InternatIonal MyeloMa FoundatIon
ASCO 2007
Highlights
for Physicians
by Lynne Lederman, PhD
This publication is funded by an unrestricted educational grant from Millennium Pharmaceuticals, Inc.
ASCO 2007 Highlights for Physicians
by Lynne Lederman, PhD
New Standards are Emerging:
signature, it will be necessary to find a way to translate this
News from the 2007 ASCO Meeting
into clinical use. In addition, although certain cytogenetic
abnormalities or genetic profiles may be used to define a
New and updated data on the use of novel therapeutics in
higher-risk population, some therapeutic agents may be
combination therapy in patients with newly diagnosed or
able to overcome this risk.
relapsed/refractory multiple myeloma were presented at the
2007 meeting of the American Society of Clinical Oncology
Mutations leading to dysregulation of the canonical (clas-
(ASCO), June 1 through 5, in Chicago, Illinois. Results from
sical) and non-canonical (alternative) NF kappa B path-
the E4A03 ECOG trial of lenalidomide plus either high- or
ways are important in myeloma. Some of these may allow
low-dose dexamethasone in newly diagnosed patients dem-
myeloma cells to by-pass signals usually provided by inter-
onstrated the advantages of low-dose dexamethasone. Addi-
action with the bone marrow microenvironment. Drugs
tional data were presented from the DOXIL-MMY-3002 trial
may interfere with the activity of mutations in one or both
of pegylated liposomal doxorubicin (Doxil®) plus bortezo-
pathways, e.g., dexamethasone affects components of the
mib in patients with relapsed/refractory myeloma who had
canonical pathway, whereas bortezomib can block both the
received at least one prior therapy. In addition, there was an
canonical and non-canonical pathways because the protea-
educational session on optimizing the therapy for multiple
some is involved in both.
myeloma; discussions on risk-based approaches to therapy;
Prediction of Response and Progression in
insights into the natural history of myeloma; updates of
Multiple Myeloma with Serum-Free Light
other clinical trials; and reports on agents in development.
Chains (sFLC)
Risk-Based Approaches to Therapy
Rami N. Khoriaty (Cleveland Clinic, Cleveland, Ohio)
presented data showing corroboration of the Interna-
According to Leif Bergsagel (Mayo Clinic, Scottsdale, Ari-
tional Myeloma Working Group (IMWG) response criteria
zona), session chair for a discussion of molecular classi-
[abstract 8047]. In a retrospective review of 89 patients
fication of myeloma and the implications for a risk-based
with myeloma, 43 (48%) had abnormal sFLC (greater than
approach to therapy,
10 mg/dL). Response rates by EBMT criteria were: 4 (5%)
there have been really exciting advances in understanding
CR, 22 (25%) PR, 26 (29%) PD. For patients with sFLC data
the pathogenesis of myeloma and in its treatment. Patients
(n=43) there were: 14 (32%) PR, 18 (42%) PD. The sensitiv-
treated today may not be cured, but their survival can be
ity and specificity of sFLC assay are quite good, particularly
extended so that they will live longer and eventually die of
the negative predictive value (92% for response and 95% for
other causes than myeloma. The heterogeneous nature of
progression). sFLC criteria reliably predicts response/PD in
survival has a genetic basis that is being investigated using
patients who have abnormal sFLC. Dr. Orlowski commented
a variety of techniques. These include gene expression pro-
that more studies comparing outcomes using the different
filing (GEP) and array comparative genomic hybridization
response criteria (EBMT and IMWG, the latter equating
(aCGH) to identify over- and under-expressed genes associ-
stringent CR with normalization of free light chain data) in
ated with disease progression, drug resistance, and progno-
a uniformly treated group of patients are needed to further
sis. aCGH allows identification of genetic variants that may
validate the new criteria. One important outcome of this
be enriched over the course of treatment and helps pin-
change in criteria is that all of the studies that have used
point progression that would be missed by fluorescent in
EBMT criteria previously may have different overall and
situ hybridization (FISH) or gene sequencing. Dr. Bergsagel
complete response rates when the new IMWG criteria are
noted that although GEP can be used to define a high-risk
applied instead.
3
Factors Predictive of Outcome in Relapsed,
Although conventional allogeneic SCT can result in pro-
Refractory Myeloma Treated with Bortezomib,
longed survival, the high mortality is unacceptable. Non-abla-
Melphalan, Prednisone, and Thalidomide
tive allografting may be an alternative, although response
(VMPT)
rates are low in patients unless there is only minimal dis-
Antonio Palumbo (University of Torino, Turin, Italy) pre-
ease. Therefore, the best regimen is unknown. Reduced
sented results of a phase I/II study of relapsed/refractory
intensity conditioning (RIC) allogeneic SCT is in clinical
myeloma in patients who had received at least one prior line
trial, but results will not be available for several years. In the
of therapy and received VMPT as salvage therapy (abstract
meantime, ASCT remains the standard of care for transplant-
8048). As second line, 57% of patients had at least VGPR,
eligible patients. Maintenance therapy may be beneficial for
while 100% had at least MR (36% CR, 21% VGPR, 21% PR,
low risk patients but the best agents are unknown. It is also
and 21% MR). No response differences were seen based on
not known if allogeneic transplant can overcome high-risk
age, beta-2-Microglobulin, CRP, deletion 13, line of treat-
cytogenetics. Dr. Bergsagel suggested enrolling patients in a
ment, or bortezomib dosage, but the power of the data is
trial to determine this.
not optimal because it was a phase I/II study. Low response
PETHEMA HDT tandem transplant with stem
rate was associated with decreased serum albumin. Lower
cell support in primary refractory myeloma
PFS was associated with CRP, third line of treatment, beta-
Results of the Spanish PETHEMA/GEM-2000 trial were pre-
2-Microglobulin, and creatinine, but not with chromosome
sented by Joan Bladé (Hospital Clinic, Barcelona, Spain)
13 deletion. These data suggest that combining novel agents
[abstract 8021]. Two populations with different outcomes
that don't overcome poor-risk cytogenetics (e.g., thalido-
were identified. Patients with primary refractory myeloma
mide in chromosome 13 deletion) with those that do (in
were most likely to benefit from early high-dose therapy
this case, bortezomib) may preserve the latter benefit, while
(HDT) and SCT. Patients received VBMCP/VBAD; if resistant,
still enhancing overall activity. Dr. Orlowski commented
they received BuMEL-140 or MEL-200/ASCT then CVB/ASCT
that this study validates that the ISS stage remains an impor-
or a mini-allogeneic transplant if there was a compatible
tant prognostic system even in the era of novel agents. A
donor. Of 81 patients with refractory myeloma, 50 (62%)
planned phase III trial of VMPT vs. VMP may answer the
had stable disease (SD) and 31 (38%) had progressive dis-
question whether post-VMPT relapse will be more resistant
ease (PD) after induction. After the first autologous trans-
and the disease more aggressive.
plant, CR rates were low. The second autologous (n=28)
Current Status of Stem Cell
or mini-allogeneic (n=9) SCT procedure resulted in 10%
Transplantation
CR with autologous vs. 33% CR with mini-allogeneic, the
small numbers of patients making statistical analysis diffi-
William Bensinger (Fred Hutchinson Cancer Center, Seattle,
cult. Median overall survival (OS) was 3.7 years for the 81
Washington) discussed the current status of stem cell trans-
patients. Patients with SD vs. PD or with chemosensitive dis-
plantation (SCT), including the issues of when, how many,
ease vs. primary refractory disease had a significantly greater
and whether they should be allogeneic, autologous, or both.
OS and progression-free survival (PFS). If the response
Autologous SCT (ASCT) results in a high response rate and
to initial chemotherapy is PD, survival is short despite
low mortality and demonstrates the impact of complete
HDT/SCT. Patients with non-responding, non-PD had a simi-
response (CR) or near (n) CR on survival, but it is still not
lar survival to that of patients with chemosensitive disease.
curative. Double transplant may be beneficial for selected
It must be determined if this is due to HDT or to the natural
patients, i.e., those who are not in CR or nCR after the first
history of a more indolent disease.
ASCT. It is not clear if SCT is of benefit to patients with CR
following chemotherapy. Although there are enough data to
Outcome after early relapse post-ASCT
show increased survival with ASCT compared with conven-
for myeloma
tional chemotherapy, it is not known if this will hold when
Risk factors for early relapse, defined as less than 12 months
ASCT is compared with novel therapies. It is also not known
after ASCT were studied by Syed T. Mahmood (Mayo Clinic,
if all CRs are equal and are independent of the treatment
Rochester, Minnesota) [abstract 8022] in a population of 432
leading to the response.
patients with newly diagnosed myeloma treated between
1994 and 2005. Patients were divided into two groups based
4
on time of relapse. Patients had received various initial ther-
deletion or hypodiploidy); platelets at least 100,000; beta-
apies including dexamethasone (38.5%), VAD (29.9%), tha-
2-microglobulin less than 3; CRP less than 6; CR; and ability
lidomide/dexamethasone (24.8%), and others; 81.3% had
to do a second SCT. There was a suggestion that OS, EFS,
undergone conditioning with MEL 200. The only significant
and CR duration is increasing for 2004 to 2006 for patients
differences in baseline characteristics for the group with
on non-TT studies compared with the past. However, OS,
early relapse (n=94) vs. late or no relapse (n=338) were
EFS, and CR duration for patients off-study do not seem
plasma cell labeling index (PCLI) of at least 1%, refractory
to have improved over this period of time. Dr. Robert Z.
disease at transplant, having received more than one induc-
Orlowski, University of North Carolina, Chapel Hill, North
tion regimen, abnormal karyotype, and circulating plasma
Carolina, who discussed the poster, noted that the data
cells at collection.
suggests incorporation of novel agents and application of
best therapy is improving outcomes. He was concerned that
The rate of OR was similar (96%) but that of CR was much
non-protocol patients have not improved, possibly because
higher in the late vs. early relapse group (18% vs. 43%).
they were older, had renal insufficiency, or other poor risk
Median post ASCT OS in the late relapse group was 75.7
factors, and that help is needed for these patients. These
months, vs. 17.6 months in the early group. Median OS
data were collected prior to the era of MP-T, MP-R, and
from diagnosis in late vs. early relapse was 82.2. months
MP-V for older patients. Bortezomib and/or lenalidomide
vs. 23.9 months, and median OS from relapse was 39.6
may help those with chromosome 13 deletion.
months vs. 7.8 months, all significantly greater for the late
relapse group. In a multivariate analysis, the three factors
Bortezomib Prior To and as Maintenance
significantly associated with early relapse were more than
Therapy After ASCT
one induction regimen, a PCLI greater than 1%, and no
Sagun D. Goyal (Washington University School of Medicine,
CR. Prognostic factors for shorter OS post-ASCT included
St. Louis, Missouri) and Robert Z. Orlowski (University of
PCLI greater than 1%, beta-2-microglobulin greater than 5.5
North Carolina) presented long-term follow-up of a phase
mg/dL, and relapse less than 12 months from ASCT. Median
II study [abstract 8044]. Of 40 patients who received bort-
OS for patients with relapse before 2002 was 12.5 months,
ezomib at a standard dose and schedule for 2 cycles post-
and after 2002, 20.5 months, suggesting the contribution of
induction before mobilization, and 6 cycles post-ASCT for
newer therapies.
4 weeks out of 5; 14/31 (45%) had at least MR (defined as an
Dr. Mahmood concluded that early relapse after ASCT is a
M-protein reduction of 25% by serum protein electrophore-
novel predictor for poor outcome; patients who have high-
sis and of 50% by urine protein electrophoresis). Stem cell
risk disease may not be obvious from conventional risk fac-
collection and engraftment were normal and 33/38 (89%)
tors; and these patients should be enrolled in clinical trials.
had an overall response rate at day 90 to 120 post transplant
He suggested the data he presented can provide a reference
of 50% or better; with 27/33 (82%) VGPR at end of study.
baseline for these trials.
Median PFS was 626 days and median OS was 64.7% at
3 years. 14/33 (42%) developed post-SCT zoster, indicating a
High-dose Melphalan-Based Autotransplant
need for prophylaxis against zoster. Dr. Orlowski suggested
Mauricio Pineda-Roman (University of Arkansas Medical Sci-
that randomized studies are needed to support the efficacy
ences, Little Rock, Arkansas) presented the Arkansas experi-
of maintenance therapy.
ence since 1989 in 3077 successive patients treated with at
Benefit of Reduced Intensity Conditioning
least one MEL auto-SCT of which 1078 received Total Therapy
(RIC) Allogeneic SCT as Salvage Treatment
(TT)-1, 2, or 3; 1104 were on studies for previously treated
for Relapsing Myeloma
patients, and 895 were off-study (abstract 8043). Patients on
protocols were younger, had better disease parameters, and
Mohamad Mohty (Institute Paoli-Calmettes, Marseille,
although cytogenetic abnormalities were similar in three
France) presented results suggesting that for the minority
groups, there were fewer cases of chromosome 13 deletion
of patients with a matched sibling donor, RIC allo-SCT is a
and hypodiploidy in TT groups. TT patients had better OS
viable option (abstract 8045). Of 32 patients with relapsed/
and EFS; TT3 was better than TT2, which was better than
refractory myeloma, 13 did not have allogeneic-matched
TT1. Parameters predicting good outcome in decreasing
donors whereas 18 received RIC allo-SCT. Of those without
order were: favorable cytogenetics (no chromosome 13
donors 11/13 had PD despite salvage, more chemotherapy,
5
and another auto-SCT; 6 (46%) were alive, of whom 5 had
25% of the patients have gone on to stem cell harvest, and
PD, and PFS was 8% at a median follow-up of 36 months.
yet, stem cells have been collected from over 90% of the
For patients with donors, 10/18 (56%) were alive with 11/18
total number of patients.
responders (4 CR, 5 PR/VGPR) and 5 PD post-SCT; PFS
was 46% (p=0.01 vs. the non-alloSCT group). Transplant-
The trial was stopped because the low-dose arm had a better
related mortality was too high at 33%.
one- year survival: 96% probability of survival vs. 87% in the
low-dose arm. Median OS was 23.6 months in the high-dose
Treatment Options for Patients with
group and not reached in the low-dose group. One year sur-
Newly Diagnosed Myeloma
vival was higher in patients less than 65 years (98% vs. 91%,
low-dose vs. high-dose) compared with age 65 years and
Late-Breaking Abstract on the E4A03
older (94% vs. 83%, low-dose vs. high-dose). The response
ECOG Trial
rates, time to progression, and PFS assessments are ongo-
S. Vincent Rajkumar (Mayo Clinic, Rochester Minnesota)
ing. Because lenalidomide plus low-dose dexamethasone is
presented the late-breaking abstract [8025] on the phase
associated with significantly superior one-year survival rate
III E4A03 ECOG trial of lenalidomide plus high-dose dexa-
and lower toxicity compared with lenalidomide high- dose
methasone vs. lenalidomide plus low-dose dexamethasone
dexamethasone, Dr. Rajkumar suggested the low-dose dexa-
in 445 patients with newly diagnosed myeloma. One goal
methasone regimen could be adopted as front-line therapy
of this trial was to compare lenalidomide plus high- or low-
for transplant candidates.
dose dexamethasone in an effort to reduce adverse events
associated with high-dose dexamethasone. Patients in the
MP-T vs. MP in patients at least 75 years of age
high-dose dexamethasone group (n=223) received the
with untreated MM ­ preliminary results
drug according to the usual schedule, with a total dose of
of IFM 01-01
480 mg per cycle; patients in the low-dose group (n=222)
Preliminary results of the IFM 01/01 trial, a randomized,
received 160 mg of dexamethasone per cycle. Before Sep-
double-blind, placebo-controlled trial of melphalan-predni-
tember 15, 2005, thromboprophylaxis with aspirin was
sone-thalidomide (MP-T) vs. MP in patients at least 75 years
recommended but not mandated; after that date it was man-
of age were presented by Cyrille Hulin on behalf of the Inter-
dated that patients receive at least aspirin, but warfarin or
groupe Francophone du Myelome (IFM) [abstract 8001].
low-molecular weight heparin (LMWH) was strongly recom-
MP-T is considered standard treatment for patients age 65
mended for patients in the high-dose dexamethasone arm.
and over. Although trials in patients over age 75 are rare, at
Baseline characteristics of patients in the two treatment
least 20% of myeloma patients are in this age group. Patients
groups were similar.
received 12 cycles MP every 6 weeks (melphalan 0.2 mg/kg
per day, days 1 through 4, prednisone 2 mg/kg per day, days
Serious adverse events (SAE) in the two groups were simi-
1 through 4). No specific anti-thrombotics were planned but
lar, with the following exceptions: neutropenia was higher
patients with a history of thrombosis were excluded. The
in the low-dose dexamethasone group (19% vs. 9.7% in
MP-T group also received 100 mg of thalidomide daily.
the high-dose group); non-hematologic toxicity was sig-
nificantly higher in the high-dose vs. the lower-dose dexa-
At interim analysis in April 2007, 200 patients (100 patients
methasone group, including infections/pneumonia (14.7%
per group) had been enrolled since April 2002; enrollment
vs. 5.1%); DVT/PE (23.8% vs. 9.1%); hyperglycemia (9.7% vs.
was stopped at 232 patients. Significantly more patients with-
6%); and cardiac ischemia (2.8% vs. 0.5%). DVT/PE in the
drew from the MP arm due to progression (60% vs. 30%),
first 4 months occurred in 20% of patients in the high dose
and significantly more patients withdrew from the MP-T
group vs. 7% in the low-dose group. Throughout the trial
arm due to toxicity (53% vs. 15%), however, 80% of patients
the incidence was 24% vs. 9%. DVT/PE occurred both before
were able to tolerate MP-T for up to 6 months and 65% of
and after mandatory prophylaxis, although many patients
patients for up to 1 year. Peripheral neuropathy, neutrope-
were already taking some type of anti-thrombotic therapy.
nia, and depression were significantly more common in the
Overall grade 3/4 non-hematologic toxicities, overall SAE,
MP-T arm. There were no significant differences between
and early deaths were significantly lower in the low-dose
treatment arms for thrombosis, constipation, somnolence,
arm, although they were lower in the high-dose arm than
nausea and vomiting, edema, or deaths due to myeloma,
in previous trials of high-dose dexamethasone. Only about
toxicity, or other reasons.
6
The best response to treatment at 12 months was signifi-
mib appears to offer advantages. For transplant candidates,
cantly higher with MP-T (61% at least PR vs. 31% with MP;
the induction regimen can't include melphalan because it
and 23% at least VGPR vs. 8%). Median PFS was signifi-
inhibits stem cell collection. Thalidomide plus dexameth-
cantly higher for MP-T (24.1 months vs. 19 months for MP).
asone appears to be replacing VAD. Dr. Rajkumar noted
Median OS was 33.3 months. Median OS was not reached
that hematologists might not be familiar with treating the
but estimated to be 45.3 months for MP-T vs. 27.7 months
non-hematologic side effects of this regimen including con-
for MP for 200 patients at interim analysis. These data must
stipation, neuropathy, and fatigue. Initial therapy with bort-
be confirmed by analysis of all 232 patients. After progres-
ezomib plus dexamethasone is another option; the addition
sion, survival time was 9.8 months for the MP group vs. 9.3
of thalidomide to this regimen may increase the response
months for the MP-T group, so salvage after failure of MP
rate. Lenalidomide plus dexamethasone also results in
is possible. MP-T is effective for patients over the age of 75
a higher response rate, and as seen in the ECOG E4A03
with newly diagnosed myeloma and is superior to MP in
trial, and lower-dose dexamethasone is associated with
prolonging PFS. Dr. Hulin concluded further that although
decreased toxicity.
the toxicity was acceptable, shortening the duration of tha-
lidomide might reduce neurotoxicity and LMWH or aspirin
For initial treatment of non-transplant candidates, future
might decrease the risk of thrombosis.
options include the use lenalidomide, bortezomib, and
low-dose dexamethasone (VRd), which will be tested in
Sagar Lonial (Emory Winship Cancer Institute, Atlanta, Geor-
clinical trials. Other more intensive regimens include CBD,
gia) commented that this was a landmark study in a difficult
CRd, and liposomal doxorubicin-containing regimens. For
population that sets the standard for the future and that the
patients with high-risk multiple myeloma, data are accumu-
age that is considered "old" keeps increasing. He noted that
lating that some of the newer therapies may overcome what
many advances in treatment have been in younger patients.
previously have been thought of as risk factors, e.g., bort-
Limitations in older patients include not just resistance to
ezomib overcoming chromosome 13 deletion. Options for
chemotherapy but increased toxicity and the frail nature of
patients with high-risk disease include bortezomib for initial
the population. Many drugs are effective but must be deliv-
treatment and SCT at first relapse; ASCT followed by non-
ered in a safe way. That the drop-out rate was higher after
myeloablative SCT in select patients; or a standard-risk treat-
3 months suggests the utility of less toxic novel agents, a
ment algorithm followed by maintenance therapy.
shorter induction followed by maintenance, or less frequent
thalidomide dosing, i.e., every other day.
Although Dr. Rajkumar prefers to see physicians treat their
patients with myeloma in the context of a clinical trial, the
Incorporation of New Agents
Mayo Clinic's mSMART offers an off-study algorithm for
S. Vincent Rajkumar (Mayo Clinic) summarized the treat-
patients based on eligibility for transplant stratified by dis-
ment of newly diagnosed myeloma, pointing out that
ease risk status (www.msmart.org). He emphasized the need
whereas the median survival from diagnosis used to be four
to determine the cause of acute renal failure, whether light-
years, a "dazzling array of options" is increasingly allowing
chain disease, amyloid, an unrelated condition, or hyper-
patients to live a normal life with myeloma, and to live long
calcemia. Acute renal failure due to myeloma may require
enough that they are more likely to die of other causes. He
plasma exchange, biopsy, and aggressive anti-myeloma
believes it is important to stratify patients using the Mayo
therapy, e.g., bortezomib plus dexamethasone or thalido-
Clinic's mSMART classification system into high risk (25%
mide plus dexamethasone or bortezomib plus dexametha-
of patients) based on deletion 17p, t(4;14), t(14;16), dele-
sone plus thalidomide; irreversible renal failure confers a
tion 13, hypodiploidy, and plasma cell labeling index 3%
bad prognosis. For patients at high-risk for DVT, including
vs. standard risk (75% of patients) based on hyperdiploidy,
those taking high dose dexamethasone with thalidomide
t(11;14), t(6;14) (Mayo Clin Proc 2007:82:323). Then
or lenalidomide, erythropoietin, Adriamycin, or doxorubi-
patients should be stratified based on eligibility for trans-
cin, he suggests prophylaxis with warfarin to an INR of 2
plant; if eligible, they should receive an upfront regimen
to 3 or LMWH; but if no risk factors, e.g. patients taking
that would not affect the ability to collect stem cells.
lenalidomide with low-dose dexamethasone, aspirin might
be sufficient because the risk of other anticoagulants might
For non-transplant candidates, initial therapy traditionally
outweigh the risk of DVT.
was MP, but MP with thalidomide, lenalidomide, or bortezo-
7
The State of Front-line Therapy
Novel Agents in Patients with
Paul Richardson (Dana-Farber Cancer Institute, Boston,
Relapsed Myeloma
Massachusetts) discussed the current state of front-line ther-
Pegylated Liposomal Doxorubicin (PLD;
apy in myeloma, noting that induction therapy with novel
Doxil) and Bortezomib
agents has changed the therapeutic paradigm. Traditionally
the aim has been CR or PR and optimizing SCT, but SCT
Jean-Luc Harousseau presented the results for TTP and OS
may become optional with more effective therapy, which
for the phase III randomized study of PLD plus bortezomib
may also improve efficacy in patients who are not transplant
(n=324) vs. bortezomib alone (n=322) in relapsed/refrac-
candidates. Thalidomide plus dexamethasone is clearly
tory myeloma on behalf of the DOXIL-MMY-3001 study
superior to dexamethasone in newly diagnosed patients,
investigators (abstract 8002), an update of an interim analy-
although with relatively low CR rates, but with meaningful
sis presented last year at the American Society of Hematology
TTP and OS. However, TE remains an important side effect.
annual conference. TTP for the bortezomib group was 6.5
months, and for the combination it was significantly (45%)
Lenalidomide with dexamethasone improves efficacy
improved at 9.3 months. In a subgroup analysis by risk fac-
and reduces side effects compared with thalidomide plus
tor, the combination favored all subgroups tested except
dexamethasone. The ECOG E4A03 will be a landmark
those with the lowest beta-1-microglobulin and those with
study, although the response data are not yet complete.
chromosome 13 deletion, where there was no difference
TE remains a key issue with this regimen and there is an
between treatment arms.
important need to evaluate optimal thrombo-prophylaxis.
Who benefits from aspirin remains an important concern.
Response rates were significantly higher in the PLD plus
Dr. Richardson said, "Lenalidomide plus low dose dexa-
bortezomib group (52%) than in the bortezomib alone
methasone constitutes the superior, and I would argue
group (44%), as was the percentage of CR + VGPR (30%
potentially a new standard, for up-front therapy, with a 96%
vs. 20%; p=.007). The survival curves for the two arms
1-year survival rate being remarkable." Bortezomib therapy
separate after 1 year of follow-up, so OS data are pending.
results in a solid and robust CR, especially in combination
There is a slight increase in adverse events in the combina-
therapies with dexamethasone or Doxil, and the DVT rate
tion arm, including gastrointestinal events, thrombocytope-
with bortezomib plus Doxil is low.
nia, and cytopenia, but discontinuations are primarily due
to bortezomib discontinuation. Some adverse events in the
Ongoing phase III trials in newly diagnosed patients include
combination, e.g., stomatitis and hand foot syndrome, are
VISTA (bortezomib plus MP vs. MP); MM-015 (lenalidomide
related to Doxil. The incidence of peripheral neuropathy
plus MP vs. MP) in the non-SCT setting; and IFM (VAD vs.
was the same in both arms and was usually mild; febrile
bortezomib plus dexamethasone) and HOVON (VAD vs.
neutropenia and hemorrhage were rare despite neutrope-
PAD) in the SCT setting. Phase III trials that are planned
nia and thrombocytopenia. TE was low (1%) in both arms,
include E1A06 (RMP vs. MPT), IFM 0701 (Rd vs. MPT), S0777
and cardiac events were similar in both arms.
(Rd vs. RVs) in the non-SCT setting, and E1A05 (RVd vs. Vd) in
the SCT setting. Dr. Richardson referred to bortezomib plus
PLD plus bortezomib significantly improved TTP and OS
lenalidomide and low-dose dexamethasone as his personal
in previously treated myeloma compared with bortezomib
favorite upfront regimen. He noted that although some of
alone. These benefits were seen in clinically relevant groups
the novel therapeutics in combination have surpassed con-
e.g., with prior IMiD therapy, post-transplant, high risk,
ventional therapies in efficacy, challenges remain, includ-
including elevated beta-2-Microglobulin, cytogenetic abnor-
ing side effects, and determining the optimum sequence of
malities other than deletion 13, and advanced age. Adverse
therapy remains an area of very active study.
events were predictable and manageable, and peripheral
neuropathy and cardiac toxicity were not increased in the
combination. TE was low and no prophylaxis was necessary.
The combination of Doxil and bortezomib was recently
approved for patients with myeloma who have not previ-
ously received bortezomib and who have received at least
one prior therapy.
8
Pieter Sonneveld presented the impact of prior thalido-
temporal activity (half life), complementary pathway effects,
mide therapy on the efficacy of PLD plus bortezomib in
and selectivity for tumor cells. Dr. Comenzo observed that
relapsed/refractory myeloma [abstract 8023] for the DOXIL
this is the first of many bortezomib combination trials. Other
MMY-3001 study investigators. This was a pre-specified sub-
agents to be tested with bortezomib include inhibitors of
group analysis of the study updated by Dr. Harousseau. The
HSP90, MAPK/ERK, IGF-1, and PI3K/AKT.
rationale for this subgroup analysis was a report of possible
resistance to lenalidomide in patients previously treated
Alternating Bortezomib and Dexamethasone
with thalidomide. This analysis assessed the differences in
Laura Rosiñol (Hospital Clinic, Barcelona, Spain) presented
efficacy, represented by time to progression (TTP), OS, and
the final results of the phase II PETHEMA trial of alternating
response rates, between treatment groups of patients with
bortezomib and dexamethasone as an induction regimen
and without prior exposure to the IMiDs lenalidomide or
prior to ASCT in younger patients [abstract 8024]. The aims
thalidomide. Of 646 patients randomized in the trial, 268
of the study were to decrease toxicity and assess M-protein
had prior IMiD exposure (94% thalidomide, 6% lenalido-
decrease per cycle. The primary endpoints were response
mide). Of these, 130 patients received PLD plus bortezomib
rates and kinetics of the response; secondary endpoints
and 138 received bortezomib alone. Of the 378 IMiD- naïve
included safety, stem cell collection, and post-transplant
patients, 194 were randomized to the combination and 184
response. The study enrolled 40 patients with a median
received bortezomib alone.
age of 54 years. The standard doses of bortezomib and
high-dose dexamethasone were given, but bortezomib was
The TTP was significantly longer in patients with prior IMiD
administered only for cycles 1, 3, and 5, and dexamethasone
exposure who received PLD plus bortezomib vs. those who
was administered only for cycles 2, 4, and 6.
received bortezomib alone and was comparable to TTP in
patients treated with PLD plus bortezomib who had no prior
The best ever overall response rate (ORR) was 82.5%; at the
IMiD exposure. In patients receiving PLD plus bortezomib,
end of induction the ORR was 77.5%. Serum M-protein but
the objective response rates were comparable whether or
not urine M-protein decreased significantly from baseline
not they had prior IMiD exposure, and OS and duration of
values. Looking at M-protein by cycle, 20 patients responded
response were also similar. There was also no difference in
to bortezomib and dexamethasone, 10 patients responded
adverse event rates between groups based on prior IMiD
to dexamethasone only, and 3 patients responded to bort-
exposure. No thromboembolic events (TE) were observed
ezomib only. Toxicity was low, with no grade 4 toxicities;
in IMiD exposed group treated with PLD plus bortezomib,
grade 3 toxicities included neutropenia and skin and liver
although there was 1 grade 3/4 event in an IMiD-naïve
toxicity, with 1 incidence of grade 2 neuropathy. Stem cell
patient treated with PLD plus bortezomib. In 126 patients
harvest was excellent. Three months after HDT, ORR was
with prior exposure to thalidomide who received lenalido-
94%, with 33% CR, 22% VGPR, and 33% PR. This alternating
mide plus dexamethasone, there were 14 TE.
approach was questioned, as it might allow a resistant clone
to survive, so it is important to see survival to PD results
Raymond Comenzo, (Sloan-Kettering, New York City, New
as well as TTP survival data. Dr. Rosiñol responded that
York), discussed the DOXIL-MMY-3001 results, noting that
the trial is for induction before ASCT, so it is too early to
the PLD formulation results in a slower clearance and long
assess survival.
half-life, and although the mechanism is not fully known,
the compound is activated intracellularly, leading to free
Total Therapy 3 (TT3)
radical formation, active oxygen species, altered cell mem-
Bart Barlogie (University of Arkansas Medical Sciences, Little
branes, DNA strand breaks, immunogenicity, suppression of
Rock, Arkansas) presented the results of a phase II study
MAPK phosphatase expression, and activation of NF kappa
of TT3 with bortezomib [abstract 8020]. The aim was to
B (not desirable in myeloma) with a selectivity for tumor
increase the CR rate and extend EFS and OS relative to TT2.
cells. He noted that the improvement in TTP with the com-
Induction therapy was reduced from 4 cycles to 2 cycles to
bination of PLD plus bortezomib is especially important for
increase compliance rates, and patients up to 75 years old
patients with relapsed disease and those who don't want to
were eligible. For the majority of patients the second trans-
take steroids. Both PLD and bortezomib are active broadly
plant took place at 6 months and the final consolidation
in cancer, are synergistic with other agents, and have similar
at 12 months from initiation of therapy. The 303 patients
9
enrolled have been followed for a median of 24 months, at
the most recent decade. CSS but not OS was significantly
which time OS was 87% and EFS was 84%. Response dura-
improved for black patients compared with white patients.
tion was CR 91%, nCR 80%, and PR 60%. At 24 months,
OS has improved 10% for patients treated in the recent vs.
treatment related mortality was 5%, and the post relapse
past decades. Some patients have been observed to survive
survival was 24%. The condensed time frame resulted in
at least 20 years, which may be associated with new treat-
more patients completing the protocol.
ments and supportive care. Dr. Jawed plans to analyze the
effect of biologics, transplantation, and targeted treatment
Gene expression profiling (GEP) based on a 70-gene model
on survival.
was used to divide patients into high and low risk sub-
groups. OS, EFS, and CR duration was significantly longer
New Therapies in Development
in the low risk group. Once the GEP score was taken into
account, FGFR3 t(4;14) did not affect survival. EFS with TT3
A New Proteasome Inhibitor
was significantly longer than with TT2 in the GEP-defined
A. Keith Stewart (Mayo Clinic, Scottsdale, Arizona) presented
low and high risk categories; survival was also significantly
the results of a phase I trial evaluating carfilzomib (PR-171),
longer with TT3 than with TT2 for the FGFR3/MMSET sub-
a new proteasome inhibitor, in patients with hematologic
group t(4:14), as was duration of CR for the GEP-defined
malignancies including myeloma [abstract 8003). The prop-
low risk subgroup. One gene the Arkansas group calls
erties of PR-171 are compared with those of the approved
micro-environment-associated gene (MAG-1), when down-
proteasome inhibitor, bortezomib, in the table below.
regulated after a test dose of bortezomib, confers a survival
advantage, although this may not be as significant as other
Pr-171
Bortezomib
risk factors.
Keto-epoxide tetrapeptide
Boronic acid dipeptide
Irreversible
Slowly reversible
New Insights into the Natural History
Highly selective for
Inhibits both chymotrypsin-
of Myeloma
chymotrypsin-like active
like and caspase-like activities
site within the proteasome
of the proteasome
Survival Outcomes Over the Last Thirty Years
Highly selective for
Cross-reactivity with serine
proteasome N-terminal
proteases
Irfan Jawed (University of Washington, Spokane, Washing-
threonine active sites
ton) presented survival outcomes for myeloma over three
decades based on a retrospective study of outcomes from
Two parallel phase I dose-escalation studies were conducted
the Surveillance, Epidemiology, and End Results (SEER)
in patients with myeloma and other hematologic malignan-
11-Registries from 1973­2003 [abstract 8019]. The purpose
cies that were relapsed or refractory after more than 2 prior
of the study was to analyze how patient characteristics,
treatments; prior bortezomib was allowed. The studies
year of diagnosis, and decade of treatment affected OS and
tested two dosing schedules, one of which continuously
cause-specific survival (CSS). The database contains prog-
suppressed proteasome activity, the other of which allowed
nostic factors including age, race, sex, age at diagnosis, and
proteasome recovery between doses. Responses were seen
year diagnosed with multiple myeloma for 40,538 patients,
with both schedules, with prolonged duration of response
which is the largest population that has been studied for
in some patients. Pharmacokinetic studies suggest that PK
myeloma survival outcomes.
parameters are unlikely to guide dose selection. Pharmaco-
dynamics (chymotrypsin inhibition assay) suggest that 80%
The estimated median survival for the entire population
proteasome inhibition correlates with response.
was 74 months. There was no significant difference in OS by
sex. Blacks and other races had significantly longer OS and
PR-171 is well-tolerated and most adverse events were
CSS than whites; younger age at diagnosis was associated
grade 1/2, but 4 patients had grade 2/3 increase in creatinine
with significantly longer OS and CSS than older age; and OS
that was reversible after the first dose.
and CSS were significantly longer for patients diagnosed in
the most recent decade for which data were available than
Reversible 3/4 thrombocytopenia occurred in patients who
in prior decades. In a multivariate analysis for OS and CSS
had grade 2 thrombocytopenia at enrollment, and there
endpoints, significant improvements were seen for patients
was no peripheral neuropathy. Dose-limiting toxicities
who were female, younger, or diagnosed and treated in
included febrile neutropenia and thrombocytopenia in the
10
continuous inhibition trial and thrombocytopenia, hypoxia,
schedule of bortezomib, given either I.V. or S.C. (n=12
and acute renal failure in the recovery dose trial. Phase II
each). Cmax (PK) was lower for the S.C. route, but the AUC
doses have been established and studies are beginning in
similar for both routes of administration. Emax (protea-
patients with refractory or relapsed myeloma. Dr. Rajkumar
some inhibition, a pharmacodynamic parameter) was lower
commented that the results are similar to those seen in the
with S.C., but not significantly. Response rates were identi-
early bortezomib trials and he hopes this drug follows a
cal for the two routes, with a similar toxicity profile. A larger
similar path, but trials are needed to determine how PR-171
study is needed to make sure these data are reproducible.
will perform.
Dr. Orlowski commented that subcutaneous bortezomib
could increase convenience for patients and providers, and
ZIO-101, An Organic Arsenical
improve quality of life by decreasing the need for clinic visits
James R. Berenson (Institute for Myeloma and Bone Cancer
and possibly the cost of therapy. Larger, randomized studies
Research, West Hollywood, California) presented updated
are needed to determine the response durability. If true, this
results of on-going phase 1/2 trials of ZIO-101 (Darinapar-
finding could facilitate outpatient therapy and other applica-
sin; S-dimethylarsino-glutathione), a novel, organic arse-
tions of bortezomib, such as in a maintenance setting, post-
nic, in patients with advanced/progressive myeloma who
transplant or post-primary or relapsed/refractory therapy.
had received at least 2 prior therapies[abstract 8109]. The
potential anti-myeloma effect of Darinaparsin may result
Other Therapies in Development
from several activities including disruption of mitochondrial
Kenneth C. Anderson, Dana-Farber Cancer Institute, dis-
function, increased production of reactive oxygen species,
cussed proteasome inhibition and other therapeutic strate-
modified signal transduction, and anti-angiogenic activity.
gies in development for myeloma. These include heat shock
protein (HSP) 90 inhibition, which has been shown to be
A phase I/II study is investigating dosing with 300 mg/m2 by
synergistic with bortezomib and well-tolerated in phase I/II
intravenous infusion once daily for 5 consecutive days every
trials. The HSP90 inhibitor tanespimycin (KOS-953) will be
4 weeks. The phase II portion of this study is determining
in a phase III trial. He noted that although no peripheral
the preliminary efficacy and safety profile of this schedule.
neuropathy has been seen with novel proteasome inhibitor
The second phase II study is investigating a dosing schedule
PR-171 (carfilzomib), it may be too early to draw conclu-
of 420 mg/m2 twice a week every 3 weeks of a 4-week cycle.
sions. NPI-002 (Salinisporamide A) is another proteasome
The purpose of this study is to determine preliminary effi-
inhibitor that has activity against the trypsin and chymotryp-
cacy and safety.
sin-like activities and against caspase and is now in phase I
There have been 14 patients treated on the first schedule;
studies. Another potential target in the proteasome pathway
of 10 patients evaluable for response 4 have SD as their best
is upstream at ubiquitin ligase.
response. Three patients have been treated on the second
Future directions include using proteasome inhibition alone
schedule, with none evaluable so far. Common side effects
and in combination in newly diagnosed patients, selecting
include vomiting, fatigue, and pain at the site of infusion
combination treatments predicated upon preclinical ratio-
in patients receiving their treatment through a peripheral
nale, and targeting protein catabolism with combination
line. More serious side effects observed in a small number
therapy that inhibits both the proteasome and aggresome.
of patients include decreased blood cell counts, confusion,
and dizziness. No clinically important neuropathy, bone
Lynne Lederman, PhD, is a medical writer based in
marrow toxicity, or cardiotoxicity have been seen so far.
Mamaroneck, New York
New Route of Administration for Bortezomib?
Phillippe Moreau (University Hospital, Nantes, France)
presented results of a prospective comparison of subcuta-
neous with intravenous administration of bortezomib in
patients with multiple myeloma: pharmacokinetics, efficacy,
and toxicity [abstract 8046]. Patients with relapsed/refrac-
tory myeloma were randomized to the standard dose and
11
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