InternatIonal MyeloMa FoundatIon
ASCO 2011
Highlights
for Patients
ASCO 2011 Annual Meeting Highlights for Patients
The 2011 Annual Meeting of ASCO (American Society of Clinical Oncology)
was held in Chicago, Il inois, USA, from June 3 to 7, 2011.
Summary
risk of progression. The risk of progression of SMM (Mayo
Clinic data) is 10% per year over the first 5 years, 3% per year
· Strategies are being developed to define risk factors in the
over the next 5 years, then 1% per year over the fol owing
progression of smoldering multiple myeloma (SMM) to
10 years. For comparison, the rate of progression of MGUS
myeloma, and to develop therapies to slow or prevent this
(monoclonal gammopathy of undetermined significance)
progression.
is 1% per year. This suggests that there are subpopulations
· Administration of zoledronic acid shows anti-myeloma activ-
within SMM, including those with either slower or more rap-
ity in addition to reduction of skeletal related events (SRE)
idly progressing disease. Therefore, it would be useful to be
such as fractures; however, additional agents active against
able to stratify the risk of progression. Two risk stratification
myeloma bone disease are needed, and some are in clinical
studies have been performed. A Mayo Clinic study of 273
trials.
patients identified the fol owing risk factors:
· Most cases of lenalidomide-related second primary malig-
· BMPC greater than 10%.
nancies (SPM) appear to be associated with melphalan-
based therapies. The low incidence of SPM must be
· M-protein greater than 3 g/dL.
considered within the context of the greater clinical benefit
· Free light chain (FLC) ratio less than 0.125 or greater than 8
of treatment vs. no treatment of myeloma. Longer fol ow-up
(that is, abnormal).
is needed to better identify the risk factors for SPM.
The overal risk of progression at 5 years was 25% vs. 51% vs.
· Promising agents in development for myeloma include the
76% if 1, 2, or 3 of these risk factors were present.
proteasome inhibitor carfilzomib and monoclonal antibod-
ies, including elotuzumab.
A PETHEMA (Spanish) study of 89 patients identified two risk
factors:
Diagnosis, Prognosis, Risk Assessment
· 95% or more abnormal vs. normal plasma cel s based on the
Smoldering multiple myeloma (SMM)
presence of certain proteins on the surface of cel s
Ivan Borel o, Johns Hopkins University School of Medi-
· Immunoparesis
(suppression
of
non-involved
cine, Baltimore, Maryland, USA, discussed Smoldering and
immunoglobulins)
asymptomatic Myeloma as part of the education session
entitled Clinical Problems in the Management of Mul-
The risk of progression at 5 years is 8%, 42%, or 82% with
tiple Myeloma (eQuestions session). Smoldering multiple
the presence of 0, 1, or 2 of these factors. It is not known if
myeloma (SMM) is defined by a serum monoclonal protein
the progression from MGUS to SMM to myeloma to plasma
(M-protein) of at least 3 g/dL and/or at least 10% clonal bone
cel leukemia (PCL) is linear. However, myeloma has been
marrow plasma cel s (BMPC) in the absence of CRAB crite-
shown to have been preceded by MGUS up to 8 years before
ria (end-organ damage such as hyperCalcemia, renal insuf-
diagnosis of myeloma in a retrospective study. The FLC ratio
ficiency, anemia, or Bone lesions) attributable to the plasma
becomes abnormal closer to the diagnosis of myeloma. There
cel disorder. There are about 5000 new cases of SMM per year
is also a linear increase of M-protein spike approaching the
in the US. The International Myeloma Working Group (IMWG)
time to diagnosis of myeloma.
recommends a baseline bone marrow biopsy and skeletal
SMM trial results and ongoing trials. Previously published
survey, plus fol ow-up laboratory tests (in 2 to 3 months to
trial results have not shown a survival benefit of early vs. late
determine rate of progression, then if stable every 4 to 6
melphalan plus prednisone or of zoledronic acid in SMM.
months for a year, then if stable every 6 to 12 months). Treat-
ment of SMM is not recommended outside of a clinical trial.
· Preliminary results of an ongoing trial of lenalidomide plus
Treatment in the context of clinical trials to delay or prevent
dexamethasone fol owed by lenalidomide maintenance
progression to symptomatic myeloma may be considered for
suggest treatment slows progression and may provide a sur-
selected patients.
vival advantage.
3
· A SWOG (Southwest Oncology Group) study is looking at
· GEP-based risk stratification correlates moderately
clinical staging using MRI (magnetic resonance imaging)
with FISH.
and PET (positron emission tomography), genetics, genom-
ics, and immune response from asymptomatic myeloma
Newly Diagnosed Myeloma
until disease progression requiring therapy.
Treatment without Transplant
Conclusions. Standard treatment for SMM is observation until
Survival outcomes in elderly patients with plasma cell
disease progression. Patients with SMM should be considered
myeloma: the three-decade eastern Cooperative oncol-
for treatment in the context of clinical trials. SMM appears to
og y Group (eCoG) experience (Abstract 8021) was pre-
have some subpopulations with a higher risk that could be
sented by Erica Campagnaro, University Hospitals Case
identified. Early treatment may reduce the risk of progression
Medical Center, Cleveland, Ohio, USA, in a poster session.
but could be associated with an increased risk of side effects
This study was a retrospective review of data from 4 phase
and disease progression.
III ECOG trials in newly diagnosed myeloma (total of 1528
patients) studying treatments other than autologous stem cel
Risk factor assessment and stratification
transplant (ASCT). The analysis divided patients into three
High-risk Myeloma was presented by Rafael Fonseca, Mayo
groups based on the dates they entered the study (1988 to
Clinic, Scottsdale, Arizona, USA, as part of the Education
1993; 1994 to 2000; and 2001 to 2006). Only patients in
Session: Identification and treatment of the "High risk
the most recent group received novel agents (thalidomide
Patient" with non-Hodgkin lymphoma and Myeloma.
plus dexamethasone or lenalidomide plus high- or low-dose
Dr. Fonseca reviewed publications on risk stratification and
dexamethasone), and these patients had a significantly bet-
treatments associated with differential survival in various risk
ter 5-year overal survival (OS) than patients in either earlier
groups. He pointed out that although many publications sug-
group. This difference was greater for patients who were less
gest identifying higher- risk populations as candidates for
than age 65 years. Progression-free survival (PFS) was longer
more intensive therapies with the goal of reaching a complete
for patients younger than age 65 years who were treated with
response (CR), this is not necessarily being done in practice,
novel agents in the most recent group, although fol ow-up
and there are no data to support this approach yet. One strat-
time is shorter. PFS for patients older than age 65 years was
egy being tested is the University of Arkansas Total Therapy
similar in al three groups, that is, novel agents did not appear
(TT) modifications based on gene expression profile (GEP)
to contribute to PFS in the older patients. Patients older than
signature. However, previously defined risks may be overcome
age 65 years were more likely to have worse performance
by newer therapies, e.g., the translocation t(4;14) may be over-
status and higher creatinine and beta-2-microglobulin (B2M)
come at least in part by use of bortezomib. There may be risk
than younger patients, but there was no difference between
factors that have different significances at different stages of
age groups in other prognostic factors such as Durie-Salmon
disease along the spectrum from MGUS to SMM to newly diag-
stage, C-reactive protein, or hemoglobin.
nosed myeloma to first relapse to second relapse to refractory
disease to plasma cel leukemia. The recent initial sequenc-
This poster was discussed by Suzanne Lentzsch, University of
ing of myeloma genomes has shown that a large number of
Pittsburgh, Pittsburgh, Pennsylvania, USA. She noted that this is
mutations are not present in al patients. This, Dr. Fonseca
an important analysis of only large, randomized trials, and asks
says, at the end of the day could mean that myeloma is an
an important question about the outcome of older patients.
"n of one," that is, each individual patient may be unique in
Weaknesses include the lack of analysis of the cause of death
risk and response to therapy. Analyses of subclones from indi-
(whether due to myeloma or other causes), which would be
vidual patients by comparative genomic hybridization (CGH)
helpful in determining whether the marginal increase in OS
show changes over time, with new clones appearing and the
in older patients is due to novel agents or better medical care,
proportion of clones changing with different treatments dur-
e.g., better cardiac care. It is not clear if the difference is due
ing the course of disease. The chal enge is to address al the
to reduced dosages or less transplant for older patients or
clones to cure the disease.
unfavorable cytogenetics. It also isn't known if increased OS
might be attributed to salvage therapy with bortezomib, and
Other key points are:
if bortezomib should be given upfront to older patients with
adverse cytogenetics. Unresolved issues include:
· FISH (fluorescence in situ hybridization) is currently the
gold standard for identification of high-risk myeloma.
· Despite more aggressive treatment, ASCT up to age 75 years,
and the use of novel agents, there has been only a marginal
4
increase in OS in patients over age 65 years.
with decreased survival and increased cost of treatment.
· PFS has not improved since 2001 in older patients, ques-
Management strategies include the fol owing:
tioning the effect of improved anti-myeloma treatment.
· Lifestyle modifications such as movement and avoidance
· Is increased OS in older patients due to better medical care?
of bed rest (although movement may cause pain), calcium
supplements, precautions to reduce fal s
· Is the increased risk of adverse cytogenetics associated with
worse outcome in older patients?
· Radiation therapy to treat painful lesions (should be used
sparingly because overuse can compromise the use of sys-
· Due to the biologic heterogeneity of patients age 65 to 75
temic therapy)
years, outcome evaluation should be based on treatment,
not on age.
· Surgical interventions: vertebroplasty (no benefit in osteo-
porosis); kyphoplasty (benefit in patients with cancer,
· More information is needed on the biology of myeloma in
including myeloma)
older patients.
· Pharmacologic management: vitamin D supplementation
Treatment with Transplant
(many patients have insufficient vitamin D, but appropri-
ate levels and dosing are unclear and trials are ongoing);
Melphalan, prednisone, lenalidomide (MPr) versus high-
bisphosphonates (inhibit osteoclast activity); treatment of
dose melphalan and autologous stem cell transplantation
myeloma (bone disease can progress in patients in com-
(Mel200) in newly diagnosed multiple myeloma (MM)
plete remission)
patients: a phase III trial (Abstract 8020) was presented by
Mario Boccadoro, University of Torino, Torino, Italy, in a poster
Bisphosphonates. Pamidronate and zoledronic acid are
session. This study was conducted in patients with newly diag-
equal y active in reducing skeletal related events (SRE), includ-
nosed myeloma who were younger than age 65 years. After
ing fractures, radiation to bone, vertebral compression frac-
four induction cycles of lenalidomide plus low-dose dexa-
tures, and hypercalcemia. Issues include:
methasone, patients were randomly assigned to either MPR
(202 patients ) or MEL 200 with ASCT (200 patients). A second
· Kidney(renal)toxicity(kidneyfunctionmustbemonitored).
random assignment was to either no maintenance or lenalid-
· Osteonecrosis of the jaw (ONJ), although good preventa-
omide maintenance. results. MEL200 was superior to MPR
tive dental care has reduced the incidence.
for PFS at 24 months, although side effects were significantly
· SRE (skeletal-related events) are decreased by 50% and pro-
higher. This is the first study to show a PFS advantage for ASCT
gression of bone disease stil occurs, although at a slower
compared with combination chemotherapy containing a novel
rate.
agent, although at this time, OS is similar for both treatments,
and longer fol ow-up is needed.
· Anti-myeloma activity of zoledronic acid has been demon-
strated in the MRC Myeloma IX trial (updated results are
Supportive Care
summarized below). This was seen in patients without as
Bone Disease Overview
wel as with bone disease, but the anti-myeloma therapy
used was not as intensive as current therapy, and newer
David Roodman, University of Pittsburgh Medical Center,
agents are active in bone. Therefore, Dr. Roodman believes
Pittsburgh, Pennsylvania, USA, presented Bone disease and
that it isn't clear that al patients should be treated with
its Management in Multiple Myeloma as part of the Edu-
bisphosphonates.
cation Session, Clinical Problems in the Management of
Multiple Myeloma (eQuestions session). Bone involvement
discussion. Dr. Roodman pointed out that there are no data
is most frequent in myeloma vs. other cancers, occurring in
about stopping bisphosphonates before dental procedures.
up to 84% of patients with advanced disease. Any bone can be
He said it is not necessary to stop bisphosphonates for routine
affected, but bones with higher red marrow content are most
cleaning or other procedures such as fil ings or root canals,
often affected, with pathologic fractures occurring most often
but bisphosphonates should be stopped for 2 to 3 months
in vertebrae (70%), fol owed by ribs (14%), thigh bones (5%),
for planned procedures like extractions or surgery. If there
and other bones. At the time of diagnosis 20% of patients have
is an emergency condition, the procedure should be per-
pathologic fractures, and 60% wil have them over the course
formed and bisphosphonates stopped until the tooth socket
of their disease. Pathologic fractures in myeloma are associated
heals. Bisphosphonates may inhibit healing after surgery
5
or extraction. He noted that in the MRC Myeloma IX trial,
Overal conclusions of these presentations include the
there was a benefit of bisphosphonates for 1 to 4 years, but
fol owing:
ONJ increases with the cumulative dose of zoledronic acid.
· Zoledronic acid significantly reduces the relative risk of
This group had preventative dental care over the fol ow-up
SREs vs. clodronate regardless of the presence of bone dis-
period of thalidomide vs. placebo maintenance, suggesting
ease at diagnosis. SRE rates were higher if there were pre-
that if there is good dental prophylaxis, bisphosphonates can
existing bone lesions at presentation.
be administered past 2 years. ASCO guidelines recommend
administration for 2 years. Dr. Roodman says that his personal
· Zoledronic acid decreases SREs even when new bone
practice, which is not based on data, is to extend the inter-
lesions were excluded from the composite definition of
val of bisphosphonate administration for patients with CR or
SRE. The decrease in SREs with zoledronic acid was seen
plateau, but if they have active disease, then he treats with
within the first year independent of bone disease status at
bisphosphonates.
presentation.
Bisphosphonates in the MRC Myeloma IX
· Zoledronic acid significantly improved OS and PFS vs. clo-
dronate in the overal population. The OS and PFS benefits
Clinical Trial
appear limited to patients with bone disease at presenta-
There were two oral presentations and one poster presenta-
tion, and were seen in both the intensive and non-intensive
tion discussing the use of the bisphosphonates zoledronic
pathways.
acid vs. clodronate in the MRC Myeloma IX clinical trial. These
presentations were updates on the data reported at ASCO
· Adverse events (AEs) were similar to those previously
2010 of 1960 patients with newly diagnosed myeloma treated
observed.
in either an intensive or non-intensive pathway. Within each
· Patients initiating therapy for myeloma have an increased
pathway, 981 patients were randomly assigned to zoledronic
risk for SRE, with prior SRE, osteolytic bone lesions,
acid and 970 patients to clodronate. Patients were further ran-
hypercalcemia, and the use of melphalan plus prednisone
domly assigned within each treatment group either to mainte-
increasing this risk. Zoledronic acid significantly decreases
nance therapy with thalidomide or to no maintenance. Note
SREs vs. clodronate regardless of bone disease status at pre-
that although clodronate is not currently approved in the US,
sentation or of treatment pathway or regimen. The benefits
it is used in other countries, including Canada and the UK.
of using zoledronic acid were seen within the first year,
supporting early initiation of zoledronic acid.
The presentations were:
· The increased OS benefit of zoledronic acid over clodro-
· does zoledronic acid (Zol) reduce skeletal-related
nate is significant within the first 4 months of treatment
events (Sres) and improve progression-free survival
and increased over time, including during the maintenance
(PFS) in patients (Pts) with multiple myeloma (MM)
portion of the trial, and is seen during each of the first 3
with or without bone disease? MrC myeloma IX study
years on study.
results (Abstract 8010) presented by Gareth Morgan, Royal
Marsden Hospital, Leeds, UK for Kevin Boyd.
· These analyses support the early initiation of zoledronic
acid to prevent SREs and prolong survival, and treatment
· are there benefits to long-term bisphosphonate treat-
at least until disease progression to provide a long-term
ment in multiple myeloma (MM)? Insights from tempo-
benefit.
ral analyses of zoledronic acid (Zol) versus clodronate
· The benefit of zoledronic acid on OS vs. clodronate is inde-
(Clo) in the MrC Myeloma IX trial (Abstract 8011) pre-
sented by Faith Davies, Institute of Cancer Research, Lon-
pendent of gender and disease stage.
don, UK.
· Zoledronic acid vs. clodronate:
· defining the biological subgroup of multiple myeloma
significantly improved OS in patients with bone disease
patients which benefits maximally from the overall
or other SREs at baseline
survival benefit associated with treatment with zole-
more effectively reduced SREs in patients with and with-
dronic acid (Abstract 8083, poster) presented by Gareth
out bone disease at baseline
Morgan, Royal Marsden Hospital, Leeds, UK.
significantly reduced risk of SREs in patients with lower-
risk but not high-risk cytogenetics
6
discussion. Abstracts 8010 and 8011 were discussed by David
of ONJ should be balanced with benefit. Dr. Davies said that
Roodman, University of Pittsburgh Medical Center, Pittsburgh,
the ONJ risk doesn't seem to increase over time.
Pennsylvania, USA. He reviewed the major findings in the pre-
sentations as wel as published results on the effect of bisphos-
Other Supportive Care Issues
phonates in myeloma and other cancers. He noted that that
In the Education session Clinical Problems in the Manage-
bisphosphonate use wil result in additional cases of ONJ, and
ment of Multiple Myeloma (eQuestions session), Sikander
assuming the rate of occurrence is the same in patients with
Ailawadhi, University of Southern California Norris Compre-
and without bone disease, the clinical economic cost of treat-
hensive Cancer Center, Los Angeles, California, USA, who
ing al patients with bisphosphonates must be considered. The
was a substitute speaker, presented Complications of anti-
increased incidence of ONJ at 3 years of treatment (seen in
Myeloma therapies. He discussed the need to be aware of
patients with breast cancer) was the basis of the ASCO guide-
and appropriately manage hematologic and gastrointestinal
lines suggesting 2 years of bisphosphonate therapy. However,
side effects, thromboembolism (clots), infections (includ-
good dental prophylaxis (preventive care) has been shown to
ing zoster reactivation associated with bortezomib), fatigue
decrease the incidence of ONJ.
associated with thalidomide, lightheadedness associated
with bortezomib, and ONJ. He mentioned guidelines for the
Important remaining questions include whether using other
management of side effects of novel therapies and steroids
regimens containing agents that may target bone, like bort-
developed by the Nurse Leadership Board of the International
ezomib or lenalidomide, would obscure the benefits of zole-
Myeloma Foundation (IMF) published in 2008 in the Clinical
dronic acid on OS in patients with bone disease, and the
Journal of Oncology Nursing and available through the IMF
SRE effects of zoledronic acid in patients without bone dis-
web site. During the discussion, someone asked if bortezo-
ease. Do patients without bone disease need less frequent
mib once a week or administered subcutaneously was the new
administration of zoledronic acid (or another bisphospho-
standard. Dr. Ailawadhi said that this was an important topic.
nate) for the same SRE benefit without increased risk of
The standard regimen of I.V. bortezomib is administration on
ONJ? Wil the lower incidence of ONJ seen with dental pro-
days 1, 4, 8, and 11. There are data supporting the weekly
phylaxis remain low with longer periods of treatment with
administration of I.V bortezomib in combination therapy such
zoledronic acid?
as modified VMP or modified CyBOR-D. There has been one
Question and answer discussion. Dr. Morgan pointed out
non-inferiority study of subcutaneous bortezomib adminis-
that because the effect of bisphosphonate treatment on high-
tered on days 1, 4, 8, 11, suggesting it is possible to main-
vs. low-risk disease wasn't part of the original design of MRC
tain efficacy with reduced adverse events such as PN [a phase
Myeloma IX, this effect must be confirmed in a prospective
III trial reported by Moreau et al. in Lancet Oncology 2011,
study. Dr. Davies said they are looking at data for the effect
12:431-440, in which time to progression (TTP) and 1 year OS
of continuous vs. intermittent vs. stopped bisphosphonate
were similar between the subcutaneous group of 145 patients
administration, but smal patient numbers in the subgroups
and the I.V. group of 73 patients, al of whom had relapsed
make this analysis difficult. Dr. Morgan said they used skeletal
myeloma]. However, subcutaneous bortezomib is not used yet
surveys, not DEXA, so they don't know the rates of generalized
in general practice and is off label, that is, this route of admin-
decreased bone density (osteopenia) in patients. Menopausal
istration has not been approved by regulatory agencies such
status, which is important in the breast cancer studies, is not
as the US FDA.
important in myeloma bone disease.
Response Assessment and Monitoring
Taimur Sher, Roswel Park Cancer Institute, Buffalo, New York,
Secondary Malignancies
USA (session co-chair) asked how long patients should be
treated based on response. Dr. Morgan said they are trying to
There were three oral presentations and one poster presen-
address this in a subsequent analysis. New osteolytic disease
tation discussing the incidence of second primary malignan-
is associated with progression, and there is always a period
cies (SPM) (other cancers occurring after the diagnosis of
when bone resorption occurs before relapse. Dr. Roodman
myeloma) in patients with myeloma who had been treated
said that Dr. Raje is using bone markers to decide on treat-
with lenalidomide. They were:
ment, and agrees these should be used, but more selectively.
· Incidence of second primary malignancy (SPM) in
Patients with breast and prostate cancers benefit at each land-
melphalan-prednisone-lenalidomide
combination
mark for at least 3 years of bisphosphonate treatment. The risk
7
followed by lenalidomide maintenance (MPr-r) in
· At 6 years of fol ow-up BiRD is highly effective in patients
newly diagnosed multiple myeloma patients (pts)
with newly diagnosed myeloma. There were no cases of
age 65 or older (Abstract 8007) presented by Antonio
MDS/AML (myelodysplastic syndrome and acute myelog-
Palumbo, Molinette Hospital, Torino, Italy. This included
enous leukemia). The frequency of SPMs was low and
an analysis of data from patients treated in the MM-015
similar to the incidence reported in the Surveil ance, Epi-
study with MPR-R vs. MPR vs. MP and data from nine EMN
demiology, and End Results (SEER) database of the US
trialist group trials of newly diagnosed patients treated with
National Cancer Institute for the patients' age group. Some
lenalidomide plus and alkylating agent vs. no lenalidomide.
patients had invasive cancers before their myeloma diag-
nosis. Al patients should have routine screening for SPMs.
· Incidence of second primary malignancies (SPM) after
(Rossi presentation).
6-year follow-up of continuous lenalidomide in first-
line treatment of multiple myeloma (MM) (Abstract
· There was no difference in invasive SPMs for lenalidomide
8008) presented by Adriana C. Rossi, Weil Cornel Medical
vs. placebo in these trials. SPM incidence rate is low and
Col ege, New York-Presbyterian Hospital, New York, New
similar to background among similar age groups in the gen-
York, USA of newly diagnosed, transplant-eligible patients
eral population. OS is significantly longer for patients given
in the BiRD phase II study treated with lenalidomide, dexa-
lenalidomide and dexamethasone. Improvement in OS
methasone, and clarithromycin.
with lenalidomide is confirmed even with half the patients
in the trial switching to lenalidomide from placebo during
· lenalidomide and dexamethasone (len plus deX)
the course of the trial. The overal benefit-risk ratio for the
treatment in relapsed/refractory multiple myeloma
use of lenalidomide remains strongly positive. (Niesvizky
(rrMM) patients (pts) and risk of second primary
presentation).
malignancies (SPM): analysis of MM-009/010 (Abstract
8009) presented by Ruben Niesvizky, Weil Cornel Medical
· Lenalidomide-based therapy did not significantly increase
Col ege, New York-Presbyterian Hospital, New York, New
the rate of SPMs compared with the incidence rate reported
York, USA (first author: Melitios Dimopoulos) of lenalido-
by SEER. The rate of SPMs was not significantly increased
mide and dexamethasone vs. placebo and dexamethasone
with increased duration of lenalidomide therapy. The ben-
in the MM-009 and -010 trials.
efit-risk profile of lenalidomide therapy for patients with
relapsed, refractory myeloma is strongly positive. (Durie
· long-term safety of lenalidomide (len) in relapsed/
presentation).
refractory multiple myeloma patients (Pts): analysis
of pooled data (Abstract 8086) presented by Brain Durie,
Secondary malignancies following multiple myeloma,
Aptium Oncology, Inc., Cedars-Sinai Outpatient Cancer
Abstracts 8007 to 8009, were discussed by Ola Landgren,
Center, Los Angeles, California, USA, a pooled analysis of
National Cancer Institute, Bethesda, Maryland, USA. He
11 Celgene-sponsored studies of lenalidomide in patients
reviewed the data and observed that the reporting of SPMs is
with relapsed/refractory myeloma (MM-007 to -010,
not perfect: there is under-reporting, the retrospective (look-
MM-012, MM-016 to -019, MM-022).
ing back) study format can introduce bias, survival among
treatment arms can be different, and there can be variations
Overal conclusions included the fol owing:
in how data are col ected. SEER data are not broken down
· Continuous lenalidomide results in unprecedented PFS
by MDS or other specific malignancies. If a patient develops a
improvement. Risk of SPM is increased by use of lenalido-
cancer common in the ageing population, e.g., prostate can-
mide plus melphalan (not lenalidomide plus dexametha-
cer, does data col ection stop? If a patient develops MDS later,
sone). However, the incidence of SPM is low. Benefit to risk
is that information col ected? Interest in SPMs after myeloma
ratio strongly favors continuous lenalidomide for patients
is not new; AML in patients with myeloma was reported in the
with newly diagnosed myeloma but current fol ow-up is
1960s and 1970s. In the 1980s MDS/AML was associated with
about 4 years and longer fol ow-up is needed. (Palumbo
melphalan- but not cyclophosphamide-containing regimens
presentation).
for myeloma. At last year's American Society of Hematology
(ASH) meeting, there were reports of the incidence of SPMs
· Although the risk of SPM with lenalidomide and alkylating
in 3 randomized studies involving lenalidomide maintenance,
agents is higher than without, the risk of dying of myeloma
which renewed interest in the topic.
is lower with lenalidomide and alkylating agents. (Palumbo
presentation).
8
Mechanisms. Little is known about the mechanisms, in part
fol ow-up is needed. The 3 studies presented that showed a
because the incidence of second cancers in untreated patients
smal increase in SPMs in the treatment arm are suggestive but
is not known. However, a Swedish study presented at the
not definitive. Dr. Palumbo agrees about fol ow-up, and both
International Myeloma Workshop, Paris, 2011, compared the
he and Dr. Landgren point out the risk of SPM has to be com-
incidence of SPMs in patients with myeloma and MGUS with
pared with the much greater benefit derived from treatment.
that in the general population. The risk of developing AML/
Dr. Campagnaro commented about the subset of patients in
MDS is about 11 times higher in patients with myeloma and
the BiRD study that presented with prior cancers, noting that
8 times higher in patients with MGUS. The isotype of MGUS
it was common. She wondered if there is an enrichment for
plays a role, with IgG and IgA associated with AML/MDS. The
other prior tumors in patients who subsequently develop
level of M-spike is also associated with increased risk. Dr. Land-
myeloma. Dr. Landgren responded that a study published this
gren proposed a model for SPM after myeloma that takes into
year reported prior tumors. However, because the average age
account treatment, myeloma-related factors, host-related fac-
of patients with myeloma is 71 years, this population can be
tors that predispose to both myeloma and SPM, environmen-
expected to have other tumors. Men have a 50% chance and
tal and behavioral factors, and the interaction of al of these.
women a 30% chance of developing tumors over their lifetime.
There must be a study of different cancer types to see if those
Clinical implications. Based on smal numbers, the 3 random-
patients have a higher risk of developing myeloma. There are
ized studies reported at ASH show more hematologic malig-
data suggesting other cancers are more likely to occur prior
nancies in the treatment arm. Other studies show a smal
to myeloma, but the question needs further investigation. Dr.
or no indication of increased risk. As competing causes, the
Lentzsch commented that it could be important to look at the
cumulative incidence of development of SPMs is about 7%,
development of AML in patients given maintenance with con-
and the cumulative probability of death due to myeloma is
tinuous lenalidomide vs. those on a 3 weeks on, 1 week off
over 90%. So the risk of dying of myeloma is a much larger
schedule. Dr. Jakubowiak (session co-chair) asked the present-
problem than SPM on average.
ers if they would recommend maintenance with lenalidomide
Summary and conclusions. Currently there is a lack of clear
after transplant or non-transplant treatment outside of clini-
answers due to smal numbers of patients and study limita-
cal trials. Dr. Palumbo said he would absolutely give lenalido-
tions. Benefits vs. risks must be considered. Even with a lack
mide after ASCT or conventional therapy but would monitor
of data, healthcare providers have to discuss the facts with
for the risk of SPMs with longer fol ow-up. Dr. Rossi said she
patients. The key point for the future is to determine the
would also definitely give lenalidomide maintenance because
mechanisms of SPM development.
the risk of progression and death outweighs the risk of SPMs.
Dr. Niesvizky proposed incorporating proteasome inhibition
discussion. Dr. Palumbo believes that the risk of SPMs, par-
for maintenance in patients with high- risk disease. Dr. Land-
ticularly hematologic malignancies, is slightly increased with
gren agreed, and stated that they need to be responsible and
the use of lenalidomide, but that the risk of dying of myeloma
monitor the patients, and try to understand the mechanisms
that isn't treated with lenalidomide is much higher. Dr. Rossi
by which second malignancies develop.
thinks the risk is increased by the use of alkylating agents, and
Dr. Niesvizky thinks that alkylators may contribute in the con-
New Therapies
text of the order of agents used in therapy, i.e., induction with
Kenneth Anderson, Dana-Farber Cancer Institute, Boston,
lenalidomide fol owed by alkylators, or the other way around.
Massachusetts, presented Bench-to-Bedside translation
There is no information on the genetic profile of AML second-
of targeted therapies in Multiple Myeloma as his David
ary to myeloma, although Drs. Palumbo and Landgren are
A. Karnofsky Memorial Award and lecture. He reviewed the
col ecting data on this profile. Dr. Landgren said the NIH is
history of therapy and identification of cel lineages, and
col aborating with CALGB and the Italian group and is inviting
emphasized immune-based therapies, discussing monoclo-
everyone to work together because the number of cases is so
nal antibodies (mAbs) for cel depletion, targeted therapies,
low. If SPMs are included as events in the trials discussed, PFS
immunotoxins, and therapeutic vaccines. He also reviewed
does not change. There was a comment about how therapy
the role of the microenvironment in myeloma pathophysiol-
could cause SPMs in such a short time period, given that most
ogy, and discussed new therapies being developed and tested
human carcinogens take longer to act. Dr. Landgren agrees
in clinical trials, summarizing recently published results. Some
latency needs to be taken into account. If AML is associated
promising therapies or approaches include the fol owing:
with treatment, it appears to occur about 4 years out, so longer
9
· Antibodies
to inhibit the proteasome, has been shown to be active
Elotuzumab (anti-CS1 mAb). A phase III registration
in a phase I/II trial in refractory myeloma.
trial for new drug approval is testing lenalidomide plus
Dr. Anderson observed that studying myeloma cel s in the con-
dexamethasone with elotuzumab vs. lenalidomide plus
text of the bone marrow microenvironment as wel as using
dexamethasone. [See mAb presentation summaries in
genomics wil help to 1) define functional y important pro-
Table 2]
teins that wil target myeloma, 2) further the understanding
· Proteasome inhibitors
of myeloma pathogenesis, and 3) identify appropriate patients
Carfilzomib, an irreversible inhibitor of chymotryptic
for given therapies with the goal of developing personalized
activity, is in ongoing phase III trials. [see presentation
treatment.
summaries below]
Carfilzomib (Proteasome Inhibitor)
· IMiDs
The results of trials of carfilzomib are summarized in Table 1.
Pomalidomide is in phase I and phase II trials in relapsed,
refractory myeloma. Dr. Anderson is "hopeful for accel-
Jonathan Kaufman, Winship Cancer Institute, Emory Univer-
erated approval because this agent wil meet an unmet
sity School of Medicine, Atlanta, Georgia, USA, discussed the
medical need."
first three carfilzomib posters in the above table during the
· PI3/AKT/mTOR inhibitors
lymphoma and Plasma Cell disorders Poster discussion.
A phase III trial of bortezomib plus the AKT inhibitor
He made the fol owing points:
perifosine vs. bortezomib in relapsed myeloma is ongo-
· In PX-171-003, carfilzomib is effective as monotherapy in a
ing for FDA approval.
heavily pretreated population of patients, is general y wel
· Histone deacetylase (HDAC) inhibitors
tolerated with minimal treatment-emergent PN, and a sub-
Panobinostat to block the aggresome, plus bortezomib
set of patients respond and can remain on therapy for a
Table 1.
Presenter
Study
Conclusions
title
Patients
abstract
Michael Wang, MD Anderson Cancer center, Houston, Texas, USA
PX-171-006, phase II
Ongoing for PFS, DOR (duration of response)
Interim results from PX-171-006, a phase 2 multicenter dose-
Relapsed, refractory myeloma
ASPIRE, ongoing phase III open-label trial is
expansion study of carfilzomib, lenalidomide, and low-dose
after 1 to 3 prior therapies
comparing CRd to Rd and is actively recruiting
dexamethasone in relapsed and/or refractory multiple myeloma
(see Moreau poster summary below)
Abstract 8025 (poster)
Keith Stewart, Mayo Clinic, Scottsdale, Arizona, USA
PX-171-004, phase II non-
Study is ongoing; 22 patients are receiving
Carfilzomib produces a high single-agent response rate in patients
randomized, open-label,
carfilzomib on extension trial PX-171-010
with bortezomib-naïve relapsed multiple myeloma: updated
single-arm
3-year long-term fol ow-up OS, DOR, TTP, and
interim results from the PX-171-004 study
Relapsed or relapsed/refractory
safety wil be reported when available
Abstract 8026 (poster)
myeloma after 1 to 3 prior
regimens excluding
David Siegel, John Theurer Cancer center, Hackensack, New Jersey, USA PX-171-003-A1, phase II open-
27 patients continuing on extension protocol
PX-171-003-a1, an open-label, single-arm phase 2 study of
label, single-arm
PX-171-010
carfilzomib in patients with relapsed and refractory multiple
Relapsed and refractory myeloma ORR and CBR rates are final; OS data wil be
myeloma: long-term follow-up and subgroup analysis
after 2 lines of therapy including updated
Abstract 8027 (poster)
bortezomib or an IMiD
Jackie Szymonifka, University of Arkansas for Medical Sciences, Little
Phase II
EFS benefit seen in GEP-defined low-risk
Rock, Arkansas, USA
Relapsed, refractory myeloma
myeloma
Phase II study of carfilzomib (CFZ) in combination with current
Carfilzomib has activity, especial y in
agents for relapsed and refractory multiple myeloma (rrMM)
combination with other agents in this
Abstract 8028 (poster)
population of patients with advanced disease
Philippe Moreau, University Hospital, Nantes, France
ASPIRE Phase III, randomized,
Treatment wil continue until disease
a randomized, multicenter, phase 3 study comparing carfilzomib,
open-label in relapsed myeloma
progression or unacceptable toxicity
lenalidomide, and dexamethasone to lenalidomide and
(1 to 3 prior regimens)
Primary endpoint is PFS, secondary endpoints
dexamethasone in patients with relapsed multiple myeloma
include OS, ORR, DOR, safety
Abstract TPS225 (poster)
10
long period of time. It is not known what the optimal dose
that there are over 10 potential mAb candidates that have
is in patients with refractory disease.
entered clinical development. The anti-tumor activity of mAbs
as single agents has been modest to date, so combination
· In PX-171-004, carfilzomib is effective as a single agent in
approaches with immunomodulatory and other drugs are
bortezomib-naïve patients. It is not known if there is a dose-
therefore required. The strength of the elotuzumab study
response effect or if higher doses should be used. There are
is that it involves a large number of patients, and therefore
no studies asking if there is a PFS or OS advantage vs. best
is probably reproducible. Randomized trials are underway
standard care. It is not known how the safety, including the
to confirm the efficacy of elotuzumab in combination with
low rate of PN, and the efficacy would compare with what
lenalidomide. It would be interesting to see if elotuzumab has
Dr. Kaufman referred to as the "optimal" bortezomib sched-
single-agent activity in SMM.
ule of once-weekly I.V. or subcutaneous administration.
· In PX-171-006, in combination with lenalidomide, no dose-
Panobinostat
limiting toxicities (DLT) were observed, and AEs were as
(Histone Deacetylase (HDAC) Inhibitor)
expected. The combination CRd is very effective in patients
PanoraMa 1: a multicenter, randomized, double-blind,
with relapsed myeloma and can be administered for pro-
placebo-controlled phase 3 study of panobinostat in com-
longed periods of time. However, it is not known if CRd
bination with bortezomib and dexamethasone in patients
has an advantage over Rd. The ASPIRE ongoing phase III
with relapsed multiple myeloma (Abstract TPS227) was
trial wil test this.
presented by Jesús San Miguel, University Hospital of Sala-
manca, Salamanca, Spain, in the Trials in Progress Poster Ses-
Elotuzumab (Monoclonal Antibody)
sion. This trial wil enrol 672 patients who have received 1 to
Development of elotuzumab, a humanized monoclonal anti-
3 prior lines of therapy and whose myeloma is not bortezo-
body (mAb) targeting human CS1, a cel surface glycoprotein
mib-refractory. The primary endpoint is PFS, and final analysis
expressed on myeloma cel s, continues. Two presentations on
wil be performed when a total of 460 PFS events have been
elotuzumab are summarized in Table 2.
observed. The study wil also col ect information on biomark-
ers and quality of life. As of May, 2011, 400 patients had been
discussion. Abstract 8012 was discussed by Nikhil Munshi,
randomly assigned to treatment.
Dana-Farber Cancer Institute, Boston, Massachusetts, USA,
who was fil ing in for Asher Alban Chanan-Khan. He observed
Table 2.
Presenter
Study
Conclusions
title
Patients
abstract
Philippe Moreau, University Hospital, Nantes, France, presented
Phase I/II study of elotuzumab plus
The ORR of 90% in patients with only 1 prior
for Paul Richardson.
lenalidomide plus low dexamethasone in
therapy provides the rationale for using this
elotuzumab with lenalidomide and low-dose
phase I, and efficacy in relapsed, refractory
combination earlier in disease.
dexamethasone in patients with relapsed multiple myeloma: myeloma in phase II.
Two phase III trials are being conducted in
a randomized phase II study.
Prior lenalidomide was al owed in phase I
relapsed myeloma and as frontline therapy.
Abstract 8014
but not phase II.
Sagar Lonial, Winship Cancer Institute, Emory University School
Phase I data from a phase I/II trial in
A phase II trial of elotuzumab in combination
of Medicine, Atlanta, Georgia, USA.
patients with relapsed/refractory myeloma.
with lenalidomide and dexamethasone is
Phase I trial of elotuzumab, lenalidomide, and low-dose
ongoing.
dexamethasone in patients with relapsed or refractory
multiple myeloma.
Abstract 8076 (poster)
11
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