InternatIonal MyeloMa FoundatIon
ASCO 2007
Highlights
for Patients
by Lynne Lederman, PhD
This publication is funded by an unrestricted educational grant from Millennium Pharmaceuticals, Inc.
ASCO 2007 Highlights for Patients
by Lynne Lederman, PhD
New Standards are Emerging: News
disease progression that would be missed by fluorescent in
from the 2007 ASCO Meeting
situ hybridization (FISH) or gene sequencing.
New and updated data on the use of novel therapeutics in
Dr. Bergsagel noted that although GEP can be used to define
combination therapy in patients with newly diagnosed or
high-risk myeloma, it is not yet being used in the clinic. In
relapsed/refractory multiple myeloma were presented at the
addition, some therapies agents may be able to overcome
2007 meeting of the American Society of Clinical Oncology
high-risk disease. For example, changes in pathways that
(ASCO), June 1 through 5, in Chicago, Illinois. Results from
myeloma cells use to grow and multiply (e.g., the NF kappa
the E4A03 ECOG trial of lenalidomide plus either high- or
B pathways) may allow them to become independent of the
low-dose dexamethasone in newly diagnosed patients dem-
bone marrow microenvironment. Therapeutic drugs may
onstrated the advantages of low-dose dexamethasone. Addi-
interfere with the activity of these changes in one or more
tional data were presented from the DOXIL-MMY-3002 trial
of these pathways. A single drug active in more than one
of pegylated liposomal doxorubicin (Doxil®) plus bortezo-
pathway may help overcome disease risk, as will combina-
mib in patients with relapsed/refractory myeloma who had
tions of drugs active in different pathways.
received at least one prior therapy. In addition, there was an
Prediction of Response and Progression in
educational session on optimizing the therapy for multiple
Multiple Myeloma with Serum Free Light
myeloma; discussions on risk-based approaches to therapy;
Chains (sFLC)
insights into the natural history of myeloma; updates of
other clinical trials; and reports on agents in development.
Rami N. Khoriaty (Cleveland Clinic, Cleveland, Ohio) pre-
sented data showing corroboration of the International
Risk-Based Approaches to Therapy
Myeloma Working Group (IMWG) response criteria [abstract
8047]. Abnormal serum free light chains (sFLC greater
Leif Bergsagel (Mayo Clinic, Scottsdale, Arizona) was the
than 10 mg/dL) can be used to predict response or disease
session chair for a discussion of molecular classification of
progression. Dr. Orlowski commented that more studies
myeloma and the implications for a risk-based approach
comparing outcomes using the different response criteria
to therapy. Dr. Bergsagel said that there have been really
in a uniformly treated group of patients are needed to fur-
exciting advances in understanding the disease process of
ther validate the new criteria. IMWG criteria for complete
myeloma and in treatment. Patients treated today may not
response (CR) requires sFLC to be normal. One important
be cured, but their survival can be extended so that they will
outcome is that all of the studies that have used European
live longer and eventually die of other causes than myeloma.
Group for Bone Marrow Transplantation (EBMT) criteria
Genetic differences may explain why some patients respond
previously may have different overall and complete response
to treatment better and survive longer than other patients.
rates when the new IMWG criteria are applied instead.
These differences are being investigated using a variety
of techniques. These techniques include gene expression
Factors Predictive of Outcome in Relapsed,
profiling (GEP) and array comparative genomic hybridiza-
Refractory Myeloma Treated with Bortezomib,
tion (aCGH) to identify genes that are over-expressed (at
Melphalan, Prednisone, and Thalidomide
higher than normal levels) and under-expressed (at lower
(VMPT)
than normal levels). Then the association of these genes is
Antonio Palumbo (University of Turin, Turin, Italy) pre-
related to disease progression, drug resistance, and prog-
sented results of a phase I/II study of relapsed/refractory
nosis (outcome). aCGH identifies differences in genes that
myeloma in patients who had received at least one prior line
may increase over the course of treatment and helps identify
of therapy and received VMPT as salvage therapy [abstract
3
8048]. As second line, 57% of patients had at least a very
low-risk patients but the best agents are unknown. It is also
good partial response (VGPR), while all patients had had
not known if allogeneic transplant can overcome high-risk
at least a minor response. No response differences were
cytogenetics. Dr. Bergsagel suggested enrolling patients in a
seen based on age, beta-2-microglobulin, C-reactive protein
trial to determine this.
(CRP), chromosome 13 deletion, line of treatment, or bort-
ezomib dosage, but it is hard to draw conclusions because
PETHEMA HDT tandem transplant with stem
this was a phase I/II study. Low response rate was associated
cell support in primary refractory myeloma
with decreased serum albumin. Lower progression-free sur-
Results of the Spanish PETHEMA/GEM-2000 trial were pre-
vival (PFS) was associated with elevated CRP, third line of
sented by Joan Blade (Hospital Clinic, Barcelona, Spain)
treatment, elevated beta-2-microglobulin, and elevated cre-
[abstract 8021]. Two populations with different outcomes
atinine, but not with chromosome 13 deletion. Thalidomide
were identified. Patients with primary refractory myeloma
does not overcome the poor risk factor of chromosome 13
were most likely to benefit from early high-dose therapy
deletion, but bortezomib does. In this trial, combining these
(HDT) and SCT. Patients with stable disease (SD) had lon-
two agents may preserve this benefit of bortezomib and
ger overall survival (OS) and progression-free survival (PFS)
enhance overall activity.
than patients with progressive disease (PD). Patients with
disease that was sensitive to chemotherapy also had longer
Dr. Orlowski commented that this study validates that the
OS and PFS than patients with primary refractory disease.
ISS stage remains an important prognostic system even in
If there is PD after initial chemotherapy, OS is short even
the era of novel agents.
with HDT/SCT. Patients with disease that did not respond
Current Status of Stem Cell
to chemotherapy but also was non-progressive had similar
Transplantation
survival to that of patients with disease that did respond to
chemotherapy. It must be determined if this is due to HDT,
William Bensinger (Fred Hutchinson Cancer Center, Seattle,
to the natural disease history, or to less aggressive disease.
Washington) discussed the current status of stem cell trans-
plantation (SCT), including the issues of when, how many,
Outcome after early relapse post-ASCT
and whether they should be allogeneic, autologous, or both.
for myeloma
Autologous SCT (ASCT) results in a high response rate and
Risk factors for early relapse, defined as less than 12 months
low mortality and demonstrates the impact of CR or near
after autologous stem cell transplant (ASCT), were stud-
(n) CR on survival, but it is still not curative. Double trans-
ied by Syed T. Mahmood (Mayo Clinic, Rochester, Minne-
plant may be beneficial for selected patients, i.e., those who
sota) [abstract 8022] in a population of 432 patients with
are not in CR or nCR after the first ASCT. It is not clear if SCT
newly diagnosed myeloma treated between 1994 and 2005.
is of benefit to patients with CR following chemotherapy.
Patients were divided into two groups based on time of
Although there are enough data to show increased survival
relapse. Patients had received various initial therapies and
with ASCT compared with conventional chemotherapy, it
most had received high-dose therapy consisting of 200mg
is not known if this will hold when ASCT is compared with
of melphalan per square meter of body mass. Early disease
novel therapies. It is also not known if all CRs are equal and
relapse was associated with a plasma cell labeling index
are independent of the treatment leading to the response.
(PCLI) of at least 1%, refractory disease at transplant, having
received more than one induction regimen, abnormal karyo-
Although conventional allogeneic SCT can result in pro-
type (pattern of chromosomes), and circulating plasma cells
longed survival, the high mortality is unacceptable. Non-abla-
at stem cell collection.
tive allografting may be an alternative, although response
rates are low in patients unless there is only minimal dis-
The group of patients with late relapse had a higher CR rate,
ease. Therefore, the best regimen is unknown. Reduced
longer OS from diagnosis, longer median OS after ASCT,
intensity conditioning (RIC) allogeneic SCT is in clinical
and longer median OS from relapse, although the overall
trial, but results will not be available for several years. In the
response (OR) rate was the same for groups with either late
meantime, ASCT remains the standard of care for transplant-
and early relapse. The three factors significantly associated
eligible patients. Maintenance therapy may be beneficial for
with early relapse were more than one induction regimen,
4
a PCLI greater than 1%, and no CR. Prognostic factors for
collected prior to the era of MP-T, MP-R, and MP-V for older
shorter OS after ASCT included PCLI greater than 1%, beta-
patients. Bortezomib and/or lenalidomide may help those
2-microglobulin greater than 5.5 mg/dL, and relapse less
with chromosome 13 deletion.
than 12 months from ASCT. Median OS for patients with
relapse before 2002 was 12.5 months, and after 2002, 20.5
Bortezomib Prior To and as Maintenance
months, suggesting the contribution of newer therapies to
Therapy After ASCT
longer survival.
Sagun D. Goyal (Washington University School of Medicine,
St. Louis, Missouri) and Robert Z. Orlowski (University of
Dr. Mahmood concluded that early relapse after ASCT is a
North Carolina) presented long-term follow-up of a phase II
novel predictor for poor outcome; patients who have high-
study [abstract 8044] in 40 patients who received bortezo-
risk disease may not be obvious from conventional risk fac-
mib at a standard dose and schedule for 2 cycles after induc-
tors; and these patients should be enrolled in clinical trials.
tion and before stem cell mobilization, and for 6 cycles after
He suggested the data he presented can provide a reference
ASCT for 4 out of every 5 weeks. Results were encouraging,
baseline for these trials.
and Dr. Orlowski suggested that randomized studies are
High-Dose Melphalan-Based Autotransplant
needed to support the efficacy of maintenance therapy. Of
note, 42% of the patients developed shingles (herpes zos-
Mauricio Pineda-Roman (University of Arkansas Medical Sci-
ter) after ASCT, indicating a need for preventive therapy.
ences, Little Rock, Arkansas) presented the Arkansas experi-
ence since 1989 in 3,077 successive patients treated with at
Benefit of Reduced Intensity Conditioning
least one MEL auto-SCT of which 1078 received Total Ther-
(RIC) Allogeneic SCT as Salvage Treatment
apy (TT)-1, 2, or 3; 1,104 were on studies for previously
for Relapsing Myeloma
treated patients, and 895 were off-study [abstract 8043].
Mohamad Mohty (Institute Paoli-Calmettes, Marseille,
Patients in studies were younger and had disease charac-
France) presented results suggesting that for the minor-
teristics associated with better outcomes. The types of chro-
ity of patients with a matched sibling stem cell donor, RIC
mosome (cytogenetic) abnormalities were similar in the
allo-SCT is a treatment option [abstract 8045]. In this study
three groups, although in the TT groups there were fewer
of 32 patients with relapsed/refractory myeloma, 11 of the
chromosome 13 deletions and hypodiploidy (chromosomes
13 patients who did not have allogeneic-matched donors
present as one copy rather than in the usual pairs).
had PD after salvage therapy, additional chemotherapy, and
another auto-SCT. The OS, response rates, and PFS were
Patients receiving TT had better OS and event-free survival
higher for the 18 patients with compatible donors, but the
(EFS). TT3 was better than TT2, which was better than TT1.
transplant-related mortality was too high at 33%.
Good outcome was predicted, in decreasing order, by favor-
able cytogenetics (no chromosome 13 deletion or hypodip-
Treatment Options for Patients with
loidy); platelets at least 100,000; beta-2-microglobulin less
Newly Diagnosed Myeloma
than 3; CRP less than 6; CR; and ability to do a second SCT.
There was a suggestion that OS, EFS, and CR duration is
Late-Breaking Abstract on the E4A03
increasing from 2004 to 2006 for patients on non-TT studies
ECOG Trial
compared with the past. However, OS, EFS, and CR dura-
S. Vincent Rajkumar (Mayo Clinic, Rochester, Minnesota)
tion for patients off-study do not seem to have improved
presented the late-breaking abstract [8025] on the phase
over this period of time. Dr. Robert Z. Orlowski, University
III E4A03 ECOG trial of lenalidomide plus high-dose dexa-
of North Carolina, Chapel Hill, North Carolina, who dis-
methasone vs. lenalidomide plus low-dose dexamethasone
cussed this poster, noted that the results suggest incorpo-
in 445 patients with newly diagnosed myeloma. One goal
rating novel agents and applying best therapy is improving
of this trial was to compare lenalidomide plus high- or low-
outcomes. He was concerned that outcomes for patients
dose dexamethasone in an effort to reduce adverse events
not on studies have not improved, possibly because they
associated with high-dose dexamethasone. Patients in the
were older, had kidney failure, or other poor risk factors,
high-dose dexamethasone group (n=223) received the drug
and that help is needed for these patients. These data were
according to the usual schedule, with a total dose of 480 mg
5
per cycle; patients in the low-dose group (n=222) received
MP-T vs. MP in patients at least 75 years of
160 mg of dexamethasone per cycle. Before September 15,
age with untreated MM preliminary results of
2005, the use of aspirin to prevent clotting or thromboem-
IFM 01-01
bolic events including deep vein thrombosis (DVT) and pul-
Preliminary results of the IFM 01/01 trial, a randomized,
monary embolism (PE) was recommended but not required.
double-blind, placebo-controlled trial of melphalan-pred-
After that date patients were required to receive at least aspi-
nisone-thalidomide (MP-T) vs. MP in patients at least 75
rin (mandatory prophylaxis), but warfarin or low-molecular
years of age were presented by Cyrille Hulin, on behalf of
weight heparin (LMWH) were strongly recommended for
the Intergroupe Francophone du Myelome (IFM) [abstract
patients receiving high-dose dexamethasone.
8001]. MP-T is considered standard treatment for patients
Serious adverse events (SAE) in the two groups were similar,
age 65 and over. Although trials in patients over age 75 are
with the following exceptions: neutropenia was higher in
rare, at least 20% of myeloma patients are in this age group.
patients receiving low-dose dexamethasone; non-hemato-
At interim analysis in April 2007, 200 patients (100 patients
logic toxicity was significantly higher with high-dose dexa-
per group) had been enrolled since April 2002. Enrollment
methasone, including infections/pneumonia, DVT/PE , high
was stopped at 232 patients. Significantly more patients
blood sugar, and reduced blood flow to the heart. DVT/PE
withdrew from the MP arm due to progression, and signifi-
in the first 4 months occurred in 20% of patients receiving
cantly more patients withdrew from the MP-T arm due to
high-dose dexamethasone compared with 7% in patients
toxicity. However, 80% of patients were able to tolerate MP-
receiving low-dose dexamethasone. Throughout the trial
T for up to 6 months and 65% of patients for up to 1 year.
the incidence was 24% vs. 9%. DVT/PE occurred both before
Peripheral neuropathy, neutropenia, and depression were
and after mandatory prophylaxis, although many patients
significantly more common in the MP-T arm. There were no
were already taking some type of anti-clotting therapy for
significant differences between treatment arms for clotting,
other reasons. Overall serious non-hematologic side effects,
constipation, somnolence, nausea and vomiting, edema, or
overall SAE, and early deaths were significantly lower with
deaths due to myeloma, toxicity, or other reasons.
low-dose dexamethasone, although they were lower in
The best response to treatment at 12 months was signifi-
patients receiving high-dose dexamethasone than in previ-
cantly higher with MP-T. Median PFS was significantly higher
ous trials of high-dose dexamethasone. Only about 25% of
for MP-T. At interim analysis, the median OS was longer for
the patients have gone on to stem cell harvest, and stem
patients receiving MP-T but the results must be confirmed
cells have been collected from over 90% of the total number
by analysis of results from all 232 patients. MP-T is effec-
of patients.
tive for patients over the age of 75 with newly diagnosed
The trial was stopped because the low-dose dexamethasone
myeloma and is superior to MP in prolonging PFS. Dr. Hulin
arm had a better one-year survival: 96% probability of sur-
concluded further that although the toxicity was acceptable,
vival vs. 87% in the low-dose dexamethasone arm. Median
shortening the duration of thalidomide might reduce neu-
OS was 23.6 months in the high-dose group and was not
rotoxicity and LMWH or aspirin might decrease the risk of
reached in the low-dose group. One-year survival was higher
thrombosis.
in patients less than 65 years of age (98% vs. 91%, low-dose
Sagar Lonial (Emory Winship Cancer Institute, Atlanta,
vs. high-dose) compared with age 65 years and older (94%
Georgia) commented that this was a landmark study in a
vs. 83%, low-dose vs. high-dose). The response rates, time
difficult population that sets the standard for the future. He
to progression, and PFS assessments are ongoing. Because
also remarked that the age that is considered "old" keeps
lenalidomide plus low-dose dexamethasone is associated
increasing. He noted that many advances in treatment have
with significantly superior one-year survival rate and lower
been in younger patients. Limitations in older patients
toxicity compared with lenalidomide high-dose dexametha-
include not just resistance to chemotherapy but increased
sone, Dr. Rajkumar suggested the low-dose dexamethasone
toxicity and the frail nature of the population. Many drugs
regimen could be adopted as front-line therapy for trans-
are effective but must be delivered in a safe way. That
plant candidates.
the drop-out rate was higher after 3 months suggests the
6
utility of less toxic novel agents, a shorter induction fol-
some of the newer therapies may overcome what previously
lowed by maintenance, or less frequent thalidomide dosing;
have been thought of as risk factors, e.g., bortezomib over-
for example, every other day.
coming chromosome 13 deletion. Options for patients with
high-risk disease include bortezomib for initial treatment
Incorporation of New Agents
and SCT at first relapse; ASCT followed by non- myeloab-
S. Vincent Rajkumar (Mayo Clinic) summarized the treat-
lative SCT in select patients; or a standard-risk treatment
ment of newly diagnosed myeloma, pointing out that
algorithm followed by maintenance therapy.
whereas the median survival from diagnosis used to be four
years, a "dazzling array of options" is increasingly allow-
Although Dr. Rajkumar prefers to see physicians treat their
ing patients to live a normal life with myeloma, and to
patients with myeloma in the context of a clinical trial,
live long enough that they are more likely to die of other
the Mayo Clinic's mSMART offers an off-study algorithm
causes. He believes it is important to stratify patients using
for patients based on eligibility for transplant stratified
the Mayo Clinic's mSMART classification system into high
by disease risk status (www.msmart.org). He emphasized
risk (25% of patients) based on chromosome deletions, cer-
the need to determine the cause of acute kidney failure,
tain translocations, hypodiploidy, and plasma cell labeling
whether the result of light-chain disease, amyloid, an unre-
index of at least 3% compared with standard risk (75% of
lated condition, or increased levels of calcium in the blood.
patients) based on hyperdiploidy (increase in number of
Acute kidney failure due to myeloma may require plasma
chromosomes) and other translocations (Mayo Clin Proc
exchange, biopsy, and aggressive anti-myeloma therapy,
2007:82:323). Then patients should be stratified based on
e.g., bortezomib plus dexamethasone, or thalidomide plus
eligibility for transplant, and if eligible, they should receive
dexamethasone, or bortezomib plus dexamethasone plus
an upfront regimen that would not affect the ability to col-
thalidomide; irreversible kidney failure is associated with
lect stem cells.
poorer outcome. For patients at high risk for DVT, including
those taking high-dose dexamethasone with thalidomide or
For non-transplant candidates, initial therapy traditionally
lenalidomide, erythropoietin, or doxorubicin, he suggests
was MP, but MP with thalidomide, lenalidomide, or bort-
preventive therapy with warfarin or LMWH. For patients
ezomib appears to offer advantages. For transplant can-
with low risk factors for clotting, e.g., patients taking
didates, the induction regimen can't include melphalan
lenalidomide with low-dose dexamethasone, aspirin might
because it inhibits stem cell collection. Thalidomide plus
be sufficient because the risk of other anticoagulants might
dexamethasone appears to be replacing VAD. Dr. Rajkumar
outweigh the risk of DVT.
noted that hematologists might not be familiar with treat-
ing the non-hematologic side effects of this regimen, includ-
The State of Front-line Therapy
ing constipation, neuropathy, and fatigue. Initial therapy
Paul Richardson (Dana-Farber Cancer Institute, Boston,
with bortezomib plus dexamethasone is another option;
Massachusetts) discussed the current state of front-line ther-
the addition of thalidomide to this regimen may increase
apy in myeloma, noting that induction therapy with novel
the response rate. Lenalidomide plus dexamethasone also
agents has changed the therapeutic paradigm. Traditionally
results in a higher response rate, and as seen in the ECOG
the aim has been CR or PR and optimizing SCT, but SCT
E4A03 trial, lower-dose dexamethasone is associated with
may become optional with more effective therapy, which
decreased toxicity.
may also improve efficacy in patients who are not transplant
candidates. Thalidomide plus dexamethasone is clearly
For initial treatment of non-transplant candidates, future
superior to dexamethasone in newly diagnosed patients,
options include the use of bortezomib, lenalidomide, and
although with relatively low CR rates, but with meaningful
low-dose dexamethasone (VRd), which will be tested in
time to disease progression (TTP) and OS. However, clot-
clinical trials. Other more intensive regimens include cyclo-
ting remains an important side effect.
phosphamide, biaxin, and dexamethasone (CBD), cyclo-
phosphamide, Revlimid, and dexamethasone (CRd), and
Lenalidomide with dexamethasone improves efficacy and
liposomal doxorubicin-containing regimens. For patients
reduces side effects compared with thalidomide plus dexa-
with high-risk multiple myeloma, data are accumulating that
methasone. The ECOG E4A03 will be a landmark study,
7
although the response data are not yet complete. Clotting
example, stomatitis (mouth sores) and hand foot syndrome,
remains a key issue with this treatment, and there is an impor-
are related to Doxil. The incidence of peripheral neuropa-
tant need to evaluate optimal therapy to prevent clotting. An
thy was the same in both arms and was usually mild; fever
important concern is determining which patients will ben-
associated with low levels of white blood cells and bleeding
efit from taking aspirin. Dr. Richardson said, "Lenalidomide
was rare despite low levels of white blood cells and plate-
plus low-dose dexamethasone constitutes the superior, and
lets. TE was low in both arms, and events affecting the heart
I would argue, potentially a new standard for up-front ther-
were similar in both arms.
apy, with a 96% 1-year survival rate being remarkable." Bort-
ezomib therapy results in a solid and robust CR, especially
Doxil plus bortezomib significantly improved TTP and OS
in combination therapies with dexamethasone or Doxil, and
in previously treated myeloma compared with bortezomib
the DVT rate with bortezomib plus Doxil is low.
alone. These benefits were seen in clinically relevant groups,
e.g., those who had prior therapy with either thalidomide or
Dr. Richardson referred to bortezomib plus lenalidomide
lenalidomide; post-transplant; high risk, including elevated
and low-dose dexamethasone as his personal favorite
beta-2-microglobulin; cytogenetic abnormalities other than
upfront regimen. He noted that although some of the novel
deletion 13: and advanced age. Side effects were predict-
therapeutics in combination have surpassed conventional
able and manageable, and peripheral neuropathy and heart-
therapies in efficacy, challenges remain, including side
related toxicity were not increased with the combination.
effects, and determining the optimum sequence of therapy
TE was low and no preventative therapy was necessary. The
remains an area of very active study.
FDA recently approved the combination of Doxil and bort-
ezomib for patients with myeloma who have not previously
Novel Agents in Patients with Relapsed
received bortezomib and who have received at least one
Myeloma
prior therapy.
Pegylated Liposomal Doxorubicin
Pieter Sonneveld presented the impact of prior thalidomide
(PLD; Doxil) and Bortezomib
therapy on the efficacy of PLD plus bortezomib in relapsed/
Jean-Luc Harousseau presented the results for TTP and OS
refractory myeloma [abstract 8023] for the DOXIL MMY-
for the phase III randomized study of Doxil plus bortezomib
3001 study investigators. This was a pre-specified subgroup
(n=324) vs. bortezomib alone (n=322) in relapsed/refrac-
analysis of the study updated by Dr. Harousseau. The ratio-
tory myeloma on behalf of the DOXIL-MMY-3001 study
nale for this subgroup analysis was a report of possible resis-
investigators [abstract 8002], an update of an interim analy-
tance to lenalidomide in patients previously treated with
sis presented last year at the American Society of Hematol-
thalidomide. This analysis assessed the differences in effi-
ogy annual conference. TTP for the bortezomib group was
cacy, represented by TTP, OS, and response rates, between
6.5 months. This was significantly (45%) improved at 9.3
treatment groups of patients with and without prior expo-
months for the combination of Doxil plus bortezomib. In a
sure to the immunomodulatory drugs (IMiDs) lenalidomide
subgroup analysis by risk factor, the combination favored all
or thalidomide. Of 646 patients randomized in the trial, 268
subgroups tested except those with the lowest beta-2-micro-
had prior IMiD exposure. Of these, 130 patients received
globulin and those with chromosome 13 deletion, where
Doxil plus bortezomib and 138 received bortezomib alone.
there was no difference between treatment arms.
Of the 378 IMiD-naïve patients, 194 were randomized to the
combination and 184 received bortezomib alone.
Response rates and the percentage of CR + VGPR were
significantly higher in the Doxil plus bortezomib group
The TTP was significantly longer in patients with prior IMiD
than in the bortezomib alone group. OS results are not yet
exposure who received Doxil plus bortezomib vs. those
available. There is a slight increase in adverse events in the
who received bortezomib alone, and was comparable to
combination arm, including gastrointestinal side effects and
TTP in patients treated with Doxil plus bortezomib who had
reduced numbers of platelets and blood cells, but discon-
no prior IMiD exposure. In patients receiving Doxil plus
tinuations are primarily due to bortezomib discontinuation.
bortezomib, the objective response rates were comparable
Some side effects for patients receiving the combination, for
whether or not they had prior IMiD exposure, and OS and
8
duration of response were also similar. There was also no
Total Therapy 3 (TT3)
difference in adverse event rates between groups based on
Bart Barlogie (University of Arkansas Medical Sciences, Little
prior IMiD exposure. No thromboembolic events (TE) were
Rock, Arkansas) presented the results of a phase II study
observed in the IMiD-exposed group treated with Doxil plus
of TT3 with bortezomib [abstract 8020]. The aim was to
bortezomib, although there was 1 serious event in an IMiD-
increase the CR rate and extend EFS and OS relative to TT2.
naïve patient treated with Doxil plus bortezomib. In 126
Induction therapy was reduced from 4 cycles to 2 cycles to
patients with prior exposure to thalidomide who received
increase compliance rates, and patients up to 75 years old
lenalidomide plus dexamethasone, there were 14 TE.
were eligible. For the majority of patients the second trans-
Raymond Comenzo, (Memorial Sloan-Kettering, New York
plant took place at 6 months and the final consolidation at
City, New York), discussed the DOXIL-MMY-3001 results,
12 months from initiation of therapy. The condensed time
noting that the Doxil formulation results in a slower clear-
frame resulted in more patients completing the protocol.
ance from the body and long half-life within the body. How
Gene expression profiling (GEP) based on a 70-gene model
Doxil acts is not yet fully known. Improvement in TTP with
was used to divide patients into high- and low-risk sub-
the combination of Doxil plus bortezomib is especially
groups. OS, EFS, and CR duration were significantly longer
important for patients with relapsed disease and those who
in the low-risk group. EFS with TT3 was significantly longer
don't want to take steroids. Dr. Comenzo observed that this
than with TT2 in the GEP-defined low- and high-risk cat-
is the first of many bortezomib combination trials.
egories, as was duration of CR for the GEP-defined low-risk
Alternating Bortezomib and Dexamethasone
subgroup. One gene the Arkansas group calls `micro-envi-
ronment-associated gene' (MAG-1), when down-regulated
Laura Rosiñol (Hospital Clinic, Barcelona, Spain) presented
after a test dose of bortezomib, confers a survival advantage,
the final results of the phase II PETHEMA trial of alternating
although this may not be as significant as other risk factors.
bortezomib and dexamethasone as an induction regimen
prior to ASCT in younger patients [abstract 8024]. The aims
New Insights into the Natural History
of the study were to decrease toxicity and assess M-protein
of Myeloma
decrease per cycle. The primary endpoints were response
rates and timing of the response; secondary endpoints
Survival Outcomes Over the Last Thirty Years
included safety, stem cell collection, and post-transplant
Irfan Jawed (University of Washington, Spokane, Washing-
response. The study enrolled 40 patients with a median
ton) presented survival outcomes for myeloma over three
age of 54 years. The standard doses of bortezomib and
decades based on a retrospective study of outcomes from
high-dose dexamethasone were given, but bortezomib was
the Surveillance, Epidemiology, and End Results (SEER) 11-
administered only for cycles 1, 3, and 5, and dexamethasone
Registries from 1973-2003 [abstract 8019]. The purpose of
was administered only for cycles 2, 4, and 6.
the study was to analyze how patient characteristics, year
of diagnosis, and decade of treatment affected OS and
Serum M-protein but not urine M-protein decreased signifi-
cause-specific survival (CSS). The database contains prog-
cantly. Looking at M-protein by cycle, 20 patients responded
nostic factors including age, race, sex, age at diagnosis, and
to bortezomib and dexamethasone, 10 patients responded
year diagnosed with multiple myeloma for 40,538 patients,
to dexamethasone only, and 3 patients responded to bort-
which is the largest population that has been studied for
ezomib only. Toxicity was low, and serious side effects
myeloma survival outcomes.
included decreased white blood cell counts and skin and
liver toxicity, with 1 incidence of neuropathy. This alter-
The estimated median survival for the entire population
nating approach was questioned, because it might allow
was 24 months. There was no significant difference in OS
myeloma cells resistant to chemotherapy to survive, so it is
by sex. Blacks and other races had significantly longer CSS
important to see survival to PD results as well as TTP survival
than whites; younger age at diagnosis was associated with
results. Dr. Rosiñol responded that the trial is for induction
significantly longer OS and CSS than older age; and OS and
before ASCT, so it is too early to assess survival.
CSS were significantly longer for patients diagnosed in the
most recent decade for which data were available than in
9
prior decades. In a multivariate analysis for OS and CSS
results of on-going phase I/II trials of ZIO-101 (darinapar-
endpoints, significant improvements were seen for patients
sin; S-dimethylarsino-glutathione), a novel, organic arse-
who were female, younger, or diagnosed and treated in
nic, in patients with advanced/progressive myeloma who
the most recent decade. CSS but not OS was significantly
had received at least 2 prior therapies [abstract 8109]. The
improved for black patients compared with white patients.
potential anti-myeloma effect of darinaparsin may result
OS has improved 10% for patients treated in the recent vs.
from several activities including disruption of mitochondrial
past decades. Some patients have been observed to survive
function, increased production of reactive oxygen species,
at least 20 years, which may be associated with new treat-
modified signal transduction, and anti-angiogenic activity.
ments and supportive care. Dr. Jawed plans to analyze the
effect of biologics, transplantation, and targeted treatment
A phase I/II study is investigating dosing with 300 mg/m2 by
on survival.
intravenous infusion once daily for 5 consecutive days every
4 weeks. The phase II portion of this study is determining
New Therapies in Development
the preliminary efficacy and safety profile of this schedule.
The second phase II study is investigating a dosing schedule
A New Proteasome Inhibitor
of 420 mg/m2 twice a week every 3 weeks of a 4-week cycle.
A. Keith Stewart (Mayo Clinic, Scottsdale, Arizona) pre-
The purpose of this study is to determine preliminary effi-
sented the results of a phase I trial evaluating carfilzomib
cacy and safety.
(PR-171), a new proteasome inhibitor, in patients with
hematologic malignancies including myeloma [abstract
There have been 14 patients treated on the first schedule; of
8003]. Compared with the approved proteasome inhibitor,
10 patients evaluable for response, 4 have SD as their best
bortezomib, PR-171 has a different structure, is not revers-
response. Three patients have been treated on the second
ible, and has different activities. Two parallel phase I dose-
schedule, with none evaluable so far. Common side effects
escalation studies were conducted in patients with myeloma
include vomiting, fatigue, and pain at the site of infusion in
and other hematologic malignancies that were relapsed or
patients receiving their treatment through a peripheral line.
refractory after more than 2 prior treatments; prior bortezo-
More serious side effects observed in a small number of
mib was allowed. The studies tested two dosing schedules,
patients include decreased blood cell counts, confusion, and
one of which continuously suppressed proteasome activity,
dizziness. No clinically important neuropathy, bone marrow
the other of which allowed proteasome recovery between
toxicity, or heart-related toxicity have been seen so far.
doses. Responses were seen with both schedules, with pro-
New Route of Administration for Bortezomib?
longed duration of response in some patients.
Phillippe Moreau (University Hospital, Nantes, France) pre-
PR-171 is well-tolerated and most side effects were mild or
sented results of a prospective comparison of subcutaneous
reversible. Dose-limiting side effects included decreased
with intravenous administration of bortezomib in patients
numbers of platelets and fever associated with decreased
with multiple myeloma: pharmacokinetics, efficacy, and
numbers of white blood cells in the continuous inhibition
toxicity [abstract 8046]. Patients with relapsed/refractory
trial, and decreased platelets, low levels of oxygen in the
myeloma were randomized to the standard dose and sched-
blood, and acute kidney failure in the recovery dose trial.
ule of bortezomib, given either I.V. or S.C. (n=12 each).
Phase II doses have been established and studies are begin-
The maximum concentration of bortezomib in the blood
ning in patients with refractory or relapsed myeloma. Dr.
was lower for the S.C. route, but the amount in the blood
Rajkumar commented that the results are similar to those
over time after a dose was similar for both routes of adminis-
seen in the early bortezomib trials and he hopes this drug
tration. The levels of proteasome inhibition were lower with
follows a similar path, but trials are needed to determine
the S.C. route, but not significantly.
how PR-171 will perform.
Response rates were identical for the two routes, with
ZIO-101, An Organic Arsenical
a similar side effect profile. A larger study is needed to
James R. Berenson (Institute for Myeloma and Bone Cancer
confirm these results. Dr. Orlowski commented that
Research, West Hollywood, California) presented updated
subcutaneous bortezomib could increase convenience
10
for patients and providers, and improve quality of life by
Future directions include using proteasome inhibition alone
decreasing the need for clinic visits, and possibly, the cost
and in combination in newly diagnosed patients, selecting
of therapy. Larger, randomized studies are needed to deter-
combination treatments predicated upon preclinical ratio-
mine the response durability. If true, this finding could
nale, and targeting protein catabolism with combination
facilitate outpatient therapy and other applications of bort-
therapy that inhibits both the proteasome and aggresome.
ezomib, such as in a maintenance setting, post-transplant,
or post-primary or relapsed/refractory therapy.
Future and Ongoing Trials
Other Therapies in Development
· Ongoing phase III trials in newly diagnosed patients
include VISTA (bortezomib plus MP vs. MP); MM-015
Kenneth C. Anderson, Dana-Farber Cancer Institute, dis-
(lenalidomide plus MP vs. MP) in the non-SCT setting;
cussed proteasome inhibition and other therapeutic strate-
and IFM (VAD vs. bortezomib plus dexamethasone) and
gies in development for myeloma. These include heat shock
HOVON (VAD vs. PAD) in the SCT setting.
protein (HSP) 90 inhibition, which has been shown to be
synergistic with bortezomib and well-tolerated in phase I/II
· Phase III trials that are planned include E1A06 (RMP
trials. The HSP90 inhibitor tanespimycin (KOS-953) will be
vs. MPT), IFM 0701 (Rd vs. MPT), S0777 (Rd vs. RVs) in
in a phase III trial. He noted that although no peripheral
the non-SCT setting, and E1A05 (RVd vs. Vd) in the SCT
neuropathy has been seen with novel proteasome inhibitor
setting.
PR-171 (carfilzomib), it may be too early to draw conclu-
· Agents to be tested with bortezomib include inhibitors of
sions. NPI-0052 (salinosporamide A) is another proteasome
HSP90, MAPK/ERK, IGF-1, and PI3K/AKT.
inhibitor that has activity against the trypsin and chymotryp-
sin-like activities and against caspase and is now in phase I
Lynne Lederman, PhD, is a medical writer based in
studies. Another potential target in the proteasome pathway
Mamaroneck, New York.
is upstream at ubiquitin ligase.
11
International Myeloma Foundation
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