InternatIonal MyeloMa FoundatIon
ASH 2006
Highlights
for Patients
with Myeloma
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 Highlights for Patients with Myeloma
by Lynne Lederman, PhD
A Changing Landscape
In a study reported by Gareth Morgan, Institute of Can-
cer Research, Royal Marsden Hospital, London, (abstract
The 48th Annual Meeting of the American Society for Hema-
#246), the BOAC team sought to identify factors that
tology (ASH) was held December 9th through 12th, 2006
might explain why patients treated with thalidomide have
in Orlando, Florida. There were at least 10 simultaneous
a higher rate of venous thromboembolic events (VTE, or
sessions that included oral presentations of studies related
blood clots) than patients treated with other anti-myeloma
to multiple myeloma, as well as about 200 myeloma-related
drugs. VTE include deep vein thrombosis (DVT), blood
posters. In addition, the International Myeloma Foundation
clots that develop most often in veins in the pelvic region
sponsored a Satellite Symposium on Innovative Strategies
and legs, and pulmonary emboli (PE), clots in the blood
for Treating Myeloma: Case Discussions, on December 8.
vessels of the lungs. VTE can cause considerable disability,
There was also an Education Program on multiple myeloma
even death. The study identified gene clusters associated
and a Scientific Committee Session on growth factor net-
with VTE by comparing patients treated with thalidomide
works in myeloma bone disease.
experiencing VTE with those treated with thalidomide who
The landscape of multiple myeloma treatment continues to
did not experience VTE. The BOAC SNP chip mentioned
evolve as research results accumulate from trials of conven-
above was used to identify genes associated with VTE risk,
tional and new therapies and from studies on risk factors
which included drug metabolism, inflammation, and DNA
and side effects.
repair genes. Although the group looked hard for variations
in genes associated with blood coagulation, these were not
Bank on a CureŽ (BOAC) Gene Bank
associated with increased VTE risk. Future work will focus
Research Presented
on developing a model to predict VTE risk as well as treat-
Brian Van Ness, University of Minnesota, used the BOAC
ment response for individual patients, so that appropriate
single nucleotide polymorphism (SNP) chip to look for
therapy can be given. The involvement of inflammation in
SNPs associated with event-free survival in patients in two
the clotting process explains in part how aspirin can be
large Phase III clinical trials, EGOG E9486 and SWOG
effective in preventing VTE, although it raises the question
S9321 (abstract # 131). The BOAC SNP chip contains 3,404
of why thalidomide, as an immunomodulatory drug (IMiD)
SNPs associated with gene functions that are expected to
is associated with increased risk of VTE. The risk for thalido-
influence disease progression and response to therapy,
mide might be related to rapid breakdown of myeloma cells
including networks involved in drug metabolism, bone
releasing factors that promote clotting via inflammation.
microenvironment, immune responses, and DNA repair.
Prevention, Identification, and Treatment
DNA from patients receiving a variety of regimens will be
of Clotting Events
compared with DNA from healthy subjects. One goal of
the SNP analysis is to determine associations with survival,
As discussed above, thromboembolic events (TE) include
toxicities, bone disease, and age at onset of myeloma. Pre-
DVT and PE. Jeffrey Zonder, Wayne State University School
liminary results show that there is a higher rate of variation
of Medicine, described the baseline risk of TE as hard to
between racial groups, e.g., white versus black individuals,
quantify. Some treatments for myeloma are associated with
than within racial groups, e.g., two different groups of white
an increased risk of TE, including VAD (vincristine, Adriamy-
individuals. Therefore, the larger data set of white individu-
cin, dexamethasone) due to the use of catheters to deliver
als will be analyzed first while additional samples from other
the drug combination, as well as to the effects of the drugs
groups are obtained. In the above clinical trials, the top two
themselves, such as Adriamycin (doxorubicin), pegylated
networks of significant SNP association with survival were
liposomal doxorubicin (PLD or Doxil), high-dose dexameth-
DNA repair and immune response. Future analyses include
asone, lenalidomide (Revlimid), and, as noted, thalidomide.
looking at the impact of genetic variation on bone disease.
Patients at higher risk for TE include those with decreased
3
mobility, compression of blood vessels by tumors, or an
that the use of thalidomide or lenalidomide as single agents,
inherited clotting disorder. Although some studies have
or use of VAD, MP, bortezomib, or bortezomib with dexa-
implicated the use of erythropoietin as a risk factor for
methasone, did not require therapy to prevent DVT. After
TE, Maurizio Zangari, University of Arkansas, presented a
the occurrence of TE, most IMWG members felt that anti-
poster (abstract #3572) concluding that patients receiving
myeloma therapy could be resumed following appropriate
total therapy II (TTII) who also received erythropoietin did
anticoagulant treatment.
not have an increase in venous thromboembolic events.
Nor did the use of bortezomib in combination with high-
IMWG members felt that TE prevention should be studied
dose dexamethasone and erythropoietin result in increased
in clinical trials. There are clinical trials underway to further
risk of TE, as presented in a poster by Jean-Luc Harous-
define prevention of TE, including the ECOG study compar-
seau, Hopital Hotel-Dieu, Nantes, France (abstract #3543).
ing aspirin to warfarin in patients treated with lenalidomide
In the latter analysis, patients had relapsed myeloma,
plus high-dose dexamethasone.
and it is known that TE is more likely to occur in newly
Bone-related Events Including
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
ment in myeloma to be more common than previously
in a patient who was receiving lenalidomide alone at the
thought. The use of bisphosphonates has resulted in sig-
time, along with the anticoagulant low molecular weight
nificant decreases in the incidence of skeletal-related events
heparin (LMWH).
and abnormally high levels of calcium in the blood. How-
ever, side effects such as osteonecrosis of the jaw (ONJ) are
Prevention of TE is important, as is recognizing an event
appearing with the long-term use of bisphosphonates and
if it occurs, followed by prompt treatment. Preventative
the development of more active bisphosphonates.
treatment may be determined by the individual physician;
patient preference and health factors; hospital policy; or
In the education session, Bhoomi Mehrotra, Long Island Jew-
reimbursement issues. In the multiple myeloma education
ish Medical Center, pointed out that most of the studies on
session, various treatments to prevent TE were discussed,
ONJ have been retrospective, and there have been no basic
including full- dose aspirin, full-dose warfarin, or therapeu-
science studies on how the condition develops, although
tic doses of LMWH. Aspirin was suggested for patients who
it has been known for over 150 years to be associated with
were adherent to therapy and were at low risk for TE. There
exposure to phosphorus (the "phospho" in bisphospho-
was no agreement on how long to give anticoagulant ther-
nates). The rate of ONJ in both retrospective and prospec-
apy once an event occurs.
tive studies in patients with myeloma varies from less than
2% to over 12%. The incidence increases with length of time
Brian Durie presented a poster (abstract #3571) summariz-
of exposure and the strength of the bisphosphonate. Risk
ing recommendations for therapy based on a survey of mem-
factors include dental disease and surgical procedures. ONJ
bers of the International Myeloma Working Group (IMWG).
may be prevented by completing dental work prior to ther-
Of 67 IMWG members contacted, 23 responded to a sur-
apy and by avoiding invasive dental procedures while taking
vey about DVT. Concerns about DVT did not prevent them
bisphosphonates. There was no consensus on what to do
from using thalidomide or lenalidomide. Aspirin, either full
if dental surgery was necessary while a patient was taking
dose (325 milligrams) or "baby" aspirin (81 milligrams) was
bisphosphonates, the length of time of return of function
preferred to prevent DVT when necessary. When doxorubi-
after stopping bisphosphonate therapy, or the duration of
cin or PLD were added to treatment, increasing the risk for
bisphosphonate therapy needed. Future trials may answer
DVT, there was a preference for warfarin or LMWH. Most felt
some of these questions.
4
New Treatment Options Change
rates, including complete response (CR) and very good
Risk Profiles
partial response (VGPR) rates. In patients receiving thalido-
mide plus dexamethasone, the rate of DVT was 18% com-
Staging systems for myeloma are based on factors that are
pared with 4% in patients receiving dexamethasone alone,
related to survival duration. Patients with shorter survival
and although routine prophylaxis was not used in the trial,
may require different therapies. However, as new treatments,
Dr. Rajkumar believes it is justified in patients receiving
particularly novel and targeted therapies, are developed,
the combination.
factors previously associated with high-risk disease may no
longer confer the same level of risk. Although chromosome
Dr. Rajkumar also presented the results of the ECOG E4A03
13 deletion [del (13)] has been identified as a risk factor,
randomized Phase III trial of lenalidomide plus high-dose
bortezomib treatment overcomes this risk. Preliminary
dexamethasone compared with lenalidomide plus low-
data of the MM016 trial was presented in a poster (abstract
dose dexamethasone in 445 patients with newly diagnosed
#3557) by Nizar Bahlis, that suggests that lenalidomide,
myeloma (abstract #799). One aim was to see if efficacy
which was administered with dexamethasone, can also
could be maintained with increased safety by lowering the
overcome the poor prognosis conferred by del (13) as well
dexamethasone dose. Initially, DVT prophylaxis with aspi-
as by translocation (4;14). Only 42 patients were treated in
rin was recommended but not required. However, after the
this trial. Although differences in response rates and event-
first 4 months, due to an 18% rate of DVT in the high-dose
free survival between groups of patients with and without
dexamethasone arm, patients enrolled after that point in
these cytogenetic abnormalities are not statistically signifi-
the trial were required to take aspirin, and the use of warfa-
cant, longer follow-up is necessary to determine whether
rin or LMWH was strongly recommended for patients in that
lenalidomide plus dexamethasone will improve overall sur-
arm of the trial. The Independent Data Monitoring Com-
vival in patients with high-risk disease.
mittee has released some of the early safety results, but the
efficacy results of this trial are not yet available. It appears
John Shaughnessy, University of Arkansas for Medical Sci-
that lowering the dose of dexamethasone in combination
ences, gave a talk (abstract #111) on analyzing gene expres-
with lenalidomide results in decreased toxicity, and that all
sion in tumor cells from 532 patients with newly diagnosed
patients should receive DVT prophylaxis. An expansion of
myeloma treated with total therapy (TT) 2 or 3 in order
this trial will compare patients randomized to lenalidomide
to identify those genes associated with an increase risk. His
plus high-dose dexamethasone and either aspirin or warfa-
group identified 70 genes, almost a third of which mapped
rin for 4 months followed by aspirin.
to chromosome 1, particularly a region known as 1q21. A
high rate of tumor cell proliferation and resistance are asso-
Dr. Orlowski presented the results of CALGB Phase II trial
ciated with overexpression of genes in 1q, and additional
10301 of combination bortezomib and the anthracycline
loss of genes in another region of chromosome 1, region
pegylated liposomal doxorubicin (PLD, or Doxil) in 63
1p, increases risk. In a poster (abstract #3396), J. Drach,
patients with newly diagnosed myeloma (abstract # 797).
Medical University of Vienna, Austria, also showed that
As a steroid-free regimen, this combination shows promis-
amplification of 1q21, determined by FISH (fluorescent in
ing activity and allows collection of stem cells for autolo-
situ hybridization) was associated with poor outcome after
gous transplant. There were no incidents of DVT or PE and
treatment with bortezomib in 46 patients with relapsed and/
no prophylaxis was used.
or refractory myeloma.
Antonio Palumbo, Division of Hematology, University of
Trial Results in Patients with Newly
Torino, Italy, presented the results of a Phase I/II trial of
Diagnosed Myeloma
lenalidomide plus melphalan and prednisone (R-MP) in
Vincent Rajkumar, Mayo Clinic, presented results of the
53 newly diagnosed patients (abstract #407). Compared
MM003 randomized, double-blind, placebo-controlled trial
with historic data of treatment with thalidomide plus mel-
of thalidomide plus dexamethasone in 470 patients with
phalan and prednisone, R-MP treatment resulted in ear-
newly diagnosed myeloma (abstract #795). Patients treated
lier and increased response rates, particularly with the
with thalidomide plus dexamethasone had a significantly
higher doses of lenalidomide and/or MP, as well as longer
longer time to disease progression and higher response
event-free survival. The MM-015 trial will compare R-MP
5
followed by lenalidomide maintenance vs. R-MP or MP with
Dr. Barlogie gave his opinion that the use of CR as a sur-
no maintenance.
rogate marker for outcome is important only for the 20%
or so of patients who have been identified as high risk by
Trial Results in Patients with Relapsed
gene expression analysis, whereas Dr. Boccadoro expressed
and/or Refractory Myeloma
the opinion that CR is a marker for prolonged survival in
Dr. Orlowski also presented the results of a planned interim
all patient subgroups. Both Drs. Harousseau and Boccadoro
analysis of a Phase III trial (DOXIL-MMY-3001) of combina-
believe that tandem autologous transplants plus one of the
tion bortezomib and PLD in 646 patients with relapsed/
new agents are appropriate in younger patients, but that
refractory myeloma. This combination resulted in signifi-
a single autologous transplant may be sufficient if a CR is
cant increases in time to disease progression and duration
achieved. For high-risk patients, Dr. Rajkumar believes that
of response compared with bortezomib alone. Subgroup
the routine use of autologous stem cell transplantation can-
analyses indicated that the combination was more effec-
not be justified and that bortezomib should be used up
tive in patients regardless of age, sex, beta-2-microglobulin
front for these patients. Dr. Barlogie recommends the use
levels, prior treatment, performance status, prior stem cell
of TT3, which includes not only intense drug therapy and
transplant, prior anthracycline or IMiD use, or presence
tandem transplants, but also a maintenance phase. How-
of cytogenetic abnormalities. Toxicity was predictable and
ever, the benefits of maintenance therapy as well as the best
manageable, and incidence of TE was low. A pharmacoeco-
maintenance regimen remain to be determined by further
nomic analysis is being performed to determine the cost
trials. Important issues include improvement of patient
of increasing the duration of response by 3 months for the
quality of life and consideration of the cost and convenience
drug combination.
of therapy. The participants were asked at the end of the
symposium which of the new agents or combinations cur-
Paul Richardson, Dana-Farber Cancer Institute, presented
rently in clinical trial they thought would most likely enter
the final results of a Phase I trial of lenalidomide plus
clinical practice. The three most popular answers were bort-
bortezomib (abstract #405) in 38 patients with relapsed
ezomib plus lenalidomide, new proteasome inhibitors, and
and/or refractory myeloma. The combination was well tol-
bortezomib plus the HSP-90 inhibitor KOS-953, which is
erated and resulted in a 58% response rate. Although 15
discussed below.
patients also received dexamethasone, the lenalidomide
plus bortezomib combination offers a "steroid sparing"
In the multiple myeloma education session, Robert Orlowski,
approach, and Phase II trials are ongoing in patients with
University of North Carolina Chapel Hill School of Medicine,
newly diagnosed myeloma as well as in the relapsed and
concluded that melphalan plus prednisone (MP) should no
refractory setting.
longer be considered the standard of care for all patients
who are not stem cell transplant candidates. Rather, MP
The Standard of Care Continues to Evolve
plus thalidomide (MPT) should be considered because it
The case discussions presented at the Satellite Symposium,
prolongs survival. Because MPT is associated with increased
chaired by Dr. Durie, demonstrated that practitioners were
toxicity, MP may be a better choice for patients with poorer
able to change their treatment concepts of specific patients
organ function. Orlowski finds RMP [MP plus lenalidomide
based on information provided by the panelists: Bart Bar-
(Revlimid)] and MPV [MP plus bortezomib (Velcade)] attrac-
logie, University of Arkansas for Medical Sciences; Mario
tive as well. A Phase III trial comparing MPT with RMP is
Boccadoro, University of Turin, Italy; Dr. Harousseau; Dr.
planned and one comparing MPV with MP is ongoing.
Rajkumar; and Dr. Jesus San-Miguel, University of Sala-
New Treatments on the Horizon
manca, Spain. Dr. Rajkumar expressed the opinion that VAD
was no longer a therapeutically valid option, and that tha-
As the natural history of myeloma is better understood,
lidomide plus dexamethasone, bortezomib, or lenalidomide
new therapies can be designed to target specific pathways
plus dexamethasone offered better response rates. Dr. San
involved in the disease. For example, it is known that inter-
Miguel suggested that for newly diagnosed patients, includ-
action of myeloma cells with the bone marrow microen-
ing elderly patients, MP with bortezomib, thalidomide, or
vironment is of central importance. New agents are being
lenalidomide were acceptable options, and that the three
developed to block adherence of myeloma cells to stromal
novel therapies were challenging MP as a standard of care.
cells in the bone marrow, which may prevent multiplication
6
of the myeloma cells, development of drug resistance, and
to identify subgroups of patients with higher risk disease,
occurrence of lytic bone lesions. As proteins essential for the
while at the same time, new therapies may be expected to
development and progression of myeloma on the surface of
overcome some, if not all, of these risk factors. Increasingly,
myeloma and stromal cells are identified, specific antibodies
physicians are considering not only event-free and overall
and vaccines may be developed.
survival, but patient quality of life and the cost and conve-
nience of treatment, as the therapeutic options for patients
Targeted therapies, that is, drugs designed to attack specific
with multiple myeloma continue to increase not only in
growth factors and other molecules involved in the develop-
number, but also in efficacy.
ment and progression of myeloma, will continue to increase
the arsenal of available treatments. Many of these therapies
Lynne Lederman, PhD, is a medical writer based in Mamaroneck, New York
will be used in combinations that exploit their activity
against different parts of the myeloma cell life-cycle. This
may allow more effective treatment without an increase in
side effects.
James Berenson, Institute for Myeloma and Bone Can-
cer Research and Oncotherapeutics, presented a poster
(abstract 3544) on a Phase I trial of bortezomib in combi-
nation with Samarium Sm 153 lexidronam, a bone-seeking
radioactive compound, with a goal of increasing efficacy
without increasing toxicity. In this dose-escalation trial, 18
patients with relapsed and refractory myeloma have been
enrolled. The drug combination has been well tolerated,
and responses have been seen in 3 patients and stable dis-
ease in 4 patients. Follow-up is continuing and a Phase II
study is planned.
Dr. Richardson presented results of a Phase I trial of Tane-
spimycin (KOS-953), a heat shock protein (HSP)-90 inhibi-
tor in combination with bortezomib in 30 heavily pretreated
patients with relapsed/refractory myeloma (abstract #406).
Toxicities were expected and manageable and sufficient
responses were seen to justify a Phase III trial in patients at
first relapse and with multiple prior therapies.
A histone deacetylase inhibitor, PXD-101, is in trial alone
and in combination with dexamethasone (Daniel Sullivan,
Lee Moffitt Cancer Center, abstract #3583) or with bortezo-
mib (Rentian Feng, University of Pittsburgh, abstract #507).
Results were encouraging enough to justify further studies
in combination with bortezomib.
Future Directions
Patients with myeloma can look forward to continuing
development of new treatment options, including novel
and targeted therapies, along with improved management
of their disease through the use of specific combinations
of existing drugs. Gene expression profiling will continue
7
International Myeloma Foundation
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Telephone:
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