6.5,
p=0.0157) but CA did not have a significant
increase in risk (HR=1.09, 95% CI=0.47-2.5,
p=0.8442). R2 for the FISH13 and CA model was
9.7%. With the addition of 98-026.1, 98-026.2,
and 98-026.3 the estimate for R2 was 38.5%, an
increase of 28.8%. This is an example of improved
modeling of disease specific event-free survival in
myeloma using microarray technology.

Importantly, the genes identified may not only
represent useful biomarkers, but may have a pathogenetic
role in disease initiation or progression and
therefore may be targeted with novel therapeutics.
A discussion of the biological relevance of these
genes will be presented.

Abstract #509

Oral Melphalan, Prednisone and
Thalidomide for Newly Diagnosed
Myeloma

From: Palumbo A, Bertola A, Musto P, Nunzi M, De Stefano
V, Callea V, Rotoli B, Petti MC, Caravita T, Lauta VM, Patti C,
Bringhen S, Cavallo F, Falco P, Carella AM, Liberati AM,
Boccadoro M. Oral Melphalan, Prednisone and Thalidomide for
Newly Diagnosed Myeloma. Blood 2003;102:148a, abstract
509. Copyright American Society of Hematology, used with
permission.

A. Palumbo, A. Bertola, P. Musto, M. Nunzi, V. De Stefano,
V. Callea, B. Rotoli, M. C. Petti, T. Caravita, V. M. Lauta,
C. Patti, S. Bringhen, F. Cavallo, P. Falco, A. M. Carella,
A. M. Liberati, M. Boccadoro

Divisione Universitaria di Ematologia, Azienda Ospedaliera
San Giovanni Battista, Torino, Italy; Italian Multiple Myeloma
Study Group

This work was supported by AIRC, AIL and MIUR

Purpose: Thalidomide (THAL) is an useful drug
for the treatment of refractory myeloma. Few data
are available on the activity of THAL for newly
diagnosed patients. No data are available on the
association of THAL with the standard oral Melphalan
and Prednisone (MP).To address this issue,
we evaluated the potential additive and synergistic
effect of the combination Melphalan, Prednisone
and Thalidomide (MP-THAL).

Materials and methods: Between June 2002 and
June 2003, 56 patients with newly diagnosed
symptomatic multiple myeloma were assigned to
a treatment with 6 monthly courses of MP (melphalan
4 mg/sqm and prednisone 40 mg/sqm for 7
days every month) plus Thalidomide that was
administered at 100 mg/day continuously until
any sign of disease progression or relapse. The
dose of THAL was reduced to 50% when grade II
WHO toxicity occurred, and suspended for any
grade III. At present, 31 patients (median age 72,
range 61-82) have completed the 6 assigned MP
courses and were evaluated.

Results: After a minimum of 3 months of treatment,
no one was in complete remission (according
to the EBMT/IBMTR criteria), 11 patients
(36%) showed a myeloma protein reduction of 75-
99%, 14 patients (45%) a response of 50-74%, and
6 (19%) a response of Abstract #135
Comparable Survival in Multiple
Myeloma With High Dose Therapy
Employing MEL 140 mg/m2 + TBI
12 Gy Autotransplants vs Standard
Dose Therapy with VBMCP and No
Benefit From Interferon Maintenance:
Results of Intergroup Trial S9321

From: Barlogie B, Kyle R, Anderson K, Greipp P, Lazarus H,
Jacobson J, Rasmussen E, Cromer J, Crowley J. Comparable
Survival in Multiple Myeloma With High Dose Therapy
Employing MEL 140 mg/m2 + TBI 12 Gy Autotransplants vs
Standard Dose Therapy with VBMCP and No Benefit From
Interferon Maintenance: Results of Intergroup Trial S9321.
Blood 2003;102:42a, abstract 135. Copyright American
Society of Hematology, used with permission.

B. Barlogie, R. Kyle, K. Anderson, P. Greipp, H. Lazarus,
J. Jacobson, E. Rasmussen, J. Cromer, J. Crowley
Myeloma Institute for Research and Therapy, University of
Arkansas for Medical Sciences, Little Rock, Arkansas; Mayo
Clinic, Rochester, Minnesota; Dana-Farber Cancer Institute,
Boston, Massachusetts; Ireland Cancer Center, University Hospital
of Cleveland, Cleveland, Ohio; Cancer Research and Biostatistics,
Seattle, Washington; on behalf of SWOG, CALGB, ECOG

ECOG, CALGB and SWOG enrolled 899 patients
with newly diagnosed MM to receive VAD
induction x 4 cycles (n=805), followed by randomization
to a single PBSC-supported HDT
(n=258) vs VBMCP (n=252) using CTX 4.5 g/m2
+ G-CSF for PBSC mobilization in all patients; 39
patients with HLA compatible sibling donors received
allo-Tx with MEL 140 + TBI 12 Gy. Responders
to VBMCP or HDT were randomized to
±IFN (n=120/119). Response rates were similar
with HDT/VBMCP: CR 17% /15%, PR 93%/91%.
Median PFS and OS from VAD were 22 and 46
mos. PFS was superior after HDT (25 vs 21 mos,
p=.05); OS was not (58 vs 53 mos, p=.8) (Fig 1).
PFS/OS from ±IFN were similar at 21/58 mos vs
19/79 mos. 52% of 161 VBMCP failures received
salvage transplants (STx), effecting PR in 59%
with a post-relapse survival of 30 mos vs 23 mos
without STx (p=.05). PFS and OS were adversely
affected by B2M > 4 mg/L and PCLI > 0.4%,
regardless of treatment arm. Excessive TRM of
39% called for early closure of alloTx arm after 39
pts, however with similar 6 yr PFS/OS rates.

The equivalent outcome after VBMCP vs HDT on
S9321, interpreted in the context of other randomized
clinical trials, may relate to (1) frequent STx in
VBMCP failures resulting in significant survival
extension in comparison to no STx; (2) superior
performance of VBMCP + CTX 4.5 g/m2 in comparison
with prior SWOG standard regimens (52 mos vs
37 mos; p=.005) in comparison to matched historical
controls (Fig 2); and (3) failure to achieve a substantial
increase in CR with HDT vs VBMCP (MEL 200
superior to MEL 140 + TBI, reported in IFM 95).

We conclude that, while S9321 results overall
are significantly improved over prior standard
SWOG regimens, the strategic purpose of HDT,
effecting sufficiently steep tumor cytoreduction
resulting in CR rates in excess of 40%, was not
achieved. SWOG 0204 evaluates, in a phase II
design, feasibility and efficacy of MEL 200-based
tandem autotransplant in the context of THAL +
DEX for induction and maintenance.

Abstract #137
High-Dose Therapy Autotransplantation/
Intensification vs
Continued Conventional Chemotherapy
in Multiple Myeloma Patients
Responding to Initial Chemotherapy.
Definitive Results from PETHEMA after
a Median Follow-Up of 66 Months

From: Blad J, Sureda A, Ribera JM, Diaz-Mediavilla J,
Garcia-Larana J, Palomera L, Fernndez-Calvo J,
Marti JM, Giraldo P, Carbonell F, Callis M, Trujillo J,
Gardella S, Moro MJ, Barez A, Soler JA, Font LI,
Fontanillas M, San Miguel JF. High-Dose Therapy
Autotransplantation/Intensification vs Continued
Conventional Chemotherapy in Multiple Myeloma
Patients Responding to Initial Chemotherapy. Definitive
Results from PETHEMA after a Median Follow-Up of
66 Months. Blood 2003;102:42a, abstract 137.
Copyright American Society of Hematology, used with
permission.

J. Blad, A. Sureda, J. M. Ribera, J. Diaz-Mediavilla,
J. Garcia-Larana, L. Palomera, J. Fernndez-Calvo, J. M. Marti,
P. Giraldo, F. Carbonell, M. Callis, J. Trujillo, S. Gardella,
M. J. Moro, A. Barez, J. A. Soler, L. I. Font, M. Fontanillas,
J. F. San Miguel, on behalf of Pethema Hospital Clinic,
Barcelona, Spain

High-dose therapy/stem cell rescue (HDT/SCT)
is offered to most younger patients with multiple
myeloma (MM) as part of the initial therapy. However,
the role of HDT/SCT in the management of
patients with MM who have responded to the initial
chemotherapy still remains controversial. The aim of
this randomized trial was to compare HDT/SCT
versus continued conventional chemotherapy in
MM patients responding to the initial treatment.

From May 1994 to October 1999, 216 patients
(122M/94F, median age 56 yrs, stage II or III,
ECOG 2/TBI 12 Gys or melphalan 200 mg/m2 (arm
B). Maintenance treatment consisted of alphainterferon
and dexamethasone in both arms. Onehundred
and eighty five patients responded to
initial chemotherapy (CR: 15%, PR: 68%, and MR:
17%). Twenty-one of these responding patients
were not randomized due to different reasons.
Among the 164 randomized patients 83 were
allocated to continued chemotherapy and 81 to
HDT/SCT. The degree of initial response as well as
prognostic features did not differ in both groups.

The results were updated as of April 30, 2003
after a median follow-up of 66 months from the
initiation of treatment and analyzed on an intention-
to-treat basis. CR (negative electrophoresis)
was significantly higher in the HDT/SCT arm (30 vs.
11%, p=0.002). However, PFS was not significantly
different between HDT/SCT and conventional chemotherapy
(median, 42 vs. 33 mos; p=NS) and the
OS was similar in both groups (median, 65 vs. 67
mos.; p=NS). The median survival after relapse was
identical (16 mos.) in both arms.

These results show that HDT/SCT intensification
when given to myeloma patients who have
responded to the initial chemotherapy, significantly
increases complete remission rate but has no
significant impact on PFS and OS.

Pages

 
Loading comments...
Please Wait 20 seconds or click here to close