InternatIonal MyeloMa FoundatIon
ASH 2010
Highlights
for Patients
with Myeloma
Summaries of Multiple Myeloma Presentations
from the 52nd Annual Meeting
of the American Society for Hematology (ASH)
held in Orlando, Florida
December 47, 2010
Compiled by Lynne Lederman, PhD
Funded by unrestricted educational grants from Celgene Corporation and Onyx Pharmaceuticals.
ASH 2010 Summaries of Multiple Myeloma
Presentations for Patients
Introduction
seem promising that are in clinical trials include bortezomib
(VELCADE®) and lenalidomide (Revlimid) in combination with
The 52nd Annual Society of Hematology (ASH) Annual Meeting
histone deacetylase (HDAC) inhibitors, monoclonal antibodies
was held December 4th through 7th, 2010, in Orlando, FL. This
(mAbs), proteasome inhibitors other than bortezomib and carfil-
report summarizes presentations at the 2010 ASH Annual Meet-
zomib, and other agents, some of which are approved for use in
ing, organized by topics rather than by sessions, providing an
other cancers, and some of which are not. Some of the agents that
overview of information on new drugs in development; clinical
are close to approval or that may be available to patients who are
trial results; treatment by patient characteristics, e.g., transplant
willing to participate in clinical trials are discussed in this report.
eligibility or stage of disease; risk stratification and staging; dis-
ease biology including bone disease and use of bisphosphonates;
Carfilzomib (PX-171): a Proteasome Inhibitor
and maintenance therapy. Although maintenance therapy is sum-
Carfilzomib is a proteasome inhibitor, the same class of drugs as
marized in its own section, some trials that include maintenance
bortezomib. One trial of carfilzomib summarized here is signifi-
therapy are summarized in more appropriate sections, as many
cant because it was the first time carfilzomib was studied in newly
trials are now including some kind of continuing treatment for at
diagnosed, rather than relapsed and refractory, myeloma. This
least some patients.
trial in patients with newly diagnosed myeloma tested carfilzomib
On December 3, the International Myeloma Foundation (IMF)
in combination with lenalidomide and dexamethasone.
and the Postgraduate Institute for Medicine sponsored a sympo-
Carfilzomib, lenalidomide, and dexamethasone In newly
sium that presented an overview of the most recent data from
diagnosed Multiple Myeloma: Initial results of Phase I/II
clinical trials to allow participants to provide better care for their
MMrC trial (abstract 862) was presented by Andrzej J. Jakubow-
patients with multiple myeloma. Dr. Brian G.M. Durie introduced
iak, University of Michigan, Ann Arbor, MI.
the presenters and topics at the symposium. Summaries of these
presentations are included under the appropriate headings.
In this early (phase I) trial, patients with newly diagnosed
myeloma received carfilzomib plus lenalidomide plus low-dose
Multiple myeloma was the topic of many presentations at ASH,
dexamethasone. The purpose of the trial was to determine the
including the following:
doses of these drugs that could be used in a later-stage (phase
· Education sessions were held on advances in the basic science
II) trial. Side effects of the drug combination included decreases
of plasma cell disorders and on supportive care in plasma cell
in the numbers of white blood cells (neutropenia), but this did
dyscrasias.
not happen frequently and was not associated with fever. No
· An education session on high risk hematologic diseases
medically significant peripheral neuropathy (PN; damage to the
included a talk on ultra high-risk myeloma.
nerves of the hand, feet, arms, or legs) was observed. Encourag-
ing responses to the combination of drugs was seen, although
· A scientific session was conducted on therapeutic targeting of
early-phase trials are not meant to determine how effective drugs
the myeloma stem cell.
are. The treatment allowed eligible patients to collect their own
· Over a dozen simultaneous oral sessions (comprising about 6
stem cells for use in transplants. Patients completing 8 cycles of
presentations each) were held specifically on myeloma, with
treatment are receiving the combination less frequently for main-
many other sessions presenting related information on trans-
tenance therapy. A phase II trial in newly diagnosed patients and
plantation, venous thromboembolism, stem cell collection,
a phase III trial in patients with relapsed myeloma are planned.
tumor cell biology, and other topics of interest.
Pomalidomide: an Immunomodulatory Drug
· Three poster sessions featured hundreds of posters about
(IMiD)
myeloma and related topics, e.g., transplantation, pharmaco-
economics, and new drugs in development.
Pomalidomide is a drug that is similar to thalidomide (Thalomid®)
and lenalidomide (Revlimid®), but has different side effects and
New Drugs in Development
activity. Three presentations that looked at the best dose for
pomalidomide are briefly summarized here.
At the IMF Symposium, Dr. Robert Z. Orlowski, MD, PhD, The
University of Texas M. D. Anderson Cancer Center, Houston, TX,
Pomalidomide Plus low-dose dexamethasone In Myeloma
pointed out that promising newer therapies include the novel
refractory to Both Bortezomib and lenalidomide:
agents carfilzomib and pomalidomide. New combinations that
Comparison of two dosing Strategies In dual-refractory
3
disease (abstract 863) was presented by Martha Lacy, MD,
Elotuzumab, a Monoclonal Antibody (mAb)
Division of Hematology, Department of Internal Medicine, Mayo
Monoclonal antibodies (mAbs) are antibodies produced in the
Clinic, Rochester, MN.
laboratory by a single clone of cells or a cell line. The mAb mol-
This presentation summarized the results of two phase II trials
ecules produced by a given clone are identical. In this respect,
looking at two different doses of pomalidomide, 2 mg or 4
mAbs resemble the M-proteins of myeloma. The clones or cell
mg, given with dexamethasone. In the study of the lower dose,
lines producing mAbs are often derived from animals such as
patients could receive the higher dose if their disease continued
mice. To avoid causing an allergic reaction in patients, parts of
to worsen. Patients in both studies had myeloma that no longer
the molecules may be changed to more closely resemble human
responded to bortezomib or lenalidomide. Most patients had
antibodies. These are called "humanized" mAbs. Elotuzumab is
side effects including decreased white blood cells, fatigue, and
a humanized monoclonal antibody (mAb) that specifically reacts
peripheral neuropathy. A few patients experienced blood clots
with a molecule that is seen in large amounts on the surface of
even though they took medications to prevent clots. Based on
myeloma cells, but not on most normal cells. Elotuzumab, when
encouraging responses, a study is testing the 4-mg dose, although
given to patients, will attach to the surface of myeloma cells and
Dr. Lacy said there may be no reason to go over a dose of 2 mg.
help the immune system destroy those cells. Elotuzumab has
been tested in combination with other anti-myeloma drugs. The
a Phase I/II Multi-Center, randomized, open label dose
results of one of the elotuzumab trials are summarized below.
escalation Study to determine the Maximum tolerated
dose, Safety, and efficacy of Pomalidomide alone or In
elotuzumab In Combination with lenalidomide and dexa-
Combination with low-dose dexamethasone In Patients
methasone In Patients with relapsed Multiple Myeloma:
with relapsed and refractory Multiple Myeloma Who Have
Interim results of a Phase II Study (abstract 986) was pre-
received Prior treatment that Includes lenalidomide and
sented by Paul G. Richardson, Dana-Farber Cancer Institute, Har-
Bortezomib (abstract 864) was presented by Paul G Richard-
vard Medical School, Boston, MA.
son, MD, Dana-Farber Cancer Institute, Boston, MA.
This is a phase II trial to evaluate the response of patients with
This study was designed to determine the best dose of pomalido-
relapsed myeloma to a combination of elotuzumab, lenalido-
mide and determine if dexamethasone increased its activity in
mide, and dexamethasone. Patients had not previously been
patients whose myeloma no longer responded to lenalidomide
treated with lenalidomide, but had received 1 to 3 previous
and bortezomib. The results of phase I and preliminary results
treatments including thalidomide and stem cell transplant. In
of phase II were presented. In phase I the doses were increased
the phase I trials, patients experienced side effects related to
until there were serious side effects, leading to a 4- mg dose being
the intravenous infusion of elotuzumab. Therefore, in this trial,
chosen for the phase II part of the study. Responses in phase
the patients received a dose of a steroid equivalent to 10 mg of
I were encouraging. In phase II, pomalidomide is being given
dexamethasone, which cut the number of these reactions in half.
either alone or with dexamethasone. Side effects in the first half
Encouraging responses were seen. The side effects that were seen
of patients treated include serious decreases in white blood cells.
were those expected in patients receiving lenalidomide and dexa-
Blood clots and peripheral neuropathy were rare. Dr. Richard-
methasone. Side effects related to elotuzumab were fatigue and
son believes that additional studies of pomalidomide should be
low fevers. Two doses were tested, and the lower dose, 10 mg/kg,
done at different doses in patients who have received less initial
is recommended for the open-label phase III trial to start in 2011.
therapy, and in combination with other novel drugs.
Maintenance Therapy
Phase II Study of 2 Modalities of Pomalidomide (CC4047)
As mentioned in the introduction, in addition to specific studies
Plus low-dose dexamethasone as therapy for relapsed
of maintenance therapy, maintenance therapy was also discussed
Multiple Myeloma. IFM 2009-02 (abstract 859) was presented
as part of other clinical trials. Dr. Phillippe Moreau, MD, Univer-
by Xavier LeLeu, Service des Maladies du Sang, Hôpital Huriez,
sity Hospital Hôtel-Dieu, Nantes, France, discussed consolidation
Lille, France.
and maintenance therapy in myeloma as part of the IMF Sympo-
In this phase II study, patients also had myeloma that no lon-
sium. This section also includes summaries of three maintenance
ger responded to lenalidomide and bortezomib. There were 2
clinical trials. Maintenance therapy is given after myeloma has
groups of patients treated, and each received 4 mg pomalido-
been controlled by induction therapy, transplant (when appro-
mide plus low-dose dexamethasone; one group received con-
priate), and consolidation therapy, with the aim of prolonging
tinuous therapy, and the other received cycles of three weeks of
remission or stable disease. Some of the agents that are being
therapy followed by one drug-free week. Side effects required
tested as maintenance therapy most recently include thalido-
the doses of both drugs to be reduced, and included decreased
mide, lenalidomide (either alone or with low- dose dexametha-
numbers of white blood cells and some peripheral neuropathy.
sone), or bortezomib. The use of lenalidomide for maintenance
Responses seemed comparable to responses in the other studies
is allowed in the US but not in some other countries. It is not
mentioned here.
4
yet known which drug is best or how long maintenance therapy
Maintenance treatment with lenalidomide after trans-
should be given.
plantation for Myeloma: Final analysis of the IFM 2005-02
(abstract 310) was presented by Michel Attal, MD, Hopital Pur-
Dr. Moreau reported that consolidation therapy following autolo-
pan, Toulouse, France.
gous stem cell transplant (ASCT) is being evaluated in clinical
trials, and that it is possible to achieve a complete remission (CR)
In IFM (French) trials, thalidomide maintenance also produced
where no abnormal cells are seen in the bone marrow (stringent
a high rate of peripheral neuropathy, shortening the duration of
CR), and DNA from the myeloma can't be detected (also known
maintenance therapy. Thalidomide maintenance had no benefit
as molecular CR). Maintenance therapy after ASCT is feasible and
for patients with the cytogenetic abnormality of deletion of chro-
prolongs the length of survival with no disease progression, but
mosome 13 (del 13) or for patients whose transplant resulted
the effect on overall survival is not known. Maintenance therapy
in a very good partial response (VGPR, defined as 90% reduc-
after combination chemotherapy in elderly patients (who do not
tion of monoclonal protein) or better. In the trial presented at
receive ASCT) is feasible and prolongs the length of survival with
this ASH meeting, patients who had consolidation therapy with
no disease progression, but again, the effect on overall survival is
lenalidomide within 6 months of ASCT were randomly assigned
not known.
to receive either lenalidomide maintenance or no maintenance
(placebo). Lenalidomide maintenance improved the complete
thalidomide Maintenance Significantly Improves Pro-
response rate and PFS regardless of the patients' initial response,
gression-Free Survival (PFS) and overall Survival (oS) of
and this effect was seen in patients with the risk factors high
Myeloma Patients When effective relapse treatments are
beta-2-microglobulin (2M) and del 13 (unlike thalidomide
used: MrC Myeloma IX results (abstract 623) was presented
maintenance). Four factors associated with improved PFS are
by Gareth J Morgan, Institute of Cancer Research, The Royal Mars-
lenalidomide maintenance, VGPR or better after consolidation;
den Hospital, London, United Kingdom.
no del 13; and low 2M. The discontinuation rate of lenalido-
mide maintenance is lower than that for thalidomide main-
Dr. Morgan believes that the take-home from this ASH meeting
tenance. However, patients may have a small increased risk of
should be that maintenance, which in myeloma is a new con-
second cancers, so they should be observed carefully. Longer
cept, is effective and likely to be around for some time because it
follow-up of this study is needed to see the effect of lenalido-
contributes to the control of residual disease. Prior agents used
mide maintenance on survival; it may require 2 to 3 years to see a
for maintenance; including alkylators, steroids, and interferon,
difference in overall survival between lenalidomide maintenance
have generally not resulted in increased survival. Prior studies
and placebo.
of thalidomide maintenance have yielded conflicting and incon-
sistent results concerning survival without disease progression
Phase III Intergroup Study of lenalidomide Versus Placebo
(progression-free survival), improved response, and effects on
Maintenance therapy Following Single autologous Hema-
quality of life (QoL). This report uses the MRC Myeloma IX study
topoietic Stem Cell transplantation (aHSCt) for Multiple
of patients randomly assigned to thalidomide or no maintenance
Myeloma: CalGB 100104 (abstract 37) was presented by
(half to each treatment) to answer these questions. Progression-
Philip L. McCarthy, MD, BMT Program, Roswell Park Cancer Insti-
free survival (PFS) was significantly longer for patients on thalido-
tute, Buffalo, NY.
mide maintenance, but there was no difference in overall survival
between patients taking thalidomide maintenance and those who
In this study, patients received a single ASCT, but unlike the
were not. For the subgroup of patients with unfavorable cyto-
French study, they did not receive consolidation therapy. Patients
genetics by fluorescence in situ hybridization (FISH), PFS was
who received lenalidomide maintenance had a longer time until
no different than for those with favorable FISH. However, those
their disease progressed, almost twice as long as patients receiving
with unfavorable FISH had a much shorter overall survival if they
placebo. Their 2M levels, and whether or not they had received
were taking thalidomide maintenance therapy, particularly if they
prior treatment with either lenalidomide or thalidomide, did not
were taking it at the time of relapse. In studies at UAMS (Uni-
affect this response. Lenalidomide was associated with more side
versity of Arkansas for Medical Sciences) with a long follow-up
effects, and second cancers were noted. Overall survival results
of 6 to 7 years, patients receiving thalidomide maintenance did
have not yet been published.
have an overall survival advantage. In Dr. Morgan's study, tha-
lidomide maintenance was of short duration (average 7 months)
due to such side effects as a high rate of peripheral neuropathy,
and slightly over half of the patients discontinued treatment.
Dr. Morgan concluded that agents with better tolerability, such
as lenalidomide, may produce better results. The following two
presentations discuss lenalidomide maintenance.
5
Bisphosphonates and Bone Disease
affecting blood cells. PN has a serious impact on patient QoL,
including physical, social, and psychological function. It is also
optimising Bone disease In Myeloma; Zoledronic acid Plus
frustrating for the physician, and may interfere with patients con-
thalidomide Combinations Improves Survival and Bone
tinuing therapy. Bortezomib and thalidomide cause PN by dif-
endpoints: results of the MrC Myeloma IX trial (abstract
ferent mechanisms; carfilzomib causes less PN than bortezomib.
311) was presented by Gareth J Morgan, Section of Haemato-
Symptoms such as cramps, weakness, or tremor must be differ-
Oncology, The Institute of Cancer Research, London, United
entiated from side effects caused by steroids in patients taking
Kingdom.
thalidomide with steroids. Lower bortezomib doses are associ-
ated with a lower incidence of PN. Diagnosis of treatment-related
This presentation focused on patients who were randomly
PN requires healthcare professionals to ask the right questions;
assigned to one of two bisphosphonate drugs used to treat
screening questionnaires may be used. Both thalidomide- and
bone disease, either zoledronic acid (Zometa®) or clodronate
bortezomib-associated PN are related to the dose and the dura-
(Bonefos®). These were given to patients in both treatment arms
tion of therapy. PN associated with thalidomide is minimally
(intense and non-intense) in the MRC Myeloma IX trial. Note
reversible, and takes years to resolve. Bortezomib-associated PN
that zoledronic acid is available in the US, but clodronate is not
improves or resolves in 2 to 3 months in 70% of patients. Doses of
(although it is available in Canada, the UK, and other countries).
either bortezomib or thalidomide may be reduced to manage PN.
Zoledronic acid was associated with significantly improved overall
Drugs such as tricyclic antidepressants, anti-seizure medications,
survival (5.5-month increase) compared with clodronate, and PFS
selective serotonin norepinephrine reuptake inhibitors (SSNRIs),
was also increased. Adjustment for skeletal-related events (SRE;
calcium channel blockers, and other agents have been used to
defined as pathologic fractures, need for radiation to the bone,
treat PN. Supplements, vitamins, and minerals are recommended
bone surgery, spinal cord compression, and similar events) still
by some physicians, but these remedies have not been tested in
favors the use of zoledronic acid, suggesting that zoledronic acid
clinical trials.
has an anti-myeloma effect. Zoledronic acid significantly reduced
SRE for patients with bone lesions at diagnosis and for those with
a Phase III Prospective randomized International Study
no lesions at the start of treatment. Zoledronic acid decreased
(MMy-3021) Comparing Subcutaneous and Intravenous
SRE compared with clodronate during maintenance therapy, and
administration of Bortezomib In Patients with relapsed
was better than clodronate regardless of the induction regimen.
Multiple Myeloma (abstract 312) was presented by Philippe
Patients receiving thalidomide-containing regimens plus zole-
Moreau, university Hospital, nantes, France.
dronic acid had better responses. Osteonecrosis of the jaw (ONJ)
was significantly higher with zoledronic acid, about 4%, but all
This was a phase III randomized study comparing two different
incidents were minor and resolved without surgery and with con-
ways to administer bortezomib, either subcutaneously (SC, injec-
servative management. Note that current treatment guidelines
tion under the skin), or intravenously (IV, administration into a
recommend starting bisphosphonates after bone disease devel-
vein). IV is the currently recommended method. Patients were
ops, but this study shows improvement in patients without bone
randomly assigned in a 2:1 ratio to SC vs. IV bortezomib. IV and
disease. Guidelines from the American Society of Clinical Oncol-
SC bortezomib were administered at the usual dose and sched-
ogy (ASCO) suggest 2 years of bisphosphonate therapy.
ule, and dexamethasone could be added. There were no differ-
ences in response between the two methods of administration
Side Effects of Therapy
after 4 cycles and after 8 cycles. Median time to disease progres-
sion and survival at one year were also similar. Some side effects
Neuropathy
were similar between the two methods, but neutropenia and PN
Pieter Sonneveld, Md, Phd, department of Hematolog y,
were significantly lower with SC administration. SC administra-
erasmus university Medical Center, rotterdam, netherlands,
tion has similar effectiveness to IV administration, is more conve-
presented dealing with neuropathy as part of the Multiple
nient, and is more tolerable.
Myeloma education Program: Supportive Care in Plasma
Cell dyscrasias, which he chaired. the talk is written up in
Clotting (Thrombosis)
the aSH education Program Book, Hematolog y 2010, and is
Sigurdur y. Kristinsson, Md, Phd, department of Medicine,
summarized here.
division of Hematolog y, Karolinska university Hospital and
Karolinska Institutet, Stockholm, Sweden, presented throm-
This talk focused on treatment-related PN in myeloma. Drugs pre-
botic Issues in Myeloma as part of the Multiple Myeloma
viously associated with PN in myeloma are the drugs vincristine
education Program: Supportive Care in Plasma Cell dyscra-
and cisplatin, which are not used much any more in myeloma.
sias Chaired by Pieter Sonneveld, Md, Phd, erasmus uni-
Currently thalidomide, and to a lesser extent lenalidomide and
versity Medical Center, rotterdam, netherlands. the talk is
pomalidomide, and the proteasome inhibitors bortezomib and
summarized here.
carfilzomib are associated with PN, which is one of the most
frequent side effects of myeloma therapy other than side effects
6
Patients with myeloma have an increased risk for clots (throm-
· Inductionregimenswithnovelagents(bortezomib,thalidomide,
bosis) in both veins (venous) and arteries (arterial). Patients
or lenalidomide), yield better responses and longer PFS.
with myeloma have an increased risk for clots in veins (venous
· ASCT and induction with novel agents are complementary, but
thrombotic events or VTE) with thalidomide and lenalidomide.
conditioning regimens can be improved.
Clots in arteries occur in young patients with myeloma treated
with vincristine, thalidomide, or bortezomib in combination with
· Patients receiving early transplant appear to have a higher
Adriamycin® and dexamethasone. Patients with MGUS (IgG or
3-year overall survival than those who continued on primary
IgA but not IgM) are also at higher increased risk of venous and
therapy.
arterial thrombosis. Thalidomide alone does not increase the risk
· Of 6 trials of thalidomide maintenance for which data are
of thrombotic events in newly diagnosed or relapsed, refractory
available, all showed increased event-free survival, and 3 also
myeloma but does increase the risk in combination therapy. The
showed increased overall survival for maintenance. However,
rate is higher in newly diagnosed patients than in patients with
in one of these trials there was increased toxicity and poorer
relapsed, refractory myeloma. Lenalidomide increases VTE risk
QoL associated with thalidomide maintenance. Lenalidomide
in combination with dexamethasone or chemotherapy in either
maintenance after ASCT was shown to yield a survival benefit
newly diagnosed or relapsed, refractory myeloma, but not as
in two trials and may maintain response or eradicate or control
a single agent. Bortezomib does not cause an increase risk of
residual tumor burden. Bortezomib maintenance after ASCT
thrombosis alone or in combination with dexamethasone or che-
also has shown benefit in increased PFS and overall survival,
motherapy in newly diagnosed or relapsed, refractory myeloma.
particularly in patients with high-risk disease.
There have been suggestions that bortezomib has a protec-
tive effect in combination with lenalidomide or thalidomide,
Dr. San Miguel continues to recommend that patients enroll in
but patients in many of these studies have been given drugs to
clinical trials, which contribute to progress in drug development
prevent clots, so this effect cannot be confirmed. Thrombotic
and increased survival and will help determine the place of the
events associated with ASCT may be related to the use of central
newer agents in treatment regimens.
venous catheters. Dr. Kristinsson suggested patients with MGUS
should be treated like the general population for clot preven-
a Phase III PetHeMa/GeM Study of Induction therapy Prior
tion. Patients with myeloma taking combination chemotherapy
to autologous Stem Cell transplantation (aSCt) In Multiple
or high-dose dexamethasone need to take agents to prevent clots,
Myeloma: Superiority of Vtd (Bortezomib/thalidomide/
but the best agents and doses haven't been confirmed. The IMWG
dexamethasone) over td and VBMCP/VBad Plus Bortezo-
guidelines suggest aspirin for patients with no risk factors, and
mib (abstract 307) was presented by Dr. Laura Rosiñol, Hospital
low-molecular-weight heparin (LMWH) or full-dose warfarin for
Clinic, Barcelona, Spain.
those with two or more risk factors. The clotting risk is highest at
the beginning of treatment, so 4 to 6 months at least of preventa-
This was a study of induction therapy comparing bortezomib
tive treatment is suggested. Treatment of VTE includes stopping
plus thalidomide plus dexamethasone (VTD) to either thalido-
thalidomide or lenalidomide, administering full anticoagula-
mide plus dexamethasone (TD) or conventional chemotherapy
tion with LMWH or warfarin, and then restarting anti-myeloma
plus VTD prior to ASCT. VTD was associated with a higher com-
therapy.
plete response rate overall, even for patients with high-risk dis-
ease, and with longer PFS. Longer follow-up is needed to confirm
Newly Diagnosed Myeloma
if bortezomib combinations can overcome at least partially the
poor survival outcome of high-risk cytogenetics.
Transplant-Eligible Patients
Molecular remission after Bortezomib-thalidomide-dexa-
IMF Symposium Case 2: evolving treatment approaches in
methasone Compared with thalidomide-dexamethasone
transplantation-eligible Patients was presented by Jesús F.
as Consolidation therapy Following double autologous
San Miguel, Md, Phd, Hospital universitario de Salamanca,
transplantation for Multiple Myeloma: results of a Qualita-
Salamanca, Spain.
tive and Quantitative analysis (abstract 861) was presented
Although overall survival for patients has increased, even a
by Carolina Terragna, Seràgnoli Institute of Hematology, Bologna
10-year survival is not acceptable for a relatively young patient
University School of Medicine, Bologna, Italy.
with many potential years ahead. Controversial issues concerning
This GIMEMA (Italian) trial tested VTD vs. TD for induction prior
treatment of young patients with myeloma include the optimal
to ASCT in young, newly diagnosed patients. Patients in both
induction treatment, the role of high-dose therapy and ASCT, the
treatment groups received maintenance therapy, which improved
value of maintenance therapy, treating according to risk stratifica-
responses for patients receiving VTD, but not TD. The lower the
tion, and the role, if any, for allogeneic transplant. Points made by
amount of myeloma, the better the response. VTD lowered the
Dr. San Miguel include the following:
amount of disease burden better than TD, and increased survival
when the amount of myeloma was decreased significantly.
7
tandem autologous Hematopoietic Stem Cell transplants
lenalidomide Plus low-dose dexamethasone (ld): Superior
(auHCt) with or without Maintenance therapy (auto-auto)
one- and two-year Survival regardless of age Compared to
Versus Single auHCt Followed by Hla-Matched Sibling non-
lenalidomide Plus High-dose dexamethasone (ld) (abstract
Myeloablative allogeneic HCt (auto-allo) for Patients with
308) was presented by Dr. David H. Vesole, John Theurer Cancer
Standard-risk (Sr) Multiple Myeloma (MM): results From
Center at Hackensack University Medical Center, Hackensack, NJ.
the Blood and Marrow transplant Clinical trials network
(BMt Ctn) 0102 trial (abstract 41) was presented by Amrita
The ECOG study E4A03 randomly assigned newly diagnosed
Krishnan, M.D., Hematology and Stem Cell Transplantation, City
patients to LD (lenalidomide plus high-dose dexamethasone)
of Hope, Duarte, CA.
vs. Ld (lenalidomide plus low dose dexamethasone), and deter-
mined response rates after 4 months of therapy. Survival of
This study showed that there was no significant difference in
patients treated with LD was worse at the initial analysis, so those
progression-free survival or overall survival for patients who
on LD crossed over to Ld. This analysis determined the effect of
received two consecutive ASCT (tandem ASCT) when compared
age on survival and side effects. Those under age 65 years had
with patients who received one ASCT followed by an allogeneic
better responses with the higher dose of dexamethasone, but not
stem cell transplant from a tissue-type-matched brother or sister
longer PFS or overall survival. For all age groups, significantly
(ASCT-alloSCT). However, after three years, deaths due to treat-
more cycles are completed with the low- than the high-dose dexa-
ment (treatment-related mortality) were significantly higher in
methasone. Overall survival was longer at 1 and 2 years for Ld
patients who received the ASCT-alloSCT, so there was no benefit
than LD. Side effects were higher in all age groups receiving high-
to being treated with ASCT-alloSCT.
dose dexamethasone. Low-dose dexamethasone is the treatment
of choice for newly diagnosed patients in all age groups. There
Transplant-Ineligible Patients
are no data in the relapsed, refractory setting for Ld.
IMF Symposium Case Study 3: emerging therapies for
transplantation-Ineligible Patients was presented by anto-
Phase IIIb uPFront Study: Safety and efficacy of Weekly
nio Palumbo, Md, university of torino and Italian Multiple
Bortezomib Maintenance therapy after Bortezomib-Based
Myeloma Study Group (GIMeMa), torino, Italy.
Induction regimens In elderly, newly diagnosed Multiple
Myeloma Patients (abstract 619) was presented by Ruben Nies-
Dr. Palumbo discussed treatment strategies for patients who are
vizky, Center of Excellence for Lymphoma and Myeloma, Weill
not eligible for ASCT. He made the following points:
Cornell Medical College, New York Presbyterian Hospital, New
York, NY.
· Combination therapy should be used up front when the risk of
side effects is lower, when the myeloma may be more sensitive,
This study determined which induction regimen would be best for
and when there is a higher chance of longer survival.
newly diagnosed elderly patients in the context of a community
· Although maintenance therapy with lenalidomide or bortezo-
oncology practice. At the time of the trial design, the best three
mib has been shown to improve PFS, in elderly patients toxicity
bortezomib-containing combinations were VD ("classic" bortezo-
might reduce survival.
mib and dexamethasone), VTD (bortezomib and dexamethasone
on the same classic schedule plus 100 mg thalidomide), and VMP
· Prevention of clots using LMWH is suggested for older patients
(bortezomib on the same schedule, melphalan and prednisone
using lenalidomide or thalidomide.
on the first 4 days of every other cycle). These three regimens
· The addition of a novel agent (thalidomide, lenalidomide, or
were evaluated in a community practice setting, along with main-
bortezomib) to melphalan plus prednisone (MP) increases PFS
tenance therapy of 1.6 mg/m2 of bortezomib once weekly for 4
and overall survival; bortezomib plus MP (VMP) is the current
weeks out of every 5. Side effects, including PN, and discontinua-
standard of care.
tion were lower with VD. The best QoL was seen with VMP, which
remains the standard of care. Bortezomib maintenance did not
· Once-weekly bortezomib as part of VMP does not decrease PFS
increase PN. Further follow-up and analysis are planned.
or overall survival, but is associated with lower rates of PN and
therapy discontinuation.
Bortezomib, Melphalan, Prednisone and thalidomide Fol-
· Although some three- and four-drug combinations with main-
lowed by Maintenance with Bortezomib and thalidomide
tenance therapy increase responses and progression-free sur-
( VMPt-Vt) for Initial treatment of elderly Multiple Myeloma
vival, they may be too toxic for patients over age 75 years.
Patients: updated Follow-up and Impact of Prognostic Fac-
tors (abstract 620) was presented by Antonio Palumbo, Myeloma
· Non-transplant-eligible patients should receive age-adjusted
Unit, Division of Hematology, University of Torino, Torino, Italy.
therapy; patients age 65 to 74 years can receive full-dose che-
motherapy, those over age 75 years should receive reduced-
Dr. Palumbo also agreed VMP is now considered to be the best
dose chemotherapy. Side effects may require further dose
standard of care for non-transplant eligible patients. VMP with no
reductions.
maintenance was compared with VMPT plus VT maintenance in
patients over age 65 years who were not ineligible for transplant.
8
Responses were higher with VMPT, but overall survival was the
summary of some of the new agents in development, including
same for both treatments. VMPT had more side effects. PN was
the following:
reduced by changing the infusion of bortezomib from twice to
· Pomalidomide, a new IMiD structurally similar to thalidomide
once weekly, and responses were not affected. Progression-free
and lenalidomide, but functionally different
survival was increased with VMPT only for patients younger than
age 75 years. For patients older than 75 years, who received half
· New proteasome inhibitors: carfilzomib, CEP 18770, NPR-0052
the dose that younger patients received due to dose reductions
· HDAC inhibitors, which target DNA methylation; activity may
or discontinuations, there was no difference in PFS between
be related to protein catabolism; as misfolded proteins accu-
treatments.
mulate, they are toxic to cells. Agents include panobinostat,
a Phase III Study evaluating the efficacy and Safety of
vorinostat, and romidepsin, which may increase the activity
lenalidomide Combined with Melphalan and Prednisone In
of bortezomib. Panobinostat and vorinostat may increase the
Patients 65 years with newly diagnosed Multiple Myeloma
activity of lenalidomide.
(ndMM): Continuous use of lenalidomide Vs Fixed-duration
· Most myeloma cells use the PI3K/Akt pathway and downstream
regimens (abstract 622) was presented by Antonio Palumbo,
targets to survive. Agents that target this pathway include the
MD, University of Torino, Torino, Italy.
Akt inhibitor perifosine, which enhances bortezomib-induced
cytotoxicity, and mTOR, which is also being tested in combina-
In this phase III study, transplant-ineligible, elderly patients were
tion with bortezomib.
assigned to one of 3 treatment arms: MPR-R, with continuous
lenalidomide at 10 mg per day as maintenance; MPR with no
· No monoclonal antibody (mAb) has been shown to have single-
maintenance; or MP with no maintenance. Both MPR and MPR-R
agent activity in myeloma, which Dr. Lonial characterized as
resulted in higher responses than MP. PFS was highest for MPR-R,
an oncologic irony. mAbs in clinical trials include elotuzumab.
particularly for patients who were age 65 to 75 years. Overall sur-
vival appears to be better in the younger patients (age 65-74), and
Dr. Lonial concluded that patient-specific issues, prior therapy,
in those with a lower disease stage, good renal function, or low
and FISH and cytogenetics should be used to guide treatment
B2M. Patients over age 75 years were more likely to discontinue
decisions.
treatment, and better therapy for this age group is needed.
Diagnosis, Risk Stratification,
novel three- and Four-drug Combination regimens of Bort-
and Staging
ezomib, dexamethasone, Cyclophosphamide, and lenalido-
mide, for Previously untreated Multiple Myeloma: results
MGUS and SMM
From the Multi-Center, randomized, Phase II eVolutIon
dr. ola landgren, Md, Phd, Medical oncolog y Branch,
Study (abstract 621) was presented by Shaji Kumar, MD, Divi-
national Cancer Institute, national Institutes of Health,
sion of Hematology, Mayo Clinic, Rochester, MN.
Bethesda, Md, presented MGuS and Smoldering Myeloma:
new Insights Into Pathophysiolog y and epidemiolog y,
The 4-drug combination VDCR (bortezomib, dexamethasone,
as part of the Multiple Myeloma education Program on
cyclophosphamide, and lenalidomide) was compared in this
advances in the Basic Science of Plasma Cell disorders,
phase I/II trial with VDR, VDC, and a fourth regimen, VDC-mod,
chaired by Sagar lonial, Md, emory university School of
that was added to improve the response with an extra dose of
Medicine, atlanta, Ga. the talk is summarized here.
cyclophosphamide, because the response rate to VDC seemed
low. Complete responses were highest with VDC-mod, which also
In its 2010 update of diagnostic criteria for plasma cell precursor
resulted in the highest overall survival. VDR was also active. There
diseases, the IMWG (the IMF-sponsored International Myeloma
is no advantage in adding the fourth drug, which causes increased
Working Group) made clinical recommendations for follow-up
toxicity. A phase III trial will compare VDR and VDC-mod.
of patients with MGUS and SMM. Dr. Landgren believes that for
patients with SMM it is reasonable to develop treatment stud-
Relapsed/Refractory Myeloma
ies. There are newer drugs to test, although studies have been
negative in the past. He doesn't think it is possible to prevent
Sagar lonial, Md, Hematolog y and Medical oncolog y,
progression at this time with the currently available drugs. How-
emory university, Winship Cancer Institute, atlanta, Ga,
ever, there is some chance to convert SMM into a chronic dis-
presented relapsed Multiple Myeloma as part of the Multiple
ease that could be managed. This should be done in the context
Myeloma education Program on advances in the Basic Sci-
of clinical trials to avoid clonal selection that might result in an
ence of Plasma Cell disorders, which he chaired. that talk is
even more aggressive disease. To answer the question whether
summarized here.
myeloma is always preceded by MGUS, the National Institutes of
Dr. Lonial discussed new treatments and approaches for the
Health (NIH) conducted a prospective screening study for can-
management of relapsed disease. Dr. Lonial's talk ended with a
cers that identified patients who developed multiple myeloma. In
9
these patients, myeloma was always preceded by MGUS. The FLC
for these patients right now. For young patients under age 50
(free light chain) ratio was abnormal in many before the develop-
years, myeloablative allogeneic transplant ("full allo") has been
ment of myeloma. The M-spike significantly increased over time
used in a small number of patients, and possibly might be effec-
as the time of diagnosis of myeloma approached. Two patterns
tive. He stated that there is no place for reduced-intensity con-
were identified: half the patients had an evolving M-spike, and
ditioning (RIC) allogeneic transplant in ultra high-risk patients.
half had no M-spike. They are currently looking at whether these
There is an urgent need for a universal definition of ultra high-
populations are different. The NIH's National Cancer Institute
risk multiple myeloma and a need for international trials in this
(NCI) has an ongoing prospective natural history and molecu-
patient group. Additionally, there is a need to identify patients'
lar profiling study. All costs are covered to get patients to the
risk factors among participants in phase III trials of agents such
study site. The vast majority of patients with MGUS will never
as carfilzomib, pomalidomide, elotuzumab, and HDAC inhibitors,
progress to myeloma so at this time there is no indication for
with the goal of identifying drugs for these high-risk patients.
screening for MGUS in the clinic. Patients with SMM should be
considered for clinical trials. Outside of clinical trials, observa-
Diagnosis, Prognosis, and Risk Assessment
tion is still considered the standard of care. Better understand-
IMF Symposium Case Study 1: diagnosis, Prognosis,
ing of the pathogenesis from MGUS to myeloma is needed. They
and risk assessment in Multiple Myeloma, presented by
are now are screening to identify patients with MGUS who didn't
S. Vincent rajkumar, Md, Mayo Clinic, rochester, Mn.
progress to myeloma. Patients with MGUS should be made aware
of the symptoms of transformation because they are the best to
Dr. Rajkumar said that the role of positron emission tomography
know when transformation or progression is occurring.
(PET scan) is in evolution. He uses it at diagnosis if he doesn't
have a good idea of disease burden or if a patient's symptoms
Ultra High-Risk Myeloma
do not correlate with the skeletal survey. A PET scan can indicate
Hervé avet-loiseau, Md, Phd, university Hospital of
myeloma disease that is not otherwise apparent, and can deter-
nantes, nantes, France presented ultra High-risk Multiple
mine if the spinal cord is compromised. For SMM and solitary
Myeloma as part of the education Program: understanding
plasmacytomas, he recommends magnetic resonance imaging
and Managing ultra High-risk Hematologic Malignancies,
(MRI) of the entire spine to confirm the diagnosis and also to
chaired by elihu J. estey, Md, university of Washington, Fred
clarify a situation where symptoms don't agree with the skele-
Hutchinson Cancer research Center, Seattle, Wa. the talk is
tal survey. He discussed the basis of the serum free light chain
summarized here.
(FLC) assay (Freelite®), noting that more than 90% of patients
with myeloma will have significant circulating light chains. There
Dr. Avet-Loiseau uses an arbitrary definition of ultra high-risk
are two results, one for kappa LC and one for lambda LC. The
myeloma as myeloma having a survival of 24 months regardless
normal ratio of kappa to lambda is 0.26 to 1.65. Current IMWG
of the patient's age. Patients with ultra-high risk myeloma may
response criteria use serum FLC if patients lack measurable dis-
constitute 20% of all patients. Classical induction regimens such
ease (M-spike). FLC is also used for risk stratification of patients
as VAD, TD, or bortezomib combinations are not active in this
with MGUS, SMM, and solitary plasmacytomas, and for screen-
population. Dr. Avet-Loiseau proposes using a rotation of com-
ing for myeloma instead of urine protein electrophoresis (UPEP),
binations of active drugs, including bortezomib, lenalidomide,
because the assay is easier than collecting a 24-hour urine sam-
dexamethasone, cyclophosphamide, and possibly doxorubicin
ple for UPEP. The Durie-Salmon staging system has stood the
for long-term treatment to reduce the aggressive myeloma clone.
test of time and is still useful to determine tumor burden. For
High-dose melphalan (HD Mel) may be useful for patients under
the International Staging System (ISS), a diagnosis of myeloma
age 65 or 70 years, although the effective number of courses is
must be confirmed first, and only then can the ISS be used
unknown. Bortezomib could be added. There are few data avail-
to stage the disease. B2M is a prognostic factor because it is a
able for the use of consolidation therapy. It probably should be
marker for renal failure and high tumor burden, and a patient
considered, but which regimen remains a question; possibly VTD
presenting with renal failure needs the best available therapy
or VRD could be used. Maintenance therapy for patients with
early on.
high-risk myeloma is also an open question. Thalidomide not
only is not effective, but it might make the myeloma worse. Bort-
Bortezomib-Based Induction treatments Improve outcomes
ezomib is marginally effective. In patients with poor-risk cytoge-
of newly diagnosed Multiple Myeloma Patients with High-
netics, treatment with lenalidomide did not lead to a significantly
risk Cytogenetic abnormalities (abstract 781) was presented
improved outcome. Total Therapy 4 for patients with high-risk
by Michele Cavo, Seràgnoli Institute of Hematology, Bologna Uni-
myeloma is based on dose-dense chemotherapy, with escalated
versity School of Medicine, Bologna, Italy.
VTD-PACE, Mel 300-VRD for two cycles; Mel-VRD for 4 cycles,
then monthly VRD for 3 years. Dr. Avet-Loiseau commented that
Patients with high-risk cytogenetic abnormalities do not benefit
Mel 300 is a very high dose. There are no survival data available,
from standard ASCT. There is some evidence that novel agents
but he thinks this regimen is the most promising that can be used
may overcome some poor prognostic factors, but the problem
10
is that the low frequency of these factors hampers meaningful
Note that The Binding Site, manufacturer of the Hevylite® test, is
analysis of clinical trial outcomes. There were two Italian trials
awaiting a pre-IDE (Investigational Device Exemption) decision
of bortezomib-based induction treatments for newly diagnosed
from the US FDA for Hevylite® diagnosis and monitoring claims.
patients, and these were analyzed for additional results after the
Dr. Avet-Loiseau has looked at progression-free survival (PFS) for
trials were completed. Patients were divided into those with no
some patients on IFM trials using traditional ISS classes based
cytogenetic abnormalities, those with del 13 q, and those with
on 2M plus albumin vs. 2M plus the Hevylite® ratio. ISS class
t(4;14) with or without del 17p. The high-risk population was
results fall in 2 prognostic groups, ISS Stage I, which has signifi-
subdivided in to those with t(4;14) with or without del 13. The
cantly longer PFS, vs. Stage II + III. The 2M plus Hevylite® ratio
three risk groups were evenly distributed across the three treat-
scoring system showed a higher level of significance for separa-
ments given (VTD, VMP, and VMPT). The high-risk group had
tion of these two prognostic groups.
a significantly greater frequency of higher ISS stage, and other
characteristics were generally same, such as age and 2M. Those
Conclusions
with t(4;14) had shorter survival and shorter PFS than those with
no cytogenetic abnormalities. Patients with both t(4;14) and del
The trend of increased survival for patients with myeloma that
17p tended to have shorter PFS than those with one abnormality,
began in the era of novel agents (bortezomib, lenalidomide, and
but survival for those with either or both was about the same at
thalidomide) is continuing. The novel agents are now part of new
18 months. For patients with t(4;14) with and without del 17p,
standards of care, with even newer agents being developed and
PFS was significantly longer if they were treated with VTD rather
tested. These newer agents include treatments that are targeted,
than TD. There was no difference in survival between VMPT vs.
that is, designed to attack specific weak points in the biology of
VMP treatment. Bortezomib-based regimens were likely to over-
myeloma cells. Future treatments are likely to be based on combi-
come poor outcome (prognosis) related to several high-risk cyto-
nations of therapies with unique ways of acting and with different
genetic abnormalities, particularly t(4;14). Data are needed on
rather than similar side effects. There have been advances in the
larger series of patients homogenously treated after long follow-
ability to identify the risk for individual patients, and to design
up before firm conclusions can be drawn and therapies tailored
treatments that meet the needs of individual patients. Increas-
according to the cytogenetic profile of a given patient. Dr. Cavo
ingly, patient quality of life is being considered in the develop-
said he had come to the conclusion that isolated del 13 q could
ment of therapies in general and in the design of treatments for
not be used to predict outcome, and should not be considered
each specific patient.
to indicate poor outcome; in most cases it is associated with
t(4;14) and del 17 p. He also noted that the initial high complete
response rate seen for patients with cytogenetic abnormalities
might be expected because the myelomas have a predominant
population of cells that responds initially; however, the complete
response is lost very rapidly.
Hevylite® Test
the ratio of Monoclonal to Polyclonal Immunoglobulins
assessed with the Hevylite test Predicts Prognosis, is Supe-
rior for Monitoring the Course of the disease, and allows
detection of Monoclonal Immunoglobulin in Patients with
normal or Subnormal Involved Immunoglobulin Isotype
(abstract 4038), was presented by Heinz Ludwig, Department of
Medicine, Wilhelminenspital, Vienna, Austria.
The Hevylite® test was used to determine the ratio of monoclo-
nal to isotype matched polyclonal immunoglobulins (heavy/light
chain ratio; HLC ratio) at the start of therapy and to evaluate
response in patients with myeloma who had normal or below-
normal levels of the involved immunoglobulin isotype. Conven-
tional prognostic factors were also measured, including IgG,
IgA, 2M, FLC, LDH, and creatinine. The HLC ratio was highly
prognostic and improved both the detection of variations in the
course of the disease as well as the diagnostic accuracy in patients
with normal or subnormal levels of the involved isotype, includ-
ing those with negative immunofixation (IFE).
11
International Myeloma Foundation
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