InternatIonal MyeloMa FoundatIon
ASH 2006
Multiple Myeloma
Highlights
for Physicians
Highlights from the 48th Annual Meeting of the
American Society for Hematology (ASH) held in
Orlando Florida, December 912, 2006
by Lynne Lederman, PhD
ASH 2006 Multiple Myeloma Highlights for Physicians
by Lynne Lederman, PhD
A Changing Landscape
Thromboembolic Event-Associated Genes
The 48th Annual Meeting of the American Society for Hema-
In a study reported by Gareth Morgan, Institute of Cancer
tology (ASH) was held December 9th through 12th, 2006,
Research, Royal Marsden Hospital, London, (abstract #246),
in Orlando, Florida. There were at least 10 simultaneous
the BOAC team sought to identify factors that might explain
sessions that included oral presentations of studies related
why patients treated with thalidomide have a higher rate of
to multiple myeloma, as well as about 200 myeloma-related
venous thromboembolic events (VTE), including deep vein
posters. In addition, the International Myeloma Foundation
thrombosis (DVT) and pulmonary emboli (PE), than patients
sponsored a Satellite Symposium on Innovative Strategies
treated with other anti-myeloma drugs. VTE can cause con-
for Treating Myeloma: Case Discussions, on December 8th.
siderable disability, even death. The study identified gene
There was also an Education Program on multiple myeloma
clusters associated with VTE by comparing patients treated
and a Scientific Committee Session on growth factor net-
with thalidomide experiencing VTE with those treated with
works in myeloma bone disease.
thalidomide who did not experience VTE. The BOAC SNP
chip mentioned above was used to identify genes associated
The landscape of multiple myeloma treatment continues to
with VTE risk, which included drug metabolism, inflamma-
evolve as research results accumulate from trials of conven-
tion, and DNA repair genes. Although the group looked hard
tional and new therapies and from studies on risk factors
for variations in genes associated with blood coagulation,
and side effects.
these were not associated with increased VTE risk. Future
work will focus on developing a model to predict VTE risk
Bank on a CureŽ (BOAC) Gene Bank
as well as treatment response for individual patients, so
Research Presented
that appropriate therapy can be given. The involvement of
Survival-Associated Genes
inflammation in the clotting process explains in part how
aspirin can be effective in preventing VTE, although it raises
Brian Van Ness, University of Minnesota, used the BOAC
the question of why thalidomide, as an immunomodulatory
single nucleotide polymorphism (SNP) chip to look for
drug (IMiD), is associated with increased risk of VTE. The
SNPs associated with event-free survival in patients in two
risk for thalidomide might be related to rapid breakdown
large Phase III clinical trials, EGOG E9486 and SWOG S9321
of myeloma cells releasing factors that promote clotting via
(abstract # 131). The BOAC SNP chip contains 3,404 SNPs
inflammation.
associated with gene functions that are expected to influ-
ence disease progression and response to therapy, including
Prevention, Identification, and Treatment of
networks involved in drug metabolism, bone microenvi-
Thromboembolic Events
ronment, immune responses, and DNA repair. DNA from
patients receiving a variety of regimens will be compared
As discussed above, thromboembolic events (TE) include
with DNA from healthy subjects. One goal of the SNP analy-
DVT and PE. Jeffrey Zonder, Wayne State University School
sis is to determine associations with survival, toxicities, bone
of Medicine. Some treatments for myeloma, which are
disease, and age at onset of myeloma. [Preliminary results
associated with an increased risk of TE, including VAD (vin-
show that there is a higher rate of variation between racial
cristine, Adriamycin, dexamethasone) due to the use of
groups, e.g., white versus black individuals, than within
catheters to deliver the drug combination, as well as to the
racial groups, e.g., two different groups of white individu-
effects of the drugs themselves, such as Adriamycin (doxo-
als. Therefore, the larger data set of white individuals will be
rubicin), pegylated liposomal doxorubicin (PLD or Doxil),
analyzed first while additional samples from other groups
high-dose dexamethasone, lenalidomide (Revlimid), and, as
are obtained.] In the above clinical trials, the top two net-
noted, thalidomide. Patients at higher risk for TE include
works of significant SNP association with survival were DNA
those with decreased mobility, compression of blood ves-
repair and immune response. Future analyses include look-
sels by tumors, or an inherited clotting disorder.
ing at the impact of genetic variation on bone disease.
3
Treatment-Associated Risks
DVT, there was a preference for warfarin or LMWH. Most felt
Although some studies have implicated the use of erythro-
that the use of thalidomide or lenalidomide as single agents,
poietin as a risk factor for TE, Maurizio Zangari, University
or use of VAD, MP, bortezomib, or bortezomib with dexa-
of Arkansas, presented a poster (abstract #3572) conclud-
methasone, did not require therapy to prevent DVT. After
ing that patients receiving total therapy II (TTII) who also
the occurrence of TE, most IMWG members felt that anti-
received erythropoietin did not have an increase in venous
myeloma therapy could be resumed following appropriate
thromboembolic events. [However, this may have related to
anticoagulant treatment.
the fact that the risk was already high with this multi-drug
IMWG members felt that TE prevention should be studied
regimen.] Nor did the use of bortezomib in combination
in clinical trials. There are clinical trials underway to further
with high-dose dexamethasone and erythropoietin result in
define prevention of TE, including the ECOG study compar-
increased risk of TE, as presented in a poster by Jean-Luc
ing aspirin to warfarin in patients treated with lenalidomide
Harousseau, Hopital Hotel-Dieu, Nantes, France (abstract
plus high-dose dexamethasone.
#3543). In the latter analysis, patients had relapsed
myeloma, and it is known that TE is more likely to occur in
Bone-related Events including
newly diagnosed myeloma.
Osteonecrosis of the Jaw
Some combinations of drugs, such as high-dose dexametha-
Gregory Mundy, Vanderbilt University, commented during
sone in combination with thalidomide or lenalidomide,
the Scientific Committee Session that "myeloma bone dis-
may increase the risk of TE, whereas others may not. In an
ease is unique. We are still guessing about the molecular
oral presentation, Paul Richardson, Dana-Farber Cancer
mechanisms for targeted therapy. As bone involvement is
Institute, noted that in a phase 1 trial of lenalidomide plus
altered, we may alter the natural history of the disease."
bortezomib (abstract #405) in 38 patients with relapsed
Improved imaging techniques have shown bone involve-
and/or refractory myeloma, the only TE, a DVT, occurred in
ment in myeloma to be more common than previously
a patient who was receiving lenalidomide without bortezo-
thought. The use of bisphosphonates has resulted in sig-
mib at the time, along with the anticoagulant low molecular-
nificant decreases in the incidence of skeletal-related events
weight heparin (LMWH).
and abnormally high levels of calcium in the blood. How-
ever, side effects such as osteonecrosis of the jaw (ONJ) are
TE Prophylaxis
appearing with the long-term use of bisphosphonates and
Prevention of TE is important, as is recognizing an event
the development of more active bisphosphonates.
if it occurs, followed by prompt treatment. Preventative
treatment may be determined by the individual physician;
In the education session, Bhoomi Mehrotra, Long Island Jew-
patient preference and health factors; hospital policy; or
ish Medical Center, pointed out that most of the studies on
reimbursement issues. In the multiple myeloma education
ONJ have been retrospective, and there have been no basic
session, various treatments to prevent TE were discussed,
science studies on how the condition develops, although
including full- dose aspirin, full-dose warfarin, or therapeu-
it has been known for over 150 years to be associated with
tic doses of LMWH. Aspirin was suggested for patients who
exposure to phosphorus (the "phospho" in bisphospho-
were adherent to therapy and were at low risk for TE. There
nates). The rate of ONJ in both retrospective and prospec-
was no agreement on how long to give anticoagulant ther-
tive studies in patients with myeloma varies from less than
apy once an event occurs.
2% to over 12%. The incidence increases with length of time
of exposure and the strength of the bisphosphonate. Risk
Brian Durie presented a poster (abstract #3571) summariz-
factors include dental disease and surgical procedures. ONJ
ing recommendations for therapy based on a survey of mem-
may be prevented by completing dental work prior to ther-
bers of the International Myeloma Working Group (IMWG).
apy and by avoiding invasive dental procedures while tak-
Of 67 IMWG members contacted, 23 responded to a sur-
ing bisphosphonates. There was no consensus on what to
vey about DVT. Concerns about DVT did not prevent them
do if dental surgery is necessary while a patient was taking
from using thalidomide or lenalidomide. Aspirin, either full
bisphosphonates, the length of time of return of function
dose (325 milligrams) or "baby" aspirin (81 milligrams) was
after stopping bisphosphonate therapy, or the duration of
preferred to prevent DVT when necessary. When doxorubi-
bisphosphonate therapy needed. Future trials may answer
cin or PLD were added to treatment, increasing the risk for
some of these questions.
4
New Treatment Options Change
6.5 months with dex alone. Complete response (CR) rates
Risk Profiles
were 7.7% for the combination compared with 2.6% for
dexamethasone; partial response (PR) rates were 55.3% and
Staging systems for myeloma are based on factors that are
43.4%, respectively, by EBMT criteria, which was statistically
related to survival duration. Patients with shorter survival
significant. By IMWG criteria, overall responses were also
may require different therapies. However, as new treatments,
significantly better for the combination. In patients receiv-
particularly novel and targeted therapies, are developed,
ing thalidomide plus dexamethasone, the rate of DVT was
factors previously associated with high-risk disease may no
18% compared with 4% in patients receiving dexamethasone
longer confer the same level of risk. Although chromosome
alone, and although routine prophylaxis was not used in the
13 deletion [del (13)] has been identified as a risk factor,
trial, Dr. Rajkumar believes it is justified in patients receiv-
bortezomib treatment overcomes this risk. Preliminary data
ing the combination. The combination was reasonably well
of the MM016 trial were presented in a poster (abstract
tolerated, and neuropathy although not severe, was com-
#3557) by Nizar Bahlis which suggest that lenalidomide,
mon and required monitoring and dose adjustment.
which was administered with dexamethasone, can also
overcome the poor prognosis conferred by del (13) as well
Dr. Rajkumar also presented the results of the ECOG E4A03
as by translocation (4;14). Only 42 patients were treated in
randomized Phase III trial of lenalidomide plus high-dose
this trial. Although differences in response rates and event-
dexamethasone compared with lenalidomide plus low-
free survival between groups of patients with and without
dose dexamethasone in 445 patients with newly diagnosed
these cytogenetic abnormalities are not statistically signifi-
myeloma (abstract #799). One aim was to see if efficacy
cant, longer follow-up is necessary to determine whether
could be maintained with increased safety by lowering the
lenalidomide plus dexamethasone will improve overall sur-
dexamethasone dose. Initially, DVT prophylaxis with aspi-
vival in patients with high-risk disease.
rin was recommended but not required. However, after the
first 4 months, due to an 18% rate of DVT in the high-dose
John Shaughnessy, University of Arkansas for Medical Sci-
dexamethasone arm, patients enrolled after that point in
ences, presented an analysis of gene expression in tumor
the trial were required to take aspirin, and the use of warfa-
cells from 532 patients with newly diagnosed myeloma
rin or LMWH was strongly recommended for patients in that
treated with total therapy (TT) 2 or 3 in order to iden-
arm of the trial. The Independent Data Monitoring Com-
tify those genes associated with an increase risk (abstract
mittee has released some of the early safety results, but the
#111). His group identified 70 genes, almost a third of
efficacy results of this trial are not yet available. It appears
which mapped to chromosome 1, particularly a region
that lowering the dose of dexamethasone in combination
known as 1q21. A high rate of tumor cell proliferation and
with lenalidomide results in decreased toxicity, and that all
resistance are associated with overexpression of genes in
patients should receive DVT prophylaxis. An expansion of
1q; additional loss of genes in another region of chromo-
this trial will compare patients randomized to lenalidomide
some 1, region 1p, also increases risk. In a poster (abstract
plus high-dose dexamethasone and either aspirin or warfa-
#3396), Johannes Drach, Medical University of Vienna, Aus-
rin for 4 months followed by aspirin.
tria, also showed that amplification of 1q21 as determined
by FISH (fluorescent in situ hybridization) was associated
Antonio Palumbo, Division of Hematology, University of
with poor outcome after treatment with bortezomib in 46
Torino, Italy, presented the results of a Phase I/II trial of R-
patients with relapsed and/or refractory myeloma.
MPlenalidomide (5 or 10 mg daily) plus melphalan (0.18
to 0.25 mg/kg days 1 through 4) and prednisone (2 mg/kg
Trial Results in Patients with
days 1 through 4) (R-MP) in 53 newly diagnosed patients
Newly-diagnosed Myeloma
(abstract #800). Patients received 100 mg aspirin per day
IMiD-Containing Regimens
and DVT occurred in 2 patients after discontinuation of aspi-
Vincent Rajkumar, Mayo Clinic, presented results of the
rin. Compared with historic data of treatment with thalido-
MM003 randomized, double-blind, placebo-controlled trial
mide plus melphalan and prednisone, treatment resulted in
of thalidomide plus dexamethasone in 470 patients with
earlier and increased response rates, particularly with the
newly diagnosed myeloma (abstract #795). Patients treated
higher doses of lenalidomide and/or MP, as well as longer
with thalidomide plus dexamethasone had a significantly
event-free survival. DLT (dose-limiting toxicity) included
longer time to disease progression, 22.4 months versus
neutropenia, neutropenic fever, and treatment delay. The
5
MM-015 trial will compare R-MP followed by lenalidomide
response was 67% in all 82 patients receiving VAD and 82%
maintenance vs. R-MP or MP with no maintenance.
in all 79 patients receiving bortezomib plus dexamethasone.
DCEP increased the overall response rate from 79% to 89%.
Bortezomib-Containing Regimens
The toxicity profiles were similar, with a higher rate of grade
Dr. Orlowski presented the results of CALGB Phase II trial
3-4 mucositis in patients treated with VAD, and a higher
10301 of combination bortezomib and the anthracycline
rate of neuropathy in patients treated with bortezomib plus
pegylated liposomal doxorubicin (PLD, or Doxil) in 63
dexamethasone. Accrual is nearly complete.
patients with newly diagnosed myeloma (abstract #797). As
a steroid-free regimen, this combination shows promising
Andrzej J. Jakubowiak presented the results of initial
activity and allows collection of stem cells for autologous
therapy with bortezomib, PLD, and dexamethasone in 36
transplant. The CR/near CR (nCR) rate was 28%, with an
patients (abstract #3093). Of 28 evaluable patients, the
overall response rate of 79%. Time to progression was 9.3
overall response was 89%, with 32% CR/nCR and 21% VGPR.
months, significantly longer than the 3.8 months seen on
The treatment did not interfere with the collection of stem
prior therapy. There were no incidents of DVT or PE and no
cells, and post autologous stem cell transplant, the overall
prophylaxis was used. Fatigue, sensory neuropathy, hand-
response rate increased to 96%. The treatment was well
foot syndrome, and syncope were the most common non-
tolerated.
hematologic AE.
Trial Results in Patients with Relapsed
Sundar Jagannath reported on the extended follow-up of a
and/or Refractory Myeloma
Phase II trial of bortezomib alone and in combination with
Bortezomib-Containing Regimens
dexamethasone in the frontline setting (abstract #796). Of
Dr. Orlowski also presented the results of a planned interim
49 patients enrolled, 13 received bortezomib alone, and
analysis of a Phase III trial (DOXIL-MMY-3001) of combina-
36 received the combination. The overall response rate
tion bortezomib and PLD in 646 patients with relapsed/
was 90%; 38% of patients had CR or VGPR. The addition
refractory myeloma (abstract #404). This combination
of dexamethasone improved response in 72% of patients.
resulted in significant increases in time to disease progres-
The one-year survival rate is 90%. The AE were predictable
sion (9.3 months) and duration of response (10.2 months)
and manageable, with the most common grade 2 or higher
compared with bortezomib alone (6.5 months and 7.0
AE being sensory neuropathy or neuropathic pain, fatigue,
months, respectively). There was no significant difference
constipation, nausea, and neutropenia. Two grade 4 events,
in overall survival or overall response, which was 43% for
neutropenia and thrombocytopenia, were observed. Com-
bortezomib alone (n=310) and 48% for the combination
bination bortezomib plus dexamethasone does not com-
(n=303). Subgroup analyses indicated that the combina-
promise hematopoietic stem cell collection or engraftment.
tion was more effective in patients regardless of age, sex,
A Phase III trial, IFM 2005-1, comparing bortezomib plus
beta-2-microglobulin levels, prior treatment, performance
dexamethasone with VAD as induction therapy prior to
status, prior stem cell transplant, prior anthracycline or
high-dose therapy with stem cell transplant is ongoing (see
IMiD use, or presence of cytogenetic abnormalities. Toxicity
next paragraph).
was predictable and manageable, and incidence of TE was
Jean-Luc Harousseau, Hopital Hotel-Dieu, Nantes, France,
low. A pharmacoeconomic analysis is being performed to
presented preliminary results of the IFM 2005-01 ran-
determine the cost of increasing the duration of response
domized, multicenter, Phase III trial of bortezomib plus
by 3 months for the drug combination.
dexamethasone versus VAD as induction therapy prior to
Ruben Niesvizky, Weill Cornell Medical College, presented
autologous stem cell transplantation in newly diagnosed
an updated analysis of response and time-to-event data from
patients with myeloma (abstract #56). Patients were ran-
the Phase II SUMMIT and Phase III APEX trials of bortezomib
domized to induction therapy with 4 cycles of either VAD
with and without dexamethasone in patients with relapsed/
or bortezomib plus dexamethasone. Half of each of these
refractory myeloma (abstract #3529). A better quality of
groups also received DCEP (dexamethasone, cyclophospha-
response was associated with better clinical benefit in terms
mide, etoposide, and cisplatinum) as consolidation therapy.
of extended treatment-free interval, time to alternative ther-
After MEL200 and transplant, patients who did not have
apy, and time to progression. The authors conclude that CR
CR/VGPR could receive a second transplant. Data are avail-
and nCR are surrogate markers for these clinical benefits in
able for the first 165 of 420 patients enrolled. The overall
6
patients with relapsed and refractory myeloma, and may be
whose disease shows a plateau of M-protein response
related to increased overall survival in some patients.
(abstract #3538). Plateau was defined as less than a 25%
change in M-protein over three measurements. Patients
Joseph Mikhael, Princess Margaret Hospital, Toronto, pre-
received 6 cycles of bortezomib and dexamethasone with
sented preliminary safety and efficacy results from an inter-
PLD added for suboptimal response. The combination of
national Phase IIIb study that allowed expanded access to
all three drugs appears to be well tolerated, with expected
bortezomib for patients with relapsed/refractory myeloma
toxicities associated with high-dose dexamethasone. Hand/
who had been treated with at least 2 prior lines of therapy
foot syndrome occurred in 2 patients, requiring discontinu-
and required therapy for relapsed or progressive disease
ation of PLD in one. The combination appeared to reduce
(abstract #3530). This study enrolled 624 patients who
tumor burden and warrants further study. In a related
received bortezomib per standard dose and schedule; dexa-
poster (abstract #2953), Jessica L. Stern reported that this
methasone was added if there was progressive disease (PD)
regimen, followed by bortezomib plus high-dose cyclophos-
after cycle 2 or stable disease (SD) after cycle 4. The safety
phamide and G-CSF, allowed collection of a high number of
profile was similar to that seen in previous Phase II and III
hematopoietic stem cells in a short time period.
trials. PR occurred in 54% of patients, median time to first
response was 42 days, and median time to best response
Donna E. Reece, Princess Margaret Hospital, presented the
was 63 days.
results of a Phase I/II trial of bortezomib plus oral cyclophos-
phamide and prednisone in patients with relapsed/refrac-
Jeffrey Lee Wolf, Alta Bates Comprehensive Cancer Cen-
tory myeloma (abstract #3536). There were 37 patients
ter, Berkeley, California, presented results of a retrospec-
enrolled in this open-label, dose-finding study. Bortezomib
tive review of bortezomib treatment and retreatment in
1.3 mg/m2 on days 1, 4, 8, and 11 or 1.5 mg/m2 on days 1,
22 patients who had received the drug in clinical trials
8, and 15 of a 28-day cycle can be added to full doses of
(abstract #3532). The 50% response rate seen upon retreat-
cyclophosphamide plus alternate-day prednisone. An over-
ment did not depend on the use of combination therapy.
all response rate of up to 84% was seen with the higher
Higher response rates (75%) upon retreatment were seen
bortezomib dose at weekly intervals with excellent tolerabil-
in patients who had a treatment-free interval of greater than
ity and no significant neurotoxicity. At the lower, more fre-
6 months, compared with a 25% response rate in patients
quent dose, thrombocytopenia occurred more frequently.
with a treatment-free interval of less than 6 months. Treat-
The incidence of shingles was 30%, therefore, prophylaxis
ment duration was 4.9 months.
is recommended. The authors conclude that progression-
free survival and overall survival compare favorably to other
Natalie S. Callander, University of Wisconsin, Madison, pre-
combination regimens.
sented the results of a Phase II trial of bortezomib combined
with weekly doxorubicin and dexamethasone in patients
IMiD-Containing Regimens
with relapsed or refractory myeloma (abstract #3545). Pro-
Stefan Knop, University Hospital, Wuerzburg, Germany,
phylactic acyclovir was required. The overall response in 12
presented preliminary results of a Phase I/II trial of lenalid-
evaluable patients was 83%, with a median time to response
omide, Adriamycin, and dexamethasone in patients with
of 6 weeks. One grade 4 AE, infection, was observed. Grade
relapsed myeloma. Patients were required to take 100 mg
3 AE included thrombocytopenia, anemia, infection, neu-
of aspirin daily to prevent DVT. In Phase I, 24 patients were
ropathy, DVT, and neutropenic fever. In myeloma cells iso-
enrolled; in Phase II, 34 additional patients were enrolled.
lated from patients, there were various levels of NF-kappa B
The trial established doses of 25 mg lenalidomide daily, 9
activity, and the activity was inhibited by treatment in only
mg/m2 Adriamycin days 1 through 4, and 40 mg dexametha-
one of the 5 patients whose cells were examined in vitro.
sone days 1 through 4 and 17 through 20 of a 21-day cycle.
Data were not sufficient to correlate bortezomib-induced
Patients also received pegfilgrastim. The overall response
NF-kappa B activity with clinical response in this study.
rate was 84% in 37 evaluable patients.
Brian A. Di Carlo, Weill Cornell Medical College, discussed
Bortezomib Plus IMiD Regimens
the results of a Phase II pilot study designed to determine
if the addition of liposomal doxorubicin (PLD) to therapy
Paul Richardson, Dana-Farber Cancer Institute, Boston,
with bortezomib and dexamethasone could improve the
Massachusetts, presented the final results of a dose esca-
response in 11 patients with previously treated myeloma
lation, Phase I trial of lenalidomide plus bortezomib
7
(abstract #405) in 38 patients with relapsed and/or refrac-
Mario Boccadoro, University of Turin, Italy; Dr. Harousseau;
tory myeloma. The combination was well tolerated and
Dr. Rajkumar; and Dr. Jesus San-Miguel, University of Sala-
resulted in a 58% response rate in 36 evaluable patients.
manca, Spain. Dr. Rajkumar expressed the opinion that VAD
The MTD (maximum tolerated dose) was defined at
was no longer a therapeutically valid option, and that tha-
15 mg/day lenalidomide plus 1.0 mg/m2 bortezomib on
lidomide plus dexamethasone, bortezomib, or lenalidomide
the standard 21-day cycle. Initially no anticoagulation was
plus dexamethasone offered better response rates. Dr. San
required, but the protocol was later amended to include
Miguel suggested that for newly diagnosed patients, includ-
325 mg/day aspirin. Although 15 patients also received dexa-
ing elderly patients, MP with bortezomib, thalidomide, or
methasone, the lenalidomide plus bortezomib combination
lenalidomide were acceptable options, and that the three
offers a "steroid sparing" approach, and Phase II trials are
novel therapies were challenging MP as a standard of care.
ongoing in patients with newly diagnosed myeloma as well
as in the relapsed and refractory setting.
Dr. Barlogie gave his opinion that the use of CR as a sur-
rogate marker for outcome is important only for the 20%
Dr. Palumbo also presented the results of a Phase I/II dose
or so of patients who have been identified as high risk by
escalation trial of bortezomib, melphalan, prednisone, and
gene expression analysis, whereas Dr. Boccadoro expressed
thalidomide (VMPT) in patients with relapsed myeloma
the opinion that CR is a marker for prolonged survival in
(abstract #407). DLT included anemia, thrombocytopenia,
all patient subgroups. Both Drs. Harousseau and Boccadoro
infections, vasculitis, fatigue, and peripheral neuropathy.
believe that tandem autologous transplants plus one of the
There was a 43% CR/VGPR rate in the 30 patients enrolled,
new agents are appropriate in younger patients, but that
compared with a 12% VGPR (0 CR) rate in historic controls
a single autologous transplant may be sufficient if a CR is
treated with MPT. The overall response rate was 100% in
achieved. For high-risk patients, Dr. Rajkumar believes that
patients receiving VMPT as their second line of therapy.
the routine use of autologous stem cell transplantation can-
Progression-free survival at 12 months was 61% and overall
not be justified and that bortezomib should be used up
survival was 84%. A trial of VMPT with bortezomib plus tha-
front for these patients. Dr. Barlogie recommends the use
lidomide maintenance compared with VMP and no mainte-
of TT3, which includes not only intense drug therapy and
nance is planned.
tandem transplants, but also a maintenance phase. How-
ever, the benefits of maintenance therapy as well as the best
Asher Alban Chanan-Khan presented the final results of a
maintenance regimen remain to be determined by further
Phase II trial of bortezomib in combination with PLD and
trials. Important issues include improvement of patient
thalidomide in patients with relapsed or refractory myeloma
quality of life and consideration of the cost and convenience
(abstract #3539). The 23 patients enrolled received 1.3 mg/
of therapy. The participants were asked at the end of the
m2 bortezomib on days 1, 4, 15, and 18 plus 20 mg/m2 PLD
symposium which of the new agents or combinations cur-
on days 1 and 15, plus 200 mg daily thalidomide in a 28-day
rently in clinical trial they thought would most likely enter
cycle. Low-dose coumadin was used for prevention of VTE.
clinical practice. The three most popular answers were bort-
The overall response rate in 18 evaluable patients was 83%
ezomib plus lenalidomide, new proteasome inhibitors, and
(22% CR), with a median progression-free survival of 10.9
bortezomib plus the HSP-90 inhibitor KOS-953, which is
months and a median overall survival of 15.7 months. Tox-
discussed below.
icities included grade 2 palmar-plantar erythrodysesthesia
(hand-foot syndrome) in 2 patients, and grade 3 cellulitis
Multiple Myeloma Education Session
in one patient. No VTE occurred. There were no significant
In the multiple myeloma education session, Robert Orlowski,
grade 3-4 toxicities, cardiotoxicities, or neuropathies.
University of North Carolina Chapel Hill School of Medicine,
The Standard of Care Continues to Evolve
concluded that melphalan plus prednisone (MP) should no
longer be considered the standard of care for all patients
IMF Satellite Symposium
who are not stem cell transplant candidates. Rather, MP
The case discussions presented at the Satellite Symposium,
plus thalidomide (MPT) should be considered because it
chaired by Dr. Durie, demonstrated that practitioners were
prolongs survival. Because MPT is associated with increased
able to change their treatment concepts of specific patients
toxicity, MP may be a better choice for patients with poorer
based on information provided by the panelists: Bart
organ function. Dr. Orlowski finds RMP [MP plus lenalido-
Barlogie, University of Arkansas for Medical Sciences;
mide (Revlimid)] and MPV [MP plus bortezomib (Velcade)]
9
attractive as well. A Phase III trial comparing MPT with RMP
may allow more effective treatment without an increase in
is planned and one comparing MPV with MP is ongoing.
side effects.
New Treatments on the Horizon
Interesting clinical trials and preclinical studies are summa-
As the natural history of myeloma is better understood,
rized in the two tables on pages 11 and 12.
new therapies can be designed to target specific pathways
Future Directions
involved in the disease. For example, it is known that inter-
action of myeloma cells with the bone marrow microen-
Patients with myeloma can look forward to continuing
vironment is of central importance. New agents are being
development of new treatment options, including novel
developed to block adherence of myeloma cells to stromal
and targeted therapies, along with improved management
cells in the bone marrow, which may prevent multiplication
of their disease through the use of specific combinations
of the myeloma cells, development of drug resistance, and
of existing drugs. Gene expression profiling will continue
occurrence of lytic bone lesions. As proteins essential for the
to identify subgroups of patients with higher-risk disease,
development and progression of myeloma on the surface of
while at the same time, new therapies may be expected to
myeloma and stromal cells are identified, specific antibodies
overcome some, if not all, of these risk factors. Increasingly,
and vaccines may be developed.
physicians are considering not only event-free and overall
survival, but patient quality of life and the cost and conve-
Targeted therapies, that is, drugs designed to attack specific
nience of treatment, as the therapeutic options for patients
growth factors and other molecules involved in the develop-
with multiple myeloma continue to increase not only in
ment and progression of myeloma, will continue to increase
number, but also in efficacy.
the arsenal of available treatments. Many of these therapies
will be used in combinations that exploit their activity
Lynne Lederman, PhD, is a medical writer based in Mamaroneck, New York
against different parts of the myeloma cell life-cycle. This
10
Clinical Trial Results
Treatment
Author
Study Design
Results and Conclusions
(abstract)
Bortezomib
Berenson
Phase I, dose-escalation trial, with The drug combination has been well-tolerated. Responses
in combination with (#3544)
a goal of increasing efficacy with-
have been seen in 3 patients and stable disease in 4 patients.
Samarium Sm 153
out increasing toxicity. 18 patients Follow-up is continuing and a Phase II study is planned.
lexidronam, a bone-
with relapsed and refractory
seeking radioactive
myeloma have been enrolled.
compound
ZIo-101,
Berenson
Phase I trial in patients with previ- ZIO-101 was well-tolerated, the MTD was determined, and
a new organic form
(#1966)
ously treated myeloma or acute
disease was stabilized for over 6 months in one patient with
of arsenic that can be
myelogenous leukemia.
rapidly progressing myeloma resistant to both arsenic triox-
given at much higher
ide and bortezomib. Phase II trials are on-going.
doses than arsenic
trioxide
SCIo-469,
Siegal
Phase II trial in patients with
There were no responses to SCIO-469 as a single agent.
an inhibitor of
(#3580)
relapsed refractory myeloma. Of
There were 12 (35%) PR and 4 (12%) minimal response
p38a mitogen-
62 patients enrolled in the trial,
(MR) among 34 patients receiving the combination
activated protein
28 patients received SCIO-469 as
(ORR = 47%). The 10 deaths that occurred were due to
kinase (MAPK), as
a single agent (60 mg P.O. tid) and progressive disease (n=7) or infection (n=3). Both treat-
monotherapy or in
34 patients received SCIO-469 in
ments were well tolerated; the most common AE for the
combination with
combination with bortezomib for
combination were fatigue, nausea, peripheral neuropathy
bortezomib
PD or SD (1.0 to 1.3 mg/m2 on the (grade 1 or 2), and thrombocytopenia. Further studies to
standard schedule).
refine the dose of SCIO-469 and to investigate other drug
combinations and patient subpopulations were proposed.
Perifosine
Richardson Phase II trial in patients with
Of 55 patients enrolled, 33 were evaluable for response,
(KrX-0401),
(#3582)
relapsed or relapsed/refractory
and best response, SD, was seen in 13 patients for a median
an oral, novel,
myeloma. Patients received 150
duration of 12 weeks. Of 23 evaluable patients who received
synthetic alkylphos-
mg perifosine daily. Dose reduc-
dexamethasone, there were 2 (9%) PR, 4 (17%) MR, and
pholipid that inhibits
tion to 100 mg was required in
11 (48%) SD. The most common AE were nausea, vomiting,
Akt, alone and with
12 patients, and to 50 mg in 4
diarrhea, fatigue, and increased creatinine. Further stud-
dexamethasone
patients.
ies are expected to evaluate other dosing schedules and
combinations with other agents, including bortezomib and
lenalidomide.
Histone deacetylase (HdaC) Inhibitors
PXd-101 alone and Sullivan
Phase II trial of PXD-101 with
PXD-101 was well-tolerated. There were no objective
in combination with (#3583)
dexamethasone (if PD) in 25
responses to the single agent, with SD in about 40% of
dexamethasone
patients with advanced myeloma;
patients. Of 8 patients who received the combination, there
900 to 1000 mg/m2 as a 30 minute were 2 PR, 2 MR, and 4 SD. Trials of PXD-101 in combina-
I.V. infusion on days 1 through 5
tion with bortezomib are planned.
of a 21-day cycle
11
Clinical Trial Results (continued)
Treatment
Author
Study Design
Results and Conclusions
(abstract)
Heat Shock Protein (HSP) Inhibitors
tanespimycin
Richardson Phase I trial in 30 heavily
Toxicities were expected and manageable. The overall
(17-aaG; KoS-953), (#406)
pretreated patients with
response rate was 57% in 23 evaluable patients, including
a HSP-90 inhibitor
relapsed/refractory myeloma.
patients who were pretreated with or refractory to bortezo-
in combination with
mib. No MTD was defined and dose escalation is continu-
bortezomib
ing. Sufficient responses were seen to justify a Phase III trial
in patients at first relapse and with multiple prior therapies.
IPI-504,
Siegel
Update of Phase I clinical trial in
No DLT or drug-related grade 3-4 AE observed. AE were
a water-soluble
(#3579)
18 patients with relapsed/refrac-
mild and included mild infusion site reactions, musculo-
HSP-90 inhibitor
tory myeloma. Escalating doses up skeletal pain, and GI symptoms. Peripheral neuropathy,
to 400 mg/m2 intravenously using myelosuppression, DVT, or clinically significant cardiac
the same schedule that is used for toxicity were not observed. The MTD was not identified. Of
bortezomib.
17 evaluable patients, best response was SD in 3 patients.
Further studies are planned.
Stem Cell Mobilizer aMd3100
aMd3100
Flomenberg AMD3100 without G-CSF
Of 9 patients with myeloma enrolled, all patients mobilized
(#3381)
to increase the number of
sufficient cells, in 3 days in 1 patient and 4 days in 8
hematopoietic stem cells
patients. All received transplants. AMD3100 was generally
mobilized
well tolerated and engraftment occurred in about 10 days.
More cells are mobilized with G-CSF, but the population is
more primitive. Further evaluation was suggested.
aMd3100 with
Douglas
AMD3100 with G-CSF
There were 11 patients with myeloma in the study.
G-CSF
(33383)
AMD3100 was generally safe and well tolerated and
increased stem cell mobilization in patients with myeloma.
Preclinical Results
Treatment
Author (abstract) Results and Conclusions
Histone deacetylase (HdaC) Inhibitors
PXd-101 in combination
Feng (#507)
The combination resulted in significantly greater inhibition of myeloma cell
with bortezomib
proliferation and viability, induced a higher degree of apoptosis, caspase
cleavage, and apoptosis-related gene expression, and more strongly inhibited
osteoclast formation in culture than either agent alone. The combination also
synergistically suppressed the growth of human myeloma xenografts compared
with either agent alone.
Proteasome Inhibitors other than Bortezomib
Pr-171 and structurally
Kirk (#3581)
PR-171 analogs are bioavailable after oral dosing and induce proteasome inhibi-
related, orally bioavailable
tion in mice, in which multiple doses were tolerated. Anti-myeloma activity was
analogs
seen in mice bearing tumors from myeloma cell lines and human xenografts.
Signal transduction Modulators
Perifosine plus traIl
David (#3446)
Synergistic induction of apoptosis in myeloma cell lines. The authors conclude
(tnF-related apoptosis-
the combination should be investigated in primary myeloma cells, and has
inducing ligand)
clinical potential.
12
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