InternatIonal MyeloMa FoundatIon
ASH 2010
Multiple Myeloma
Highlights
for Physicians
Summaries of Multiple Myeloma Presentations
from the 52nd Annual Meeting
of the American Society for Hematology (ASH)
held in Orlando, Florida
December 4­7, 2010

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Compiled by Lynne Lederman, PhD
Funded by unrestricted educational grants from Celgene Corporation and Onyx Pharmaceuticals.

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ASH 2010 Summaries of Multiple Myeloma
Presentations for Physicians
Introduction
· Elotuzumab, a monoclonal antibody
· Temsirolimus, an inhibitor of the mammalian target of
The 52nd Annual Society of Hematology (ASH) Annual Meeting
rapamycin
was held December 4th through 7th, 2010, in Orlando, Florida.
This report summarizes presentations at the 2010 ASH Annual
· PD0332991, an inhibitor of cyclin-dependent kinases
Meeting, organized by topics rather than by sessions, providing
IMF Symposium: Case Study 5: novel agents and regimens
an overview of information on new drugs in development; clini-
was presented by Robert Z. Orlowski, MD, PhD, The University of
cal trial results; treatment by patient characteristics, e.g., trans-
Texas M. D. Anderson Cancer Center, Houston, TX.
plant eligibility or stage of disease; risk stratification and staging;
disease biology including bone disease and use of bisphospho-
Most of the symposium participants agreed that relapsed/refrac-
nates; and maintenance therapy. Although maintenance therapy
tory myeloma could be defined as progressive disease on or
is summarized in its own section, some trials that include mainte-
within 60 days of the last treatment. The National Comprehen-
nance therapy are summarized in more relevant sections, as many
sive Cancer Network (NCCN) practice guidelines for multiple
trials are now including some kind of continuing treatment for at
myeloma recommend repeating the primary therapy if relapse
least some patients.
occurs at greater than 6 months; there is the most evidence for
using bortezomib, bortezomib plus pegylated liposomal doxoru-
On December 3, the International Myeloma Foundation (IMF)
bicin (PLD), or lenalidomide plus dexamethasone; other possi-
and the Postgraduate Institute for Medicine sponsored a sympo-
bilities include bendamustine, bortezomib plus dexamethasone,
sium that presented an overview of the most recent data from
lenalidomide, high-dose cyclophosphamide alone or with VAD,
clinical trials to allow participants to provide better care for their
thalidomide alone or with dexamethasone, dexamethasone
patients with multiple myeloma. Dr. Brian G.M. Durie introduced
alone, DCEP, or DT-PACE. Dr. Orlowski commented that he
the presenters and topics at the symposium. Summaries of these
would prefer to repeat the primary therapy if relapse occurs at 12
presentations are included under the appropriate headings.
months or more. Upcoming promising approaches include the
Multiple myeloma was the topic of many presentations at ASH,
novel single agents carfilzomib and pomalidomide, which are dis-
including the following:
cussed below. New combinations that seem promising that are in
trial include bortezomib and lenalidomide in combination with
· Education sessions were held on advances in the basic science
histone deacetylase (HDAC) inhibitors, monoclonal antibodies,
of plasma cell disorders and on supportive care in plasma cell
proteasome inhibitors, and other agents. It is also possible to add
dyscrasias.
old agents that are new again to prior active regimens, e.g., cyclo-
· An education session on high risk hematologic diseases
phosphamide. Agents that have been used previously can be used
included a talk on ultra high-risk myeloma.
again in different combinations.
· A scientific session was conducted on therapeutic targeting of
the myeloma stem cell.
Carfilzomib (PX-171): a Proteasome Inhibitor
· Over a dozen simultaneous oral sessions (comprising about 6
two carfilzomib trials are summarized in table 1.
presentations each) were held specifically on myeloma, with
(see page 13)
many other sessions presenting related information on trans-
Carfilzomib, lenalidomide, and dexamethasone In newly
plantation, venous thromboembolism, stem cell collection,
diagnosed Multiple Myeloma: Initial results of Phase I/II
tumor cell biology, and other topics of interest.
MMrC trial (abstract 862) was presented by Andrzej J. Jakubow-
· Three poster sessions featured hundreds of posters about
iak, University of Michigan, Ann Arbor, MI.
myeloma and related topics, e.g., transplantation, pharmaco-
economics, and new drugs in development.
results of PX-171-003-a1, an open-label, Single-arm,
Phase II (Ph 2) Study of Carfilzomib (CFZ) In Patients
New Drugs in Development
(pts) with relapsed and refractory Multiple Myeloma
(MM) (abstract 985) David Samuel diCapua Siegel, John
Studies of new drugs in development discussed in this report
Theurer Cancer Center, Hackensack University Medical Center,
include:
Hackensack, NJ.
· Carfilzomib (PX-171), a proteasome inhibitor
· Pomalidomide, an immunomodulatory drug
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Pomalidomide: an Immunomodulatory Drug
Side effects: The AE profile was mostly as expected with lenalid-
(IMiD)
omide and dexamethasone. Higher-grade hematologic AE were as
expected and were manageable. Elotuzumab-related AE included
Four pomalidomide trials are summarized in table 2.
fatigue and low-grade fever and were manageable. There was no
(see page 13)
treatment-related mortality. Infusion reactions occurred in 89%
Pomalidomide Plus low-dose dexamethasone In Myeloma
in the phase I portion of this trial, but with phase II management
refractory to Both Bortezomib and lenalidomide: Com-
this was cut in half. Infusion reactions were typical of those asso-
parison of two dosing Strategies In dual-refractory disease
ciated with mAbs.
(abstract 863) was presented by Martha Lacy, MD, Division of
results: ORR was 90% with the 10 mg/kg dose. The best con-
Hematology, Department of Internal Medicine, Mayo Clinic,
firmed response of at least PR occurred in 90% of patients on
Rochester, MN.
the 10 mg/kg dose and in 72% of patients on the 20 mg/kg
A Phase I/II Multi-Center, Randomized, Open Label Dose Escala-
dose. The study was not powered to determine the differences
tion Study to Determine the Maximum Tolerated Dose, Safety,
between doses; both doses had a sCR/CR rate of 5%. At least
and Efficacy of Pomalidomide Alone or In Combination with
VGPR occurred in 37% of patients overall, and was 42% for the
Low-Dose Dexamethasone In Patients with Relapsed and Refrac-
10 mg/kg dose. Patients with higher beta-2-microglobulin (B2M)
tory Multiple Myeloma Who Have Received Prior Treatment That
responded. Median time to best response was 2 months for both
Includes Lenalidomide and Bortezomib (Abstract 864) was pre-
arms. Median follow-up was 4.9 months, and median PFS was
sented by Paul G Richardson, MD, Dana-Farber Cancer Institute,
not reached, which Dr. Richardson called encouraging. At both
Boston, MA.
doses CS1 was saturated on CD38+ and CD138+ cells. The 10
mg/kg dose is recommended for the open label phase III trial to
Phase II Study of 2 Modalities of Pomalidomide (CC4047)
start next year.
Plus low-dose dexamethasone as therapy for relapsed
Multiple Myeloma. IFM 2009-02 (abstract 859) was presented
New Targeted Therapies in Early Trials
by Xavier LeLeu, Service des Maladies du Sang, Hôpital Huriez,
early trial results for two new targeted therapies in early
Lille, France.
clinical trials are summarized in table 3. (see page 14)
Elotuzumab, a monoclonal antibody (mAb)
The PI3K (phosphoinositol 3 kinase) pathway is important in
elotuzumab In Combination with lenalidomide and dexa-
enhancing cell survival by stimulating cell proliferation and inhib-
methasone In Patients with relapsed Multiple Myeloma:
iting apoptosis. mTor (mammalian target of rapamycin) inhibitors
Interim results of a Phase II Study (abstract 986) was pre-
may overcome resistance to bortezomib because they are syn-
sented by Paul G. Richardson, Dana-Farber Cancer Institute, Har-
ergistic with bortezomib in vitro and in co-culture. PD0332991
vard Medical School, Boston, MA.
is a selective, reversible, orally bioavailable inhibitor of cyclin-
dependent kinases (CDK) 4 and 6. CDK4/6 are two positive
Elotuzumab (HuLuc63) is a humanized monoclonal antibody
regulatory factors involved in the cell cycle that are associated
(mAb) targeting CS1, a cell surface glycoprotein highly and uni-
with phosphorylation of Rb and increasing cell proliferation with
formly expressed on myeloma cells, with restricted expression
disease progression in myeloma. PD0332991 has a low toxicity
on natural killer (NK) cells. In phase I studies of 5, 10, and 20
and there is a reproducible functional assay for patient samples.
mg/kg, elotuzumab-related AEs were primarily infusion-related in
PD0332991 is thought to have high specificity for CDK4/6. Induc-
89% patients, mostly grade 1 to 2, with no DLT, and MTD was not
tion of prolonged G1 arrest by inhibition of CDK4/6 may disrupt
reached. Median time to progression (TTP) was not reached at a
coupling of gene expression from the cell cycle, thereby sensitiz-
median follow-up of 12.7 months. Elotuzumab saturated the CS1
ing cells to killing by other agents, e.g. lenalidomide or bortezo-
binding sites in bone marrow myeloma cells at 10 mg/kg.
mib. Because this inhibition is reversible, release from G1 arrest
objectives of phase II: to evaluate the ORR of the elotuzumab
may synchronize cells and improve killing by bortezomib. Note
plus lenalidomide and dexamethasone in patients with relapsed/
that temsirolimus, an mTOR inhibitor, is approved for advanced
refractory myeloma after 1 to 3 prior therapies, and to evaluate
renal cell carcinoma, whereas PD0332991 is still investigational.
doses of 10 and 20 mg/kg.
mtor (Mammalian target of rapamycin)
doses: elotuzumab weekly for the first 4 cycles, then every other
Final results of the Phase I/II trial of Weekly Bortezomib
week; lenalidomide 25 mg; low- dose dexamethasone weekly;
In Combination with temsirolimus (CCI-779) In relapsed
Solu-Medrol (methylprednisolone) at the equivalent of 10 mg of
or relapsed/refractory Multiple Myeloma Specifically In
dexamethasone and other drugs to prevent infusion reactions.
Patients refractory to Bortezomib (abstract 990) was pre-
sented by Irene M. Ghobrial, Medical Oncology, Dana-Farber
Patients: no prior lenalidomide, most had a prior transplant,
Cancer Institute, Harvard Medical School, Boston, MA.
most had received prior thalidomide; safety population N= 63
receiving 10 mg/kg doses (n=31) or 20 mg/kg doses (n=32).
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CdK4/CdK6 (Cell Cycle)
the results of three maintenance studies are summarized in
a Phase I Study of Pd 0332991: Complete CdK4/6 Inhibition
table 4. (see page 14)
and tumor response In Sequential Combination with Bort-
thalidomide Maintenance Significantly Improves Pro-
ezomib and dexamethasone for relapsed and refractory
gression-Free Survival (PFS) and overall Survival (oS) of
Multiple Myeloma, (abstract 860) was presented by Ruben
Myeloma Patients When effective relapse treatments are
Niesvizky, MD, Medicine and Hematology/Oncology, Weill Cor-
used: MrC Myeloma IX results (abstract 623) was presented
nell Medical College, New York, NY.
by Gareth J Morgan, Institute of Cancer Research, The Royal Mars-
Maintenance Therapy
den Hospital, London, United Kingdom.
IMF Symposium: Case Study 4: Consolidation and Mainte-
Maintenance treatment with lenalidomide after trans-
nance therapy in Myeloma was presented by Phillippe Moreau,
plantation for Myeloma: Final analysis of the IFM 2005-02
MD, University Hospital Hôtel-Dieu, Nantes, France.
(abstract 310) was presented by Michel Attal, MD, Hôpital Pur-
pan, Toulouse, France.
Dr. Moreau discussed whether patients with VGPR after autolo-
gous stem cell transplant (ASCT) need additional treatment, and
Phase III Intergroup Study of lenalidomide Versus Placebo
if so, what kind. In 2009, the IMWG updated its definition of strin-
Maintenance therapy Following Single autologous Hema-
gent CR to require negative clonal cells by multiparametric flow
topoietic Stem Cell transplantation (aHSCt) for Multiple
cytometry (minimum of 4 colors). Stringent CR (sCR) is defined
Myeloma: CalGB 100104 (abstract 37) was presented by
as CR plus the absence of phenotypically aberrant plasma cells in
Philip L. McCarthy, MD, BMT Program, Roswell Park Cancer Insti-
the bone marrow with a minimum of 3000 total plasma cells ana-
tute, Buffalo, NY.
lyzed by multiparametric flow cytometry ("immunophenotypic
Myeloma Biology
CR"). Molecular CR was also incorporated into the IMWG (the
IMF-sponsored International Myeloma Working Group) criteria
Bisphosphonates and Bone Disease
and is defined as stringent CR plus negative ASO-PCR (allele-
There were two presentations on sub-analyses of the MRC
specific oligonucleotide polymerase chain reaction). Because
Myeloma IX trial concerning myeloma bone disease.
depth of response and time to progression are correlated, it is
important to identify the best consolidation therapy after ASCT.
optimising Bone disease In Myeloma; Zoledronic acid Plus
The BMT-CTN phase III study will randomly assign patients to no
thalidomide Combinations Improves Survival and Bone
consolidation vs. consolidation with VRD x 4 or with Mel (mel-
endpoints: results of the MrC Myeloma IX trial (abstract
phalan); all patients receive Mel 200 so the Mel consolidation is
311) was presented by Gareth J Morgan, Section of Haemato-
a second ASCT. All groups will then receive lenalidomide main-
Oncology, The Institute of Cancer Research, London, United
tenance. The new IMWG criteria will be used to assess response.
Kingdom.
Dr. Moreau reviewed published and on-going studies of mainte-
objectives: This presentation focused on randomization to zole-
nance therapy. IFM 2005-02 supports lenalidomide maintenance
dronic acid or clodronate in both treatment arms (intense and
after ASCT, showing improved PFS but no OS advantage. The
non-intense) in the MRC Myeloma IX trial. Note that zoledronic
CALGB 100104 study is an ongoing phase III trial of lenalidomide
acid is available in the US, but clodronate is not (although it is
vs. placebo as maintenance after ASCT. PFS and TTP are improved
available in Canada, the UK, and other countries).
in the lenalidomide arm but there is no difference in OS (see
Patients: Approximately 1960 patients were enrolled in this
below). The HOVON-65/GMMG-HD4 is another ongoing phase
study; median follow-up is 3.7 years.
III trial. An additional trial, MM-015, is comparing melphalan plus
prednisone plus lenalidomide followed by lenalidomide main-
Side effects: There was no excess renal toxicity. Osteonecrosis of
tenance (MPR-R) vs. MPR vs. MP for long-term control in newly
the jaw (ONJ) was significantly higher with zoledronic acid, about
diagnosed myeloma. PFS at the first interim analysis showed a
4%, but all incidents were minor and resolved without surgery
50% reduction risk. MPR-R vs. MPR in a landmark analysis of PFS
and with conservative management.
after cycle 9 showed a 75% reduced risk. Again, there is no differ-
results: Zoledronic acid was associated with significantly
ence in OS. The FIRST study of lenalidomide and low-dose dexa-
improved OS (5.5 month increase) vs. clodronate, and PFS
methasone vs. MPT (MP plus thalidomide) (IFM 07-01) included
was also increased. Adjustment for skeletal-related events (SRE;
almost 1600 patients and just closed to enrollment. Lenalidomide
defined as pathologic fractures, need for radiation to the bone,
and low-dose dexamethasone until progression is being tested in
bone surgery, spinal cord compression, and similar events) still
one arm. During the discussion, it was noted that lenalidomide
favors zoledronic acid, suggesting an anti-myeloma effect. Zole-
maintenance outside of the clinical trial setting is allowed in the
dronic acid was associated with higher OS and longer PFS for
US but not in Italy, France, or Spain. Data supporting bortezomib
both intensive and non-intensive treatment groups, although
maintenance therapy have also been presented. How long to give
the difference was not significant for the intensive pathway.
maintenance therapy is not known.
Zoledronic acid significantly reduced SRE for patients with bone
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lesions at presentation and for those with no lesions at baseline,
significant. The sensitivity and specificity of the training set were
suggesting that all patients should be treated even if they have
87% and 72% respectively; these were validated in the test set.
no bone lesions at baseline. Zoledronic acid decreased SRE com-
The SRE predictor, which includes the 7 genes plus calcium, is
pared with clodronate during maintenance therapy, and was
clinically applicable to estimating the risk of SRE before relapse
better than clodronate regardless of induction regimen. Patients
despite a patient being on bisphosphonate treatment. This was
receiving thalidomide-containing regimens plus zoledronic acid
validated in subgroups of patients with and without baseline
had the best responses.
bone disease treated with and without zoledronic acid or clodro-
nate. The genes identified give insight into the biology of under-
Defining Myeloma Patients at High Risk of Developing Bone Dis-
lying SRE development. This test could be used in future clinical
ease While on Bisphosphonate Treatment (Abstract 782) was pre-
trials to identify patients at high risk for bone disease even while
sented by Ping Wu, Section of Haemato-Oncology, The Institute
on bisphosphonates.
of Cancer Research, London, United Kingdom.
objectives: This analysis investigated the molecular basis of bone
Renal Impairment
disease at presentation, and developed a gene expression-based
Meletios A. Dimopoulos, Greek Myeloma Study Group, Greece,
predictor applicable to patients with myeloma at presentation for
presented renal Insufficiency and Failure as part of the Multi-
high risk of developing myeloma bone disease.
ple Myeloma education Program: Supportive Care in Plasma
Cell dyscrasias, chaired by Pieter Sonneveld, MD, PhD, Erasmus
Methods: Gene expression profiling (GEP) was performed on
University Medical Center, Rotterdam, Netherlands.
samples from 261 patients comprising a training set (n=205) and
test set (n=56). Differential expression of genes was scored by
The main points include the following:
SAM (significance analysis of microarray).
· Renal function should be assessed in patients with myeloma.
results: There was a shorter OS in patients presenting with bone
Diagnosis involves evaluation of serum creatinine, urinary Na,
disease defined by presence of any lytic lesion or x-ray indica-
K, Ca, calculation of estimated glomerular filtration rate (eGFR)
tion. There were 50 genes associated with bone disease at pre-
using the MDRD formula, determination of total protein in a
sentation by SAM score. Of those that were up-regulated, most
24-hour urine sample, urine protein electrophoresis (UPEP)
were involved with growth factors, apoptosis, and transcription
and immunofixation, and serum free light chains (FLC).
factor regulation. This suggests that patients with bone disease
· Management of myeloma-associated renal dysfunction includes
have a different myeloma metabolism. The top 10 genes most sig-
hydration, alkalinizing the urine, managing hypercalcemia,
nificantly associated with bone disease at presentation included
treating infections, and avoiding nephrotoxic agents while
DKK1 (Wnt signaling inhibitor), RNASEH2B (involved in DNA
managing the myeloma. High-dose steroids may be effective.
replication), genes involved in apoptosis, and 2 genes associated
Plasma exchange with hemodialysis or hemodialysis alone does
with growth factor signaling. FRZB and DKK1 are both up-regu-
not appear to be very effective, although high cut-off perme-
lated. In the group of patients with low bone disease, these genes
ability filters could remove large amounts of FLC.
are both down-regulated. Insulin-like growth factor (IGF)-1 is
one of the growth factors involved in bone destruction. Two neg-
· Doses of melphalan should be reduced with renal impairment.
ative regulators of IGF signaling are down- regulated with bone
· Thalidomide has negligible renal excretion, so it can be used
disease. The time to first SRE (TTFSRE) curve shows rapid onset
in patients with renal dysfunction, but there are case reports
of events within the first two months for patients treated with
of associated hypokalemia. Thalidomide may reverse renal
zoledronic acid or clodronate in the MRC trial, so they looked at
impairment in some patients.
this point of the curve; the SREs level off after this point. There
was a 26% relative reduction in all events with zoledronic acid
· Because lenalidomide is primarily excreted by the kidneys,
within the first 2 months, which may be related to disease con-
dose reduction, based on creatinine clearance (CrCl) is manda-
trol. Excluding the first 2 months, 97% of patients had their first
tory in renal impairment.
SREs within 2 months to 2 years. Of the 14 genes identified as
· There is a strong rationale for using bortezomib in patients with
associated with SRE development, all are up-regulated in SRE.
renal impairment. Pharmacokinetics are independent of renal
These include interferon-induced genes reported by UAMS to be
function, there is a rapid response, and bortezomib is gener-
associated with poor prognosis.
ally well tolerated; about 50 to 60 % of patients experience
A 7-gene signature for SRE was developed that has good predic-
improved renal function. Dialysis may be avoided or no longer
tive power. Looking at all patients in the trial, other SRE-asso-
required in some patients treated with bortezomib. Improved
ciated parameters included t(4;14), hyperdiploidy, presenting
renal function has also been seen in bortezomib-based combi-
bone disease, and high calcium levels. In the gene expression
nation therapy. Bortezomib should be given after dialysis.
data set high calcium, presenting bone disease, and hyperdiploidy
· IMWG proposes bortezomib-based therapy in patients with
were significantly associated with SRE development; when added
renal impairment with high-dose dexamethasone, pos-
individually to the 7-gene signature, only calcium was statistically
sibly with the addition of a third agent, e.g., thalidomide,
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cyclophosphamide, or doxorubicin, and is recommended for
to find myeloma precursor cells in the peripheral blood, in part
patients with renal impairment of any grade.
because in aggressive and end-stage disease, extramedullary dis-
ease occurs as a result of spread via the circulation. There is some
Targeting the Myeloma Stem Cell
evidence that important tumorigenic activity is occurring within
Ad Hoc Scientific Committee on Plasma Cell
the plasma cell compartment.
Biology: Targeting the Myeloma Stem Cell.
Constantine S. Mitsiades, MD, PhD, Jerome Lipper Multiple
Chair Raymond Powles, Parkside Oncology Clinic, Wimbledon,
Myeloma Disease Center, Dana-Farber Cancer Institute, Har-
United Kingdom, said that the committee will change its name to
vard Medical School, Boston, MA, presented How to overcome
Plasma Cell Neoplasia.
Myeloma Stem Cell resistance to therapy - targeting the
Stem Cell niche (SCI-6). The main points of this presentation
William Matsui, MD, Sidney Kimmel Comprehensive Cancer Cen-
include the following:
ter, The Johns Hopkins University School of Medicine, Baltimore,
MD, presented the origin of the Myeloma Stem Cell (SCI-4),
· Mechanisms of drug resistance in myeloma include differential
and discussed the concept of myeloma cancer stem cells. His
dependence on oncogenic pathways compared with the bulk
main points include the following:
of the tumor population, e.g., hedgehog, notch, and Wnt sig-
naling pathways. These pathways all have multiple ligands and
· Clonogenic tumor cells are rare. Relapse in cancer requires
receptor proteins, are complex, and interact with each other,
chemoresistance and clonogenic potential. It is possible that
providing multiple points in these pathways that can be tar-
chemotherapy removes tumor cells but cancer stem cells have
geted in myeloma and other cancers. Agents targeting these
intrinsic drug resistance. It is not clear if tumorigenic cells in
pathways are in clinical development. Although mutations
myeloma are involved in initiation, relapse, or progression.
activating these pathways seem to occur in other cancers, they
have not been seen in myeloma.
· Patient-specific factors, including disease stage and type (MGUS,
myeloma, PCL), whether newly diagnosed or relapsed, as well
· A caveat to targeting developmental pathways in cancer stem-
as genetics, e.g., presence of hyperdiploidy vs. Ig-transloca-
like cells is that agents developed to do so may have side effects
tions, affect the ability to isolate putative myeloma stem cells.
on normal stem cells.
· To identify potential targets of small molecules that might be
· There is an additional need to screen agents against the myeloma
used to attack myeloma stem cells, a discovery approach using
stem cells in the presence of accessory (stromal) cells. Some
GEP and proteomics is required. For this, a homogenous cell
developmental pathways or cancer stem cell pathways seem to
population is needed and it has not been possible to achieve
be more active in the presence of bone marrow stromal cells
this yet in any cancer.
(BMSC), maybe because they target the interactions or have
multi-target effects. Any agent targeting "stemness" needs to be
· Treatment of myeloma requires targeting two compartments:
tested in the presence of the local microenvironment.
plasma cells and stem cells. It has been reported that Rituximab
could target stem cells; if it did so in myeloma, then cyclophos-
· It is not known if most of the tumor is capable of reverting back
phamide could be used to debulk plasma cells, followed by
to stem cell-like cells, and if there is bi-directional transition
more Rituximab for residual stem cells.
of tumor cells between stem cell-like and non-stem cell-like
states, likewise between drug resistant and non-resistant states,
· There is a need for novel clinical trial designs to detect activity
and if these are influenced by the microenvironment.
against the small population of tumor cells. Stem cell-based
biomarker strategies need to be developed.
Side Effects of Therapy
Martin Pérez Andrés, PhD, Universidad de Salamanca, Salamanca,
Neuropathy
Spain, discussed Immunophenotypic analysis of Myeloma
Precursors: antigens for therapeutic targeting (SCI-5). He
Pieter Sonneveld, MD, PhD, Department of Hematology, Erasmus
proposed three features that all tumor stem cells should have:
University Medical Center, Rotterdam, Netherlands, presented
ability to differentiate, ability to self-renew, and resistance to
dealing with neuropathy as part of the Multiple Myeloma
therapy. He reviewed properties of putative myeloma precur-
education Program: Supportive Care in Plasma Cell dyscra-
sor cells, reiterating that the clonogenic fraction is small. The
sias, which he chaired. The talk is summarized here. Important
strongest evidence for them is the ability to reproduce tumors
points include the following:
in vitro and in vivo. He believes these cells have features of ger-
· In all plasma cell diseases, up to 54% of newly diagnosed
minal center cells, that is, B cells not plasma cells, although not
patients, including those with MGUS, myeloma, POEMS, and
everyone agrees. His hypothesis is that a precursor cell in the
Castleman disease, have peripheral neuropathy (PN). PN is also
plasma cell compartment needs to circulate to spread throughout
associated with amyloidosis and cryoglobulinemia.
bone marrow. Another hypothesis is that the cells derive from
memory B cells. Whatever model is correct, it should be possible
· The causes of baseline PN in myeloma include mechanical
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compression of nerves, including the spinal cord; radiculopa-
development of Bortezomib-Induced Peripheral neuropa-
thy; carpal tunnel syndrome; hyperviscosity; diabetes; vitamin
thy (BiPn) In Multiple Myeloma: Incidence and Molecular
deficiencies, e.g., of B12; and possibly genetic susceptibility.
Characterization In newly diagnosed Patients treated with
Bortezomib (abstract 304) was presented by Annemiek Broyl,
· Treatment with vincristine and cisplatin, which are not used
MD, Hematology, Erasmus MC, Rotterdam, Netherlands.
much any more in myeloma, thalidomide, and to a lesser
extent lenalidomide and pomalidomide, and the proteasome
a Phase III Prospective randomized International Study
inhibitors bortezomib and carfilzomib, are associated with PN.
(MMy-3021) Comparing Subcutaneous and Intravenous
PN is one of the most frequent non-hematologic side effects
administration of Bortezomib In Patients with relapsed
of myeloma therapy and has a serious impact on patient QoL,
Multiple Myeloma (abstract 312) was presented by Philippe
including physical, social, and psychological functions. It is also
Moreau, University Hospital, Nantes, France.
frustrating for the physician, and may interfere with patients
continuing therapy.
Thrombosis
· The anatomic damage caused by thalidomide and bortezo-
Sigurdur Y. Kristinsson, MD, PhD, Department of Medicine, Divi-
mib are different. Axons are damaged more by thalidomide,
sion of Hematology, Karolinska University Hospital and Karo-
whereas bortezomib is toxic to small afferent fibers. Carfilzo-
linska Institutet, Stockholm, Sweden, presented thrombotic
mib causes less sensory PN (less than 15%) than bortezomib.
Issues in Myeloma as part of the Multiple Myeloma education
Program: Supportive Care in Plasma Cell dyscrasias, chaired
· Thalidomide causes mixed sensory motor PN with degenera-
by Pieter Sonneveld, MD, PhD, Erasmus University Medical Cen-
tion of the longest axons, inhibits vascular supply to nerves,
ter, Rotterdam, Netherlands. The main points were:
and leads to demyelination, which may be irreversible. Thalido-
mide-emergent PN can be predominantly sensory or sensorim-
· Patients with cancer, including myeloma, have an increased risk
otor, with symmetric hypoesthesia, tingling, or hyperesthesia
for both venous and arterial thrombosis.
of the fingers and toes. Motor PN occurs less frequently than
· Thalidomide and lenalidomide increase the risk of venous
sensory PN. Symptoms such as cramps, weakness, or tremor
thromboembolism (VTE). Thalidomide is associated with an
must be differentiated from steroid-induced effects in patients
increased risk in combination chemotherapy, particularly in
taking thalidomide with steroids.
newly diagnosed patients; lenalidomide increases the risk in
· Bortezomib-emergent PN is typically sensory, and presents as
combination with dexamethasone or chemotherapy in either
hyperesthesia, hypoesthesia, tingling, or temperature sensi-
newly diagnosed or relapsed, refractory myeloma.
tivity, and causes burning sensations in the soles and palms,
· Arterial thrombosis occurs in younger patients with myeloma
starting distally with possible progression to proximal PN.
treated with VAD, TAD, or PAD.
Bortezomib-associated motor PN, if present, follows sensory
· Bortezomib does not cause an increase risk of VTE alone or in
PN. Autonomic PN may present as orthostatic hypotension,
combination with dexamethasone or chemotherapy in newly
sexual dysfunction, or constipation, and generally appears and
diagnosed or relapsed, refractory myeloma. There have been
progresses slowly. Lower bortezomib doses are associated with
suggestions that bortezomib has a protective effect in combi-
a lower incidence of PN.
nation with lenalidomide or thalidomide but patients in many
· Both thalidomide and bortezomib-associated PN are time
studies have been given anti-thrombotic prophylaxis.
dependent and dose dependent. PN associated with thalido-
· Thrombotic events associated with ASCT may be related to the
mide is minimally reversible, and takes years to resolve. Bort-
use of central venous catheters.
ezomib-associated PN improves or resolves in 2 to 3 months in
70% of patients. To manage PN, doses of bortezomib or thalido-
· Published guidelines from the IMWG suggest aspirin for
mide should be modified.
patients with no risk factors and LMWH or full-dose warfarin
for those with two or more risk factors. Duration of throm-
· The key to intervention is prevention, because there is little
boprophylaxis depends on patient- and treatment-related risk
treatment, and prevention is more important than medication.
factors. Risk is highest at the beginning of treatment, so pro-
Vitamin C may interfere with bortezomib efficacy. Tricyclic
phylaxis for 4 to 6 months at least is suggested. There are no
antidepressants, anti-seizure medications, selective serotonin
studies of thromboprophylaxis in patients with myeloma and
norepinephrine reuptake inhibitors (SSNRIs), calcium channel
renal failure, but if CrCl is less than 30 mL/min, it is best to dose
blockers, and other agents have been used to treat PN. Supple-
adjust LMWH or use warfarin.
ments, vitamins, and minerals are sometimes recommended,
but have not been tested in clinical trials.
· Treatment of VTE includes stopping thalidomide or lenalido-
mide, administering full anticoagulation with LMWH or warfa-
two studies assessing peripheral neuropathy are summa-
rin, and then restarting anti-myeloma therapy.
rized in table 5. (see page 15)
8

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Newly Diagnosed Myeloma
dexamethasone) over td and VBMCP/VBad Plus Bortezo-
mib (abstract 307) was presented by Dr. Laura Rosiñol, Hospital
Transplant-Eligible Patients
Clinic, Barcelona, Spain.
IMF Symposium Case 2: evolving treatment approaches
Frontline therapy with Bortezomib, lenalidomide, and
in transplantation-eligible Patients was presented by Jesús
dexamethasone ( Vrd) Induction Followed by autologous
F. San Miguel, MD, PhD, Hospital Universitario de Salamanca,
Stem Cell transplantation, Vrd Consolidation and lenalido-
Salamanca, Spain.
mide Maintenance In newly diagnosed Multiple Myeloma
Controversial issues concerning treatment of young patients with
Patients: Primary results of the IFM 2008 Phase II Study
myeloma include the optimal induction treatment, the role of
(abstract 624) was presented by Murielle Roussel, Hématologie
high-dose therapy and ASCT, the value of maintenance therapy,
Clinique, Hôpital Purpan, Toulouse, France.
treatment according to risk stratification, and the role, if any, for
Molecular remission after Bortezomib-thalidomide-dexa-
allogeneic transplant. The main points of this presentation were:
methasone Compared with thalidomide-dexamethasone
· Induction regimens with bortezomib, thalidomide, or lenalido-
as Consolidation therapy Following double autologous
mide yield better responses and longer PFS than VAD.
transplantation for Multiple Myeloma: results of a Qualita-
· Induction with novel agents and ASCT are complementary, but
tive and Quantitative analysis (abstract 861) was presented
conditioning regimens can be improved by adding bortezomib
by Carolina Terragna, Seràgnoli Institute of Hematology, Bologna
to melphalan; busulfan plus melphalan is showing promising
University School of Medicine, Bologna, Italy.
results.
tandem autologous Hematopoietic Stem Cell transplants
· The IFM-DFCI trial should answer the question about early vs.
(auHCt) with or without Maintenance therapy (auto-auto)
late ASCT. Patients receiving early transplant appear to have a
Versus Single auHCt Followed by Hla Matched Sibling non-
higher 3-year OS than those who continued on primary ther-
Myeloablative allogeneic HCt (auto-allo) for Patients with
apy. With up-front transplant patients are more likely to toler-
Standard-risk (Sr) Multiple Myeloma (MM): results From
ate intensive and repetitive therapies. ASCT is associated with
the Blood and Marrow transplant Clinical trials network
a long treatment-free interval and good QoL, and although
(BMt Ctn) 0102 trial (abstract 41) was presented by Amrita
relapsed myeloma after high-dose (HD) Mel is sensitive to
Krishnan, M.D., Hematology and Stem Cell Transplantation, City
novel agents, it isn't known whether relapsed myeloma after
of Hope, Duarte, CA.
novel therapies is sensitive to HD Mel.
Transplant-Ineligible Patients
· In general, thalidomide, lenalidomide, and bortezomib as
maintenance therapy have shown benefits.
IMF Symposium Case Study 3: emerging therapies for
transplantation-Ineligible Patients was presented by Antonio
· Treatment stratification according to risk factors would offer
Palumbo, MD, University of Torino and Italian Multiple Myeloma
intensive treatment to patients with high-risk disease, and less
Study Group, Torino, Italy. The main points were:
intense approaches for patients with lower-risk disease or for
those who are in CR. If there is no molecular remission, there
· For patients who are not eligible for ASCT, use combinations
is a higher risk of relapse. If cure is the goal, under-treating low-
up front, especially novel agent combinations, because the dis-
risk patients may not be the best approach because they should
ease is more likely to be sensitive and there is a higher chance
be the first group of patients who could be cured. Better tools
of longer survival.
to evaluate treatment efficacy are needed.
· PFS is longer with molecular response, e.g., PCR negative. All
· A particular regimen can't be recommended for high-risk dis-
CR are not the same. Combination therapy may increase the CR
ease based on current data, and trials are needed.
rate via profound cytoreduction, whereas continuous therapy
· Rather than using allogeneic transplantation, Dr. San Miguel
prolongs PFS. CR predicts the long-term outcome in elderly
recommends induction with a novel combination, e.g., VRD
patients.
with or without cyclophosphamide, ASCT with Mel 200 plus
· Toxicity of maintenance therapy with lenalidomide or bortezo-
bortezomib; then if the patient has CR, maintenance with
mib in elderly patients might reduce survival.
lenalidomide; if no CR, then consolidation with VRD, then
maintenance.
· The standard of care for elderly patients should be addition
of a novel agent to MP, e.g., MPT (increases PFS and OS, but
Four studies in transplant-eligible, newly diagnosed patients
requires prophylaxis for VTE) or VMP (once-weekly bortezo-
with myeloma are summarized in table 6. (see page 16)
mib as part of VMP does not decrease PFS or OS, and is associ-
a Phase III PetHeMa/GeM Study of Induction therapy Prior
ated with lower rates of PN and discontinuation). VMPT-VT and
autologous Stem Cell transplantation (aSCt) In Multiple
MPR are other options, but not for patients over age 75 years
Myeloma: Superiority of Vtd (Bortezomib/thalidomide/
because increased dose intensity means increased toxicity and
9

---

discontinuation. Those age 75 years and above should receive
Transplant-based salvage would be appropriate for patients with
reduced-dose chemotherapy. Further dose reductions may be
DOR after their first transplant of 18 to 24 months. The second
necessary based on AE.
duration of remission is usually shorter. It may offer a benefit for
patients with pancytopenia that limits further therapy on or off
Five studies in transplant-ineligible patients with myeloma
clinical trials. The goal of salvage transplant may be to restore
are summarized in table 7. (see page 17)
hematopoiesis to allow further chemotherapy treatment. Patients
lenalidomide Plus low-dose dexamethasone (ld): Superior
with aggressive, rapid, multiple relapses require combination
one- and two-year Survival regardless of age Compared to
therapy, and therapy should not be delayed until symptomatic
lenalidomide Plus High-dose dexamethasone (ld) (abstract
relapse. Transplant-based therapy is short lived in this setting but
308) was presented by Dr. David H. Vesole, John Theurer Cancer
offers quick disease control and reconstitution of bone marrow,
Center at Hackensack University Medical Center, Hackensack, NJ.
allowing patients to receive aggressive maintenance therapy after.
Ablative allogeneic transplant has a high transplant-related mor-
Phase 3b uPFront Study: Safety and efficacy of Weekly
tality (TRM), up to 40 to 50% within 1 year. Non-myeloablative
Bortezomib Maintenance therapy after Bortezomib-Based
transplant has a lower risk of TRM but equivalent mortality at
Induction regimens In elderly, newly diagnosed Multiple
2 years. Graft vs. host disease (GvHD) and relapse are issues
Myeloma Patients (abstract 619) was presented by Ruben Nies-
beyond 2 years.
vizky, Center of Excellence for Lymphoma and Myeloma, Weill
Cornell Medical College, New York Presbyterian Hospital, New
Dr. Lonial's talk ended with a summary of some of the new agents
York, NY.
in development, including:
Bortezomib, Melphalan, Prednisone and thalidomide Fol-
· Pomalidomide, an IMiD structurally similar to thalidomide and
lowed by Maintenance with Bortezomib and thalidomide
lenalidomide, but functionally different.
( VMPt-Vt) for Initial treatment of elderly Multiple Myeloma
· New proteasome inhibitors: carfilzomib, CEP 18770, NPR-0052
Patients: updated Follow-up and Impact of Prognostic Fac-
tors (abstract 620) was presented by Antonio Palumbo, Myeloma
· HDAC inhibitors, which target DNA methylation, including
Unit, Division of Hematology, University of Torino, Torino, Italy.
panobinostat, vorinostat, and romidepsin, which may be syner-
gistic with bortezomib. Panobinostat and vorinostat may be syn-
novel three- and Four-drug Combination regimens of Bort-
ergistic with lenalidomide.
ezomib, dexamethasone, Cyclophosphamide, and lenalido-
mide for Previously untreated Multiple Myeloma: results
· Agents that target the PI3K/Akt pathway and downstream targets
From the Multi-Center, randomized, Phase II eVolutIon
include the Akt inhibitor perifosine, which enhances bortezomib-
Study (abstract 621) was presented by Shaji Kumar, MD, Divi-
induced cytotoxicity, and mTOR inhibitors, which are also being
sion of Hematology, Mayo Clinic, Rochester, MN.
tested in combination with bortezomib.
a Phase III Study evaluating the efficacy and Safety of
· Monoclonal antibodies, including elotuzumab.
lenalidomide Combined with Melphalan and Prednisone In
Dr. Lonial concluded that there is no easy algorhythm for treat-
Patients 65 years with newly diagnosed Multiple Myeloma
ing relapsed myeloma. Patient-specific issues, prior therapy, and
(ndMM): Continuous use of lenalidomide Vs Fixed-duration
FISH and cytogenetics should be considered and used to guide
regimens (abstract 622) was presented by Antonio Palumbo,
MD, University of Torino, Torino, Italy.
treatment decisions.
Relapsed/Refractory Myeloma
Combination of Bendamustine, lenalidomide, and dexa-
methasone In Patients with refractory or relapsed Multiple
Sagar Lonial, MD, Hematology and Medical Oncology, Emory Uni-
Myeloma Is Safe and Highly effective: results of a Phase I
versity, Winship Cancer Institute, Atlanta, GA presented relapsed
Clinical trial (abstract 989) was presented by Suzanne Lentzsch,
Multiple Myeloma as part of the Multiple Myeloma education
Department of Medicine, Division of Hematology/Oncology, Uni-
Program on advances in the Basic Science of Plasma Cell
versity of Pittsburgh School of Medicine and Cancer Institute,
disorders, which he chaired.
Pittsburgh, PA
Dr. Lonial discussed new treatments and approaches for the man-
objectives: The objectives of this study included determining
agement of relapsed disease. OS and event-free survival (EFS) are
MTD, safety, and the dose for a phase II study of bendamustine,
poor in patients with disease resistant to bortezomib, thalidomide,
lenalidomide, and dexamethasone.
and lenalidomide. The options in the relapsed setting include
doses: Bendamustine was given on days 1 and 2, lenalidomide
existing novel agents, existing older agents, and new agents in
on days 1 to 21, dexamethasone on days 1, 8, 15, and 22 at 40 mg
clinical trials. Early relapse should be treated with combination
in 28-day cycles for a maximum of 8 cycles and 2 beyond the best
therapy; later relapse with a single agent. If the previous myeloma
response. Doses of bendamustine and lenalidomide were esca-
was aggressive, when it relapses it will require therapy sooner.
lated with a fixed dose of dexamethasone for three dose levels.
10

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Patients: Patients with relapsed or refractory myeloma who were
were the most likely to know when transformation or progres-
not transplant eligible (N=25) were included.
sion is occurring.
Side effects: There were no DLTs at level 1; at level 2 there was
Ultra-High Risk Myeloma
one instance of neutropenia, at level 3 there were several. The
Hervé Avet-Loiseau, MD, PhD, University Hospital of Nantes,
MTD was 75 mg bendamustine, 10 mg lenalidomide. There were
Nantes, France presented ultra high-risk multiple myeloma
no grade 4 non-hematologic events; grade 3 events included
as part of the education Program: understanding and Man-
fatigue. Hematologic events included cytopenias; grade 3 to 4
aging ultra High-risk Hematologic Malignancies chaired by
AE were mostly myelosuppression. Grade 1 PN occurred in 20%,
Elihu J. Estey, MD, University of Washington, Fred Hutchinson
grade 2 in 8%, with no grade 3 or 4 PN. All serious AE resolved
Cancer Research Center, Seattle, WA. The main points of this pre-
(n=3). Patients received aspirin and no TE were seen.
sentation include the following:
results: The best responses after 2 or more cycles in 23 evaluable
·An arbitrary definition of ultra high-risk myeloma is patients
patients were ORR 66%, clinical benefit response 91%, at least
having a survival of 24 months regardless of their age. This is in
PR 66%. Median follow-up was 8.8 months. PD occurred in 13
contrast with median survival in the IFM trials for those under
patients, and 4 died. Time to best response was 1.8 months, TTP
age 65 years of almost 8 years and for older patients of some-
was 4.3 months, time to next therapy was 6.7 months, and the
what over 4 years.
trial is still ongoing, with the last patient enrolled. Treatment was
tolerated in patients up to age 81 years (range 40 to 81 years),
· Extrinsic factors contributing to high-risk myeloma include
and was active in heavily pretreated patients.
2M and lactate dehydrogenase (LDH).
Diagnosis, Risk Stratification,
· Intrinsic factors contributing to high-risk myeloma include
and Staging
plasma cell proliferation, leukemic presentation, and cer-
tain genetic changes. Important chromosomal abnormalities
MGUS and SMM
include t(4;14) and 17p deletion.
Dr. Ola Landgren, MD, PhD, Medical Oncology Branch, National
· The ISS stage is also prognostic. For patients of any age, sur-
Cancer Institute, National Institutes of Health, Bethesda, MD,
vival curves differ depending on stage; those over age 65 years
presented MGuS and Smoldering Myeloma: new Insights
with ISS stage III have a median OS of less than 24 months, for
Into Pathophysiolog y and epidemiolog y as part of the Mul-
those under age 65 years OS is probably about 28 months.
tiple Myeloma education Program on advances in the Basic
· Several groups are identifying GEP profiles, SNPs, and chro-
Science of Plasma Cell disorders, chaired by Sagar Lonial, MD,
Emory University School of Medicine, Atlanta, GA.
mosomal copy number abnormalities that are associated with
good or poor prognosis and that when combined with 2M
To answer the question whether myeloma is always preceded by
could be used to define the population with poor survival.
MGUS, the National Institutes of Health (NIH) conducted a pro-
spective screening study for cancers, which identified 71 patients
· Plasma cell leukemia or leukemic presentations have a very
who developed multiple myeloma. In these patients, myeloma
poor prognosis but there are no publications with a large num-
was always preceded by MGUS. The FLC ratio was abnormal in
ber of patients with this condition.
many before the development of myeloma. The M-spike signifi-
· High-risk myeloma can be defined currently as ISS stage III,
cantly increased over time as the time of diagnosis of myeloma
presence of del 17p, poor risk genomics by GEP or SNP array,
approached. Two patterns were identified: half the patients had
or leukemic presentation.
an evolving M-spike, and half had no M-spike. They are currently
looking at whether these populations are different. NIH/National
·Classical induction regimens such as VAD, TD, or bortezomib
Cancer Institute (NCI) has an ongoing prospective natural history
combinations are not active, and Dr. Avet-Loiseau proposes
and molecular profiling study. All costs are covered to get patients
treating with a rotation of combinations of active drugs, includ-
to the study site. The vast majority of patients with MGUS will
ing bortezomib, lenalidomide, dexamethasone, cyclophospha-
never progress to myeloma, so at this time there is no indication
mide, and possible doxorubicin for long-term treatment to
for screening for MGUS in the clinic. Patients with SMM should be
reduce the aggressive myeloma clone. HD Mel may be useful
considered for clinical trials. Outside of clinical trials, observation
for patients under age 65 or 70 years, although the effective
is still considered the standard of care. Better understanding of
number of courses is unknown. Bortezomib could be added;
the pathogenesis from MGUS to myeloma is needed. Dr. Land-
possibly VTD or VRD could be used. Maintenance therapy for
gren observed that there are 3 million people with MGUS in the
patients with high-risk myeloma is also an open question; tha-
US, and only about 20,000 patients each year are diagnosed with
lidomide may be deleterious, and little benefit has been shown
myeloma. They are now screening to identify patients with MGUS
for bortezomib or lenalidomide.
who didn't progress to myeloma. Patients with MGUS should be
· There is an urgent need for a universal definition of ultra
made aware of the symptoms of transformation because they
high-risk multiple myeloma and a need for international trials
11

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in this patient group. Additionally, there is a need to identify
Prognostic Impact of Genetic Subgroups and development
risk factors in phase III trials of agents such as carfilzomib,
of Gene Classifiers for response, PFS and oS In Multiple
pomalidomide, elotuzumab, and HDAC inhibitors, with the
Myeloma Patients treated with Bortezomib or Conventional
goal of identifying drugs for these high-risk patients, who may
agents In HoVon65/GMMG-Hd4 trial (abstract 445) was
constitute as much as 20% of the myeloma patient population.
presented by Annemiek Broyl, MD, Department of Hematology,
Erasmus MC, Rotterdam, Netherlands.
Diagnosis, Prognosis, and Risk Assessment
IMF Symposium: Case Study 1: diagnosis, Prognosis, and
Bortezomib-Based Induction treatments Improve outcomes
risk assessment in Multiple Myeloma was presented by
of newly diagnosed Multiple Myeloma Patients with High-
S. Vincent Rajkumar, MD, Mayo Clinic, Rochester, MN. Major
risk Cytogenetic abnormalities (abstract 781) was presented
points of this presentation include the following:
by Michele Cavo, Seràgnoli Institute of Hematology, Bologna Uni-
versity School of Medicine, Bologna, Italy.
· Positron emission tomography (PET scan) can indicate myeloma
Hevylite® test
disease that is not otherwise apparent, and can determine if the
spinal cord is compromised. For SMM and solitary plasmacyto-
the ratio of Monoclonal to Polyclonal Immunoglobulins
mas, magnetic resonance imaging (MRI) of the entire spine can
assessed with the Hevylite® test Predicts Prognosis, is Supe-
be used to confirm the diagnosis and to determine the extent
rior for Monitoring the Course of the disease, and allows
of disease when symptoms don't agree with the skeletal survey.
detection of Monoclonal Immunoglobulin in Patients with
Lytic bone lesions are seen in 67% of patients at presentation;
normal or Subnormal Involved Immunoglobulin Isotype
the use of PET-CT (computed tomography) or MRI can detect
(abstract 4038), was presented by Heinz Ludwig, Department
more.
of Medicine, Wilhelminenspital, Vienna, Austria. The Hevylite®
test was used to determine the ratio of monoclonal to isotype-
· Current IMWG response criteria use FLC if patients lack mea-
matched polyclonal immunoglobulins (heavy/light chain ratio;
surable disease (M-spike). FLC is also used for risk stratification
HLC ratio) at baseline and to evaluate response in 133 patients
of patients with MGUS, SMM, and solitary plasmacytomas, and
with myeloma who had normal or below normal levels of the
for screening in lieu of UPEP because it is easier to do a serum
involved immunoglobulin isotype. Conventional prognostic fac-
assay than to collect a 24-hour urine sample.
tors were also measured, including IgG, IgA, 2M, FLC, LDH, and
creatinine. Survival analysis and Cox proportional hazards were
· A work-up of myeloma should consist of M-protein analysis
performed. The HLC ratio is highly prognostic, improves detec-
using serum protein electrophoresis (SPEP; detection rate is
tion of variations in the course of the disease, and increases the
82%) or serum immunofixation electrophoresis (IFE; detection
diagnostic accuracy in patients with normal or subnormal levels
rate is 93%); if FLC or UPEP/UIFE is added, M-protein detection
of the involved isotype, including those with negative immu-
rises to 97-98%.
nofixation (IFE). Note that The Binding Site, manufacturer of
· The Durie-Salmon staging system has stood the test of time and
the Hevylite® test, is awaiting a pre-IDE (Investigational Device
is still useful to determine tumor burden. For the ISS a diagno-
Exemption) decision from the US FDA for Hevylite® diagnosis
sis of myeloma must be confirmed first; then ISS can be used
and monitoring claims. Dr. Avet-Loiseau has looked at progres-
to stage the disease.
sion-free survival (PFS) for 338 patients on IFM trials using tradi-
tional ISS classes based on 2M plus albumin vs. 2M plus the
· The role of GEP in risk stratification remains to be determined.
Hevylite® ratio. ISS class results fall in 2 prognostic groups: ISS
2M is a prognostic factor because it is a surrogate for renal
Stage I, which has significantly longer PFS, vs. Stage II + III. The
failure and high tumor burden, and a patient presenting with
2M plus Hevylite® ratio scoring system showed a much lower
renal failure needs the best available therapy early on.
p-value for separation of these two prognostic groups.
Genetic Factors
Conclusions
three studies assessing the role of genetic factors in
myeloma are summarized in table 8. (see page 18)
The trend of increased survival for patients with myeloma that
began in the era of novel agents (bortezomib, lenalidomide,
Clinical outcome according to Both Cytogenetic abnor-
and thalidomide) is continuing. The novel agents are now part
malities (Ca) detected by Fluorescence In Situ Hybridiza-
of new standards of care, with "novel-er" agents in development
tion (FISH) and Hyperdiploidy assessed by Flow Cytometry
and early and late clinical trials, and include targeted therapies.
(FCM) In elderly newly diagnosed Myeloma Patients treated
Future regimens are likely to be based on combination therapies
with a Bortezomib-Based Combination, (abstract 309) was
with unique mechanisms of action and non-overlapping toxicities.
presented by María Victoria Mateos, University Hospital of Sala-
Risk stratification and tailoring of therapy to individual patients'
manca, Salamanca, Spain.
needs is advancing, and is including patient quality of life.
12

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Table 1. Summary of Carfilzomib Studies
abstract
Patients Phase Follow-up
agents and doses
Side effects
responses
First author
abstract 862
newly diagnosed patients
carfilzomib (C) days 1, 2, 8,
mostly mild; grade 3 to 4
stringent complete response
A.J. Jakubowiak phase I: the maximum
9, 15, and 16; 20 to 27 to
neutropenia infrequent, no
(sCR)/CR/near (n)CR=55%
tolerated dose (MTD); dose-
38 mg/m2 lenalidomide (R):
fevers or decline in neutrophils
sCR=22% partial response (PR)
limiting toxicities (DLT), n=
continuously on days 1 to
with treatment; no emergence of
or better=96% (100% after 4
21; 25 mg per day low-dose
clinically significant peripheral
cycles) at least very good (VG)
31 (27 evaluable) phase II:
dexamethasone (d); (CRd) days
neuropathy (PN)
PR=83% and CR/nCR=67%
to be initiated median F/U 6
1, 8, 15, and 22 of a 28 day
after 8 cycles
months
cycles CRd every other week as
maintenance
abstract 985
patients with progressive disease
carfilzomib first dose 20 mg/m2,
77% of patients had pre-existing
A1 responses: overall response
D.S. Siegel
(PD) after last therapy with
registration cohort dose was 27
PN treatment-emergent adverse
rate (ORR)=24%, at least
prior lines of therapy, including
mg/m2
events (AE) included few grade
VGPR=5.5% (0.4 % CR),
bortezomib (100%) and
3 to 4 hematologic toxicities:
PR=18.7%, minimal response
thalidomide or lenalidomide
neutropenia=10% non-
(MR)=10% median progression-
phase II: A1 n=257 evaluated
hematologic toxicities: 12% any
free survival (PFS)=3.7
for response of the 266 patients
grade PN and 0.8% grade 3 and
months median overall
enrolled and in the safety
4 PN; most discontinuations due
survival (OS)=15.5 months;
population
to PD and none to emerging
median OS not reached in
PN 95 deaths on study mostly
responders duration of response
due to progressive disease (PD);
(DOR)=8.3 months in both
16% of patients completed all
PR and MR populations clinical
12 cycles
benefit (at least MR)=34%
Table 2. Summary of Pomalidomide Studies
abstract
Patients Phase Follow-up
agents and doses
Side effects
responses
First author
abstract 863
patients with relapsed myeloma
pomalidomide 2 mg daily days
most patients experienced
PR or better=26%; MR or
M.Q. Lacy
resistant or refractory to both
1 to 28 (could be escalated to
hematologic toxicity; non-
better=49%; median time
lenalidomide and bortezomib;
4 mg if PD) dexamethasone 40
hematologic toxicities included
to response (TTR) 1 month;
n=35 Phase I/II median F/U 9.1
mg days 1, 8, 15, 22 full-dose
fatigue and PN in most patients;
DOR 12 months; survival at 6
months
aspirin or low-molecular-weight
70% PN at study entry, 20%
months=78%; median survival
heparin (LMWH) or warfarin
pomalidomide-related PN
not reached
during study; 2 instances of
deep vein thrombosis (DVT)
and 1 myocardial infarction (MI)
abstract 864
patients with myeloma
pomalidomide 21 of 28 days
grade 3 to 4 myelosuppression
phase I: PR or greater 27% for
P.G. Richardson
refractory to lenalidomide
with and without low-dose
was the dominant AE with
the 4 mg dose, 29% for the 5 mg
and bortezomib phase I: MTD
dexamethasone; phase I: 2
low incidences of venous
dose, and 25% overall median
phase II: open label, Arm A=
mg (n=6), 3 mg (n=8), 4 mg
thromboembolism (VTE) and
OS=79.6 weeks phase II (first
pomalidomide 4 mg plus low
(n=14), 5 mg (n=10), total
PN; =4 mg
120 efficacy evaluable patients
dexamethasone vs. Arm B=
enrollment, N=38; if PD or no
enrolled): best response of at
pomalidomide 4 mg alone,
response after 4 cycles option to
least PR combining both arms
endpoint is PFS; N=221
add low dexamethasone at 40
by EBMT criteria = 25% and by
mg per week
IMWG criteria = 28%
abstract 859
patients with myeloma
Arm A= 4 mg pomalidomide
most hematologic AE were
ORR 42% for Arm A vs. 39% for
X. LeLeu
refractory to at least 2
and low dexamethasone for
neutropenia; some PN, and
Arm B TTR was 2 months for
cycles of lenalidomide and
21 days of 28 per cycle; N=43
no DVT; dose reduction for
Arm A vs. 1.7 months for Arm
bortezomib and a creatinine
Arm B, 28 days of continuous
pomalidomide was required for
B PR = 33% for Arm A, 34%
clearance (CrCl) of 50 mL/min
4 mg pomalidomide plus low
49% in Arm A vs. 41% in Arm B
for Arm B time to progression
randomized phase II median
dexamethasone; N=41 aspirin
(TTP) similar in both arms; 5
follow-up 6.5 for Arm A vs. 7
or LMWH recommended for all
vs. 6 deaths, 88% vs. 85% of
months for Arm B
patients
patients surviving at 6 months
13

---

Table 3. Summary of New Targeted Therapy Trials
abstract
Patients Phase Follow-up
agents and doses
Side effects
responses
First author
abstract 990
patients had 1 prior therapy
IV temsirolimus at 15 to 25 mg weekly on
phase I: the most common
phase II: ORR=40%
I.M. Ghobrial
and were heavily pretreated
days 1, 8, 15, 22, and 29 of 35 day cycles
AE was thrombocytopenia;
excluding 3 unevaluable
with dexamethasone; most
bortezomib at 1.3 to 1.6 mg/m2 weekly
1 death due to septic shock
patients; in with bortezomib-
had received thalidomide,
on days 1, 8, 15, and 22 dexamethasone
phase II: toxicities included
resistant disease ORR=20%;
bortezomib, and lenalidomide
not permitted
thrombocytopenia and fatigue;
in bortezomib-sensitive
phase I (dose-escalation)
no sensory neuropathy due
disease ORR=53% median
n=20 Phase II n=43
to temsirolimus or weekly
PFS=5 months median
bortezomib; 3 deaths
TTP=5.7 months
abstract 860
patients with symptomatic
PD0332991 in combination with
schema A: DLTs required dose
PD0332991 abrogated
R. Niesvizky
relapsed and/or refractory
bortezomib and dexamethasone, given
reductions; Schema B: DLT
phosphorylation of Rb in
myeloma after >1 treatment
on two different schedules Schema
at the first dose escalation
80% of patients; 1 patient on
who were Rb positive and
A: PD0332991 daily for 21 days plus
AEs were related to the
each Schema had VGPR
had disease with a high
bortezomib and dexamethasone, n=9
combination of PD0332991
proliferation rate phase I dose
schema B:PD0332991 daily for 11 days
and bortezomib and included
escalation study; determine
plus bortezomib and dexamethasone,
cytopenias
MTD for Phase II
n=12: used for phase II: PD0332991 will
be 100 mg, bortezomib 1.0 mg/m2 and
dexamethasone 20 mg
Table 4. Summary of Maintenance Studies
abstract
Patients Phase
agents and doses
Side effects
responses
First author
Follow-up
abstract 623
820 patients
thalidomide or no maintenance (half
high rate of PN led to slightly over
PFS significantly longer for patients
G. Morgan
to each arm) median 7 months of
half of patients discontinuing
on thalidomide maintenance overall
maintenance
maintenance
with most benefit for those with
favorable FISH; no difference in OS
abstract 310
614 patients under
placebo (n=307) or lenalidomide
discontinuation rate 15% for
CR and PFS improved with
M. Attal
age 65 years with
(n=307) maintenance therapy
placebo vs. 21% with lenalidomide;
lenalidomide maintenance 4
non-progressive
lenalidomide caused significant non-
factors associated with improved
disease within 6
febrile neutropenia, and 2% DVT vs.
PFS: lenalidomide maintenance,
months of ASCT; phase
0 for placebo recommendation to
VGPR after consolidation (most
III median F/U 34
monitor for second malignancies
important), no del 13, and low
months post-random
B22M no differences in OS 5 years
assignment
post-diagnosis between groups
(80%).
abstract 37
patients with stable
placebo (n=229) or lenalidomide
lenalidomide maintenance
lenalidomide associated with 60%
P. McCarthy
disease (SD) or better
maintenance (n=231) at a starting
associated with significantly more
reduction in the risk of disease
within a year of
dose of 10 mg/day, escalated to
AE, including thrombocytopenia,
progression or death vs. placebo
induction therapy and
15 mg/day after 3 months, and
neutropenia, febrile neutropenia,
median TTP for lenalidomide =
ASCT Mel 200
continued until PD, with dose
and infections 15 new malignancies
42.3 months vs. 21.8 months for
reductions or discontinuation if
after randomization in patients
placebo TTP independent of B2M
necessary for toxicity
receiving lenalidomide vs. 6 in the
levels or prior lenalidomide or
placebo arm
thalidomide no difference in OS not
yet published
14

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Table 5. Summary of Peripheral Neuropathy Studies
abstract
Patients Phase
agents and doses
Side effects
results
First author
Follow-up
abstract 304 patients with myeloma
induction therapy
incidence of early onset bortezomib-
Early onset BiPN was associated with
A. Broyl
(n=369) phase III
with bortezomib (PAD;
induced PN (BiPN) (within one treatment
genes involved in drug-induced apoptosis,
prospective, randomized n=250) followed by
cycle) in the bortezomib-treated patients
peripheral nervous system development
trial (HOVON65/
bortezomib maintenance
was not significantly different from the
and function, DNA repair, mitochondrial
GMMG-HD4) sub-study
vs. conventional
incidence of early onset vincristine induced dysfunction, and AMPK signaling.
to analyze genetic
vincristine (VAD; n=250) PN (ViPN) in VAD-treated patients late
Late- onset BiPN was associated with
variation associated with induction therapy
onset (after cycle 2 to 3); BiPN was
different genes involved in peripheral
BiPN the "Bank on a
followed by thalidomide
significantly greater (grade 2 to 4) than
nervous system development and
Cure" (BOAC) SNP chip,
maintenance
ViPN, 25% vs. 7%
function, apoptosis, calcium ion binding,
containing 3404 SNPs in
inflammation, transcription regulation,
functional regions within
and DNA repair. ViPN was associated with
983 cellular function
different genetic factors.
genes and pathways
abstract 312 74 patients in the IV
subcutaneous (SC)
grade 3 and 4 AE were reduced, but not
ORR=42% in both arms after 4 cycles
P. Moreau
arm, 148 patients in the
bortezomib (2.5 mg/mL)
statistically significantly with SC:, 57% for
VGPR for IV = 16% vs. 17% for SC
SC arm
vs. IV bortezomib (1 mg/
SC and 70% for IV neutropenia significantly After 8 cycles 52% ORR and 25% VGPR
mL) at the usual dose and reduced with SC administration;
for both arms median TTR=1.4 months
phase III randomized
schedule dexamethasone
thrombocytopenia and anemia the same
in both arms median TTP=9.4 months
study
after 4 cycles if response
for SC and IV PN statistically significantly
for IV and 10.4 months for SC 1 year
was <PR
different: any PN 53% with IV vs. 38% with
survival=76% for IV and 73% for SC PK
SC; grade 2 PN 41% with IV vs. 24% with
and pharmacodynamics are the same,
SC; grade 3 PN 16% with IV and 6% with
and differences in Cmax and Tmax might
SC. Local site reactions (redness) in 6% of
explain the improved safety profile with the
patients; 1% of patients had a severe site
SC route
reaction
15

---

Table 6. Summary of Studies in Transplant-eligible, Newly Diagnosed Patients
abstract
Patients Phase
agents and doses
Side effects
results
First author
Follow-up
abstract 307 390 patients (130 per
n=129 for QT
grade 3 to 4 adverse events were similar
CR was significantly higher with VTD
L. Rosinol
arm) GEM05 MENOS65
+V (conventional
among the arms; neutropenia was higher
(35%) than QTD (21%) or TD (14%);
median F/U = 27 months chemotherapy: VBMCP/
for QT+V PN was higher with VTD
post-ASCT CR was 38% for QT+V, 24%
VBAD plus bortezomib),
for TD, and 48% for VTD; CR for patients
n=127 for TD, n=130
with t(4;14) was higher with VTD; CR
for VTD
for patients with t(11;14) was better
with QT+V; OS at 4 years was 76% with
no significant differences across groups
but was shorter for high- risk patients
regardless of treatment
abstract 624 newly diagnosed younger VRD induction, SC
almost all patients experienced
RR improved with each stage of
M. Roussel
patients (n=31) phase II
collection, ASCT with HD
hematologic toxicities; grade 3 to 4 events
treatment; VGPR was over 80%;
open label (IFM 2008)
Mel, consolidation with
included 39% neutropenia (decreased
CR in almost half of patients
VRD, maintenance for 12
to 26% with dose reduction), 13%
months with lenalidomide
thrombocytopenia, and 6% anemia; PN in
at a dose of 10 mg for 3
68% of patients, 55% during induction,
months; if tolerated, the
13% during consolidation, all grade 1 and
dose was increased to 15
2, requiring bortezomib dose reduction
mg per day continuous
in 23%; 2 TE; 5 needed second-line
lenalidomide
mobilizing agent for SC collection;
collection not possible in one patient
abstract 861 young, newly diagnosed
VTD vs. TD for
results
C. Terragna
patients sub-study of
induction prior to ASCT
TD arm: 10 of 32 (31%) PCR negative at baseline; at consolidation 15 of 31 (48%) were
GIMEMA looking for
random assignment to
PCR negative; at F/U, MCR was 37.5%; 41% had persistently positive PCR. VTD arm:
minimal residual disease
consolidation with VTD
13 of 33 (39%) PCR negative at baseline; at consolidation 21 of 32 (64%) were PCR
(MRD) in bone marrow
(n=34) or TD (32) after
negative; MCR was 45.5%, and 21 % of patients were persistently PCR positive.
at consolidation using
ASCT; maintenance for
patient-specific IgH gene
both arms
An upgrade in PCR- negative status after consolidation occurred with VTD but not TD.
rearrangements and
PFS was significantly longer for patients who were PCR negative at consolidation
patient-specific PCR
(two primers designed
for each)
abstract 41
patients biologically
initial ASCT with HD
treatment-related mortality (TRM) at 3
84% of patients assigned to thalidomide
A. Krishnan
assigned to ASCT
Mel 200 then ASCT or
years was significantly higher in the ASCT-
maintenance did not complete it. PFS and
(n=436) or to alloSCT
alloSCT on basis of donor
alloSCT group (12%) than in the tandem
OS were similar and results were pooled
(n=189) on the basis
graft-versus-host disease
ASCT group (4%)
for all tandem ASCT patients; after
of availability of an
(GvHD); prophylaxis
the first ASCT, 3- year PFS was similar
eligible, HLA-matched
was cyclosporine and
between groups (46% for tandem ASCT
sibling donor after ASCT
mycophenolate mofetil.
vs. 43% for ASCT-alloSCT), and 3- year
phase III
Iif tandem ASCT, random
OS was 80% vs. 77%. Nno significant
assignment to maintenance
difference in 3- year progression/relapse
with thalidomide plus
between the tandem ASCT (46%) and
dexamethasone (n=217)
ASCT-alloSCT (40%) groups
or observation (n=219)
for one year
16

---

Table 7. Summary of Studies in Transplant-ineligible Patients
abstract
Patients Phase
agents and doses
Side effects
responses
First author
Follow-up
abstract 308
newly diagnosed
LD (lenalidomide plus high
toxicity was higher in all age groups
OS for Ld was superior to that of LD at
D. Vesole
patients ECOG study
dose dexamethasone) vs. Ld
receiving high- dose dexamethasone
1 and 2 years OS across all age groups
E4A03
(lenalidomide plus low dose
using an age-smoothing technique to
dexamethasone) survival of
correct for age as a continuous variable;
patients treated with LD was
by this method, there is no age group
inferior at the initial analysis
for which high-dose dexamethasone
so those on LD crossed over
is superior LD results in a higher RR
to Ld, which is a confounding
in patients under age 65 years but not
variable for a long-term study
improved PFS or OS
abstract 619
newly diagnosed
8 cycles of induction therapy
for the first 100 patients treatment-
PFS for the three arms is similar, around
R. Niesvizky
elderly patients
and 6 cycles maintenance
emergent grade 3 or more AE were
13 to 17 months, but these are early
ineligible for transplant
VD ("classic" bortezomib
high; PN was significant, especially
results; global health improved at the
in the context of a
and dexamethasone) vs.
with VTD, which was also associated
time of maintenance, and the best QoL
community oncology
VTD (bortezomib and
with the highest rate of AE overall;
was seen for the VMP group (poster
practice (n=502 for
dexamethasone on the same
grade 3 or higher PN was 15%,
Abstract 3026)
ITT population) F/U is
classic schedule plus 100
26%, and 20% for VD, VTD, or VMP,
ongoing
mg thalidomide) vs. VMP
respectively, and the respective
(bortezomib on the same
discontinuation rates were 7%, 17%,
schedule, melphalan and
and 18%;serious AE (SAE) included
prednisone on the first 4
pneumonia and thrombosis associated
with VT; during maintenance there
days of every other cycle)
was no increase in toxicities, including
maintenance with 1.6 mg/m2
PN or SAE
of bortezomib once weekly for
4 weeks out of every 5
abstract 620
patients over age
VMP and no maintenance
VMPT increases neutropenia to 35%,
CR = 24% for VMP, and 42% for VMPT
A. Palumbo
65 years (n=511);
(n=257) vs. VMPT, adding 50
thrombocytopenia and anemia are
(statistically significant difference) no
median maintenance
mg continuous thalidomide
similar for both treatments; grade
difference in OS between groups; 3 year
duration of 18 months
for 9 courses, with bortezomib
3 to 4 non-hematologic AE were
OS approached 80% for VMP and 85%
twice monthly as maintenance
significantly increased; risks of cardiac
for VMPT-VT landmark analysis at the
(VMPT-VT; n=254)
toxicity and TE and a non-significant
end of 9 cycles showed a 52% reduced
increase in infections with VMPT;
risk of progression for VMPT-VT clinical
decrease in any grade PN for VMP
benefit from the 4-drug combination is
from 43% to 21%, and reduction of
an increasing CR rate with maintenance
grade 3 or 4 PN from 4% to 2% with
prolonging response median PFS
change of twice- to once-weekly
for VMPT-VT was 37 months; VMPT
infusion of bortezomib; AE during
associated with longer PFS in patients
maintenance included PN in 6% of
younger than age 75 years; for patients
patients; discontinuation for AEs was
older than 75 years, there was no
around 11%
difference in PFS between treatments
abstract 621
patients ASCT- eligible
VDCR (standard bortezomib,
toxicities generally similar across arms:
CR = 5% to 12%, higher in the VDC-
S. Kumar
or not eligible phase
40 mg dexamethasone,
nearly all patients had at least 1 grade
mod arm; about half of patients with
I/II (NCT00507442)
cyclophosphamide, and
3 AE; 2 on-study deaths in the VDCR
CR had MRD; about half the patients in
phase I dose escalation
lenalidomide) vs. VDR vs.
arm due to renal dysfunction about
each arm had a best confirmed response
of cyclophosphamide
VDC; VDC-mod (extra dose of
15% grade 3 to 4 PN neutropenia
of VGPR 1 year estimated PFS = 85%
and determine regimen
cyclophosphamide to improve
higher with cyclophosphamide-
estimated OS at 1 and 2 years were 92%
for phase II median
response rate) 8 cycles of
containing regimens; SC collected in
and 76%, respectively for VDCR, and
F/U 18 to 21 months
induction and ASCT or 4
nearly half of patients, and failure to
100% for VDC-mod
a phase III trial will
cycles of maintenance
collect occurred in newly diagnosed
compare VDR and
patients
VDC-mod
(Table 7 continues on next page)
17

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Table 7. Summary of Studies in Transplant-ineligible Patients (continued)
abstract
Patients Phase
agents and doses
Side effects
responses
First author
Follow-up
abstract 622
transplant ineligible,
MPR-R then continuous
hematologic toxicities the major AEs
VGPR = 30% for MPR and MPR-R, 3 times
A. Palumbo
elderly patients phase
lenalidomide at 10 mg per day
during induction grade 4 TE in 10% of
higher than with MP (60% reduced risk of
III median F/U 25
as maintenance vs. MPR with
patients non-hematologic grade 3 to
progression overall, 69% for patients age
months
no maintenance; vs. MP with
4 AE included 10% infection and 2%
65 to 75 years, 61% for patients over age
no maintenance
to 5 % pulmonary embolism (PE) and
75 years) PFS = 31 months for MPR-R,
DVT AE during maintenance included
14 months for MPR, and 13 months for
a low rate of cytopenias due to shorter
MPT MPR-R associated with longer PFS for
follow-up and dose reductions to avoid
patients under the age of 75 years, with ISS
discontinuation; low rate of infection,
stages I and II, and with lower 2M 69%
some late thrombosis discontinuation
reduced risk of progression after 9 cycles
rate higher for patients over the age of
of MPR with lenalidomide maintenance,
75 years up to 3% solid tumors occurred
significantly better than MPR without
(2% with MPR-R), 2% AML, and less
maintenance no difference in OS among
than 1% MDS, but the risk of secondary
treatments; 1- year survival about 92%,
tumors is higher with alkylating agents
2-year survival 75% to 82%
Table 8. Summary of Studies in Assessing Genetic Factors
abstract
Patients Phase
Genetic analysis
results
First author
Follow-up
agents and doses
abstract 309
patients age greater
Patient samples were analyzed
Response results recently published in Lancet Oncology. Hypodiploidy is associated
M.V. Mateos
than 65 years (n=260)
by flow cytometry for ploidy.
with poorer prognosis. DNA ploidy analysis found hyperploidy in 132 (59%)
(GEM05;) induction
232 patients with FISH data: 188
of patients and non-hyperdiploidy (which included hypodiploidy due to small
therapy of VMP vs.
were considered standard risk by
numbers of patients with this abnormality) in 92 patients. After induction therapy
VTP for 6 cycles with
cytogenetics, 44 (19%) high risk,
there were no significant differences in efficacy and similar responses were seen
weekly bortezomib,
after maintenance; there were no differences seen between VT vs. VP maintenance.
with t(4;14) and del 17 p; the
PFS from the first and second randomizations were similar, but OS was significantly
then each group split to
high-risk group also had slightly
shorter in the non-hyperdiploid patients; it was 63% at 3 years, and the difference
maintenance with either
higher 2M and advanced stage
was more pronounced for VTP induction. With bortezomib-based combinations,
VT or VP
of disease
the RR and CR rates are similar between high- and standard-risk cytogenetics, but
this does not overcome the poor prognosis of high-risk cytogenetics in terms of PFS
and OS.
abstract 445
HOVON-65/GMMG-HD
clusters of patients were
Bortezomib overcomes poor prognosis associated with some clusters. Probes
A. Broyl
4 (HD4) trial, n= 832
defined based on translocations:
selected from HD4 were those most likely to detect high risk patients. The HD4
n = 570 bone marrow
CD-1, CD-2, MS, and MF; 2
high risk signature was validated in two independent data sets and identified a
for plasma cell (PC)
hyperdiploid clusters: HY and
proportion of patients with significantly lower survival irrespective of treatment and
purification, n = 341 PC
PR; a low bone sub-cluster:
whether newly diagnosed or with relapsed disease. The predominant 1q and 1p
samples had a purity of
LO; a myeloid cluster; 2 novel
aberrations in the UAMS set are not seen in the HD4 set, and there seems to be little
or no overlap. Patients with a higher hazard ratio were also found in the APEX trial
over 80%
clusters CTA and PRL3. GEP was
used to determine a high risk
data set, but more work is needed for better prediction.
signature. The HD4 trial samples
were used as a training set. Two
independent data sets were used
as external validation: UAMS
patients on TT2 (n=351)and on
TT3 (n=208)
abstract 781
post-hoc analysis of
218 were transplant eligible
Of the total 590 patient population, 261 (44%) had no cytogenetic abnormalities;
M. Cavo
two GIMEMA trials
and received 5 cycles of VTD
175 (30%) had del 13 q and 154 (26%) had t(4;14) with or without del 17p. The
of bortezomib-based
induction and consolidation
high- risk population was subdivided in to those with t(4;14) with or without del
induction treatments for
after ASCT. There were 372
13. The three risk groups were evenly distributed across the three treatments (VTD,
newly diagnosed patients,
transplant-ineligible patients, of
VMP, and VMPT). The high-risk group had a significantly higher frequency of higher
n=813; after excluding
ISS stage, and other demographic characteristics were generally same, age and
whom 181 received VMP for 9
2M.
When stratified by cytogenetic abnormalities, those with t(4;14) had shorter survival
223 patients treated with
cycles and 191 received VMPT
and lower PFS than those with no cytogenetic abnormalities. Patients with both
TD, 590 patients received
for 9 cycle
t(4;14) and del 17p tended to have shorter PFS than those with one abnormality,
bortezomib; bone
but survival for those with either or both was about the same at 18 months. For
marrow PC at diagnosis
patients with t(4;14) with and without del 17p, PFS was significantly higher if
were isolated using
they were treated with VTD vs. TD. There was no difference in survival between
CD138-coated magnetic
treatment with VMPT vs. VMP. Bortezomib-based regimens were likely to overcome
beads to purity in excess
poor prognosis related to several high-risk cytogenetic abnormalities, particularly
of 90%. For the analysis,
t(4;14). There were only small numbers of patients with del 17p, so the difference
baseline data on del 13,
in response was less clear, but regimens containing combinations of three or four
drugs might help; however, this is speculation.
t 4;14), and del 17 p had
to be available
18

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International Myeloma Foundation
12650 Riverside Drive, Suite 206
North Hol ywood, CA 91607 USA
Telephone:
800-452-CURE (2873)
(USA & Canada)
818-487-7455
Fax: 818-487-7454
TheIMF@myeloma.org
www.myeloma.org

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