From www.bloodjournal.org by guest on July 5, 2017. For personal use only.
Blood First Edition Paper, prepublished online July 5, 2017; DOI 10.1182/blood-2017-03-726703
How I treat first relapse of myeloma Jean Luc Harousseau, MD and Michel Attal, MD
Institutions
JL Harousseau : Groupe Confluent Nantes France
M Attal : IUCT Oncopole Toulouse France
Adresses
[email protected]
[email protected]
Abstract 197 words Text 4023 words References 104 Tables 5 Figure 1
1
Copyright © 2017 American Society of Hematology
From www.bloodjournal.org by guest on July 5, 2017. For personal use only.
HOW I TREAT FIRST RELAPSE OF MYELOMA
ABSTRACT
The standard treatment of relapsed multiple myeloma (MM) was either lenalidomide-dexamethasone (RD)
or bortezomib-dexamethasone (VD) but it is changing rapidly for two reasons. Firstly lenalidomide and
bortezomib are currently used in frontline treatment and many patients become resistant to these agents
early in the course of their disease. Secondly six second-line new agents have been recently developed and
offer
new
possibilities
(pomalidomide,
carfilzomib
and
ixazomib,
panobinostat,
elotuzumab
and
daratumumab). Recent randomized studies have shown that triple combinations adding one of these new
agents (except pomalidomide) to the RD or VD regimens were superior to the double combinations in
terms of response rate and progression-free survival (PFS). Their place in the treatment of first relapse is
discussed here. Among these agents daratumumab is clearly a breakthrough and daratumumab-based
combinations might become the preferred option in the near future.
However all these drugs are expensive and are not available or affordable in all countries. We propose a
decision algorithm for first relapse in fit patients with the objective of achieving the best PFS. The choice of
salvage
regimen
is
based
on
lenalidomide/bortezomib
resistance,
daratumumab
availability,
and
cost.
Autologous transplantation should be considered in younger patients if not used upfront.
2
From www.bloodjournal.org by guest on July 5, 2017. For personal use only.
INTRODUCTION
Prognosis of Multiple Myeloma (MM) has considerably improved in the past few years, mostly due to the
introduction
of
immunomodulatory
drugs
(IMIDs)
and
proteasome-inhibitors
(PIs),
initially
in
relapsed
disease and very rapidly in frontline treatment. For newly diagnosed patients, two new concepts have been
evaluated recently.
1)
Triple
combinations
including
one
IMID
and
one
PI
lenalidomide and bortezomib) for induction treatment
2)
Prolonged
treatment
with
lenalidomide
or
(usually
1-5
bortezomib
6:
either maintenance treatment after High-Dose Therapy plus
Autologous Stem Cell Transplantation (HDT/ASCT) in younger
patients
7-8
or continuous therapy in elderly patients
9-10
These new strategies have dramatically increased the depth of response, with a higher complete remission
(CR) rate, and the progression-free survival (PFS). Moreover it is now possible to achieve a high level of
tumor burden reduction
leading to
negative
minimal residual
disease (MRD)
as
methods such as next-generation flow cytometry and next generation sequencing
associated with prolonged PFS and possibly long overall survival (OS)
12-13
assessed by
11
sensitive
. MRD negativity is
. In younger patients treated with
IMIDs plus PI before and after HDT/ASCT, median PFS may be over 5 years and median OS may exceed 10
14-16
years
. And the hope of cure for some patients becomes reality
However the
great majority
of patients ultimately
17
.
relapse and treatment of
relapse
remains a
major
challenge. Since MM has become a chronic disease with a longer succession of remissions and relapses,
finding an effective treatment at each consecutive relapse is critical for prolonging OS. This is increasingly
difficult along the course of the disease since increasing drug-resistance reduces therapeutic possibilities
and remission duration with each successive regimen
18
.
In the past, treatment of relapsed MM was thalidomide-dexamethasone (TD). Due to its frequent toxicity,
thalidomide
has
been
replaced
in
most
high-income
countries
by
lenalidomide.
Lenalidomide-
3
From www.bloodjournal.org by guest on July 5, 2017. For personal use only.
dexamethasone (RD) and bortezomib- dexamethasone (VD) combinations have become standard of care,
after
publication
of
large
randomized
studies
versus
dexamethasone
alone
19-21
.
But
the
landscape
of
relapsed MM treatment is constantly evolving. Large use of lenalidomide and bortezomib for both newly
diagnosed and relapsed patients has increased the proportion of patients with MM refractory to one agent
or both. Prognosis of patients who are resistant to both bortezomib and lenalidomide is poor
22
. But in the
same time, new possibilities have emerged with the approval by FDA and EMA of not less than six new
agents since 2012 : a new IMID (pomalidomide
23-29
), new PIs (carfilzomib
30,31
different modes of action like histone-deacetylase inhibitors (panobinostat
34
and daratumumab
35-37
and ixazomib32 ) and drugs with
33
) and antibodies (elotuzumab
) Reviews on the treatment of relapsed MM have been recently published
39-41
but
they do not include the most recent results , specially those with daratumumab.
GENERAL CONSIDERATIONS
1) Available therapies
Clinical efficacy of second-line new agents given alone or with dexamethasone in Phase II trials
23-35
is
summarized in Table 1. Rate and duration of response, and PFS depend on the inclusion criteria (number of
prior lines of treatment, resistance to lenalidomide/bortezomib). However, these trials have shown the
efficacy of pomalidomide, carfilzomib, ixazomib and daratumumab in heavily pretreated patients, including
patients refractory to bortezomib, lenalidomide or both. Efficacy of panobinostat and elotuzumab has been
evaluated directly in combination after Phase I trials
31, 32
. Safety data
33-35, 40-47
are shown in Table 2.
These new agents have also been tested in combination with older ones in Phase II trials (Table 3)
48-54
. We
now have several therapeutic classes which can be combined in multiple ways, leading to a large variety of
possibilities
at
each
stage
of
the
disease.
Moreover
high-dose
therapy
plus
autologous
stem-cell
4
From www.bloodjournal.org by guest on July 5, 2017. For personal use only.
transplantation (HDT/ASCT) and allogeneic stem-cell transplantation can still be proposed for relapsed MM
therapy. Their indications have been recentlly reviewed
31, 55
.
Randomized trials in relapsed MM have shown the superiority of triple combinations (triplets) containing
two new agents compared to double combinations (doublets) with only one new agent. The first of these
trials
showed that in
first
relapse
after HDT/ASCT,
superior to TD in terms of response rate, PFS and OS
bortezomib-thalidomide-dexamethasone
(VTD)
was
56.
More recently, seven large randomized trials compared triplets with the addition of one new agent to one
57-60
of the back-bone combinations, either RD
or VD
61-64
. These trials are summarized in Table 4.
The triplet was always superior to the standard doublet in terms of response rate and PFS. However the
follow-up of these studies was generally short and at time of publication the benefit in terms of OS was not
always significant. This may be partly due to the multiple possibilities of salvage treatment at the time of
subsequent relapses.
2) Parameters to consider at relapse
Relapse MM is a heterogeneous situation and there are multiple parameters that can impact the result of
relapsed MM treatment. They have been listed in recent reviews
36, 37
and are summarized in Table 5.
Disease-associated parameters are mostly prognostic factors and have currently little impact on the choice
of treatment. Compared to RD or VD, triplets improve PFS both in standard-risk and in high-risk patients as
defined by beta2-microglobulin
57-60
or ISS
57,59,64
, and by cytogenetics
poor prognosis associated with high-risk cytogenetics
which
might
be
more
active
in
specific
prognostic
65
57-59
, although they do not abrogate the
. Moreover, there is currently no targeted-therapy
subgroups.
Therefore
triplets
should
be
preferred
whatever the prognostic factors, including cytogenetics. Some patients have very aggressive relapse with
5
From www.bloodjournal.org by guest on July 5, 2017. For personal use only.
rapid onset and for instance hypercalcemia, renal insufficiency or extra medullary disease. These patients
require immediate treatment, usually with a triplet including one IMID and one PI
37,39
.
Patients’ characteristics are important for determining the benefit/risk ratio of a given treatment. Age and
comorbidities are major factors to consider at the time of choosing relapse treatment. Again triplets were
superior to standard doublets even in older patients and in patients with renal dysfunction
57-60,64,66
. However
clinical trials do not reflect real life since frail patients and patients with end-stage renal failure are usually
excluded.
ECOG
performance
status
or
frailty
index
67
should
be
considered
in
elderly
patients.
Comorbidities and adverse events of previous treatments can serve to exclude one of these agents because
of its specific toxicity. All-oral combinations may be preferred by some patients, particularly those living far
from the hospital.
Previous treatments parameters
-
A previous ASCT and the interval between ASCT and relapse define the indication of ASCT at
relapse
-
37, 55
.
The number of prior lines of treatment is an important prognostic factor and an inclusion factor
in clinical trials. Pomalidomide has been developed mostly in heavily pretreated patients
panobinostat is more active in patients with 2 prior lines or more
62
and
Carfilzomib, Ixazomib and
Daratumumab combinations are superior whatever the number of lines (1 to 3)
-
40
58,68,69
.
The prior use and results of IMIDs and PIs are becoming important issues. Patients with prior
treatment are bortezomib or lenalidomide-exposed, others are bortezomib or lenalidomide-
naive. A
patient who previously responded to a given agent without major toxicity can be
retreated at relapse with the same agent or with an agent of the same class
37
. More difficult is
the treatment of refractory patients. According to IMWG criteria refractoriness is defined by
progression occurring on therapy or
Blood First Edition Paper, prepublished online July 5, 2017; DOI 10.1182/blood-2017-03-726703
How I treat first relapse of myeloma Jean Luc Harousseau, MD and Michel Attal, MD
Institutions
JL Harousseau : Groupe Confluent Nantes France
M Attal : IUCT Oncopole Toulouse France
Adresses
[email protected]
[email protected]
Abstract 197 words Text 4023 words References 104 Tables 5 Figure 1
1
Copyright © 2017 American Society of Hematology
From www.bloodjournal.org by guest on July 5, 2017. For personal use only.
HOW I TREAT FIRST RELAPSE OF MYELOMA
ABSTRACT
The standard treatment of relapsed multiple myeloma (MM) was either lenalidomide-dexamethasone (RD)
or bortezomib-dexamethasone (VD) but it is changing rapidly for two reasons. Firstly lenalidomide and
bortezomib are currently used in frontline treatment and many patients become resistant to these agents
early in the course of their disease. Secondly six second-line new agents have been recently developed and
offer
new
possibilities
(pomalidomide,
carfilzomib
and
ixazomib,
panobinostat,
elotuzumab
and
daratumumab). Recent randomized studies have shown that triple combinations adding one of these new
agents (except pomalidomide) to the RD or VD regimens were superior to the double combinations in
terms of response rate and progression-free survival (PFS). Their place in the treatment of first relapse is
discussed here. Among these agents daratumumab is clearly a breakthrough and daratumumab-based
combinations might become the preferred option in the near future.
However all these drugs are expensive and are not available or affordable in all countries. We propose a
decision algorithm for first relapse in fit patients with the objective of achieving the best PFS. The choice of
salvage
regimen
is
based
on
lenalidomide/bortezomib
resistance,
daratumumab
availability,
and
cost.
Autologous transplantation should be considered in younger patients if not used upfront.
2
From www.bloodjournal.org by guest on July 5, 2017. For personal use only.
INTRODUCTION
Prognosis of Multiple Myeloma (MM) has considerably improved in the past few years, mostly due to the
introduction
of
immunomodulatory
drugs
(IMIDs)
and
proteasome-inhibitors
(PIs),
initially
in
relapsed
disease and very rapidly in frontline treatment. For newly diagnosed patients, two new concepts have been
evaluated recently.
1)
Triple
combinations
including
one
IMID
and
one
PI
lenalidomide and bortezomib) for induction treatment
2)
Prolonged
treatment
with
lenalidomide
or
(usually
1-5
bortezomib
6:
either maintenance treatment after High-Dose Therapy plus
Autologous Stem Cell Transplantation (HDT/ASCT) in younger
patients
7-8
or continuous therapy in elderly patients
9-10
These new strategies have dramatically increased the depth of response, with a higher complete remission
(CR) rate, and the progression-free survival (PFS). Moreover it is now possible to achieve a high level of
tumor burden reduction
leading to
negative
minimal residual
disease (MRD)
as
methods such as next-generation flow cytometry and next generation sequencing
associated with prolonged PFS and possibly long overall survival (OS)
12-13
assessed by
11
sensitive
. MRD negativity is
. In younger patients treated with
IMIDs plus PI before and after HDT/ASCT, median PFS may be over 5 years and median OS may exceed 10
14-16
years
. And the hope of cure for some patients becomes reality
However the
great majority
of patients ultimately
17
.
relapse and treatment of
relapse
remains a
major
challenge. Since MM has become a chronic disease with a longer succession of remissions and relapses,
finding an effective treatment at each consecutive relapse is critical for prolonging OS. This is increasingly
difficult along the course of the disease since increasing drug-resistance reduces therapeutic possibilities
and remission duration with each successive regimen
18
.
In the past, treatment of relapsed MM was thalidomide-dexamethasone (TD). Due to its frequent toxicity,
thalidomide
has
been
replaced
in
most
high-income
countries
by
lenalidomide.
Lenalidomide-
3
From www.bloodjournal.org by guest on July 5, 2017. For personal use only.
dexamethasone (RD) and bortezomib- dexamethasone (VD) combinations have become standard of care,
after
publication
of
large
randomized
studies
versus
dexamethasone
alone
19-21
.
But
the
landscape
of
relapsed MM treatment is constantly evolving. Large use of lenalidomide and bortezomib for both newly
diagnosed and relapsed patients has increased the proportion of patients with MM refractory to one agent
or both. Prognosis of patients who are resistant to both bortezomib and lenalidomide is poor
22
. But in the
same time, new possibilities have emerged with the approval by FDA and EMA of not less than six new
agents since 2012 : a new IMID (pomalidomide
23-29
), new PIs (carfilzomib
30,31
different modes of action like histone-deacetylase inhibitors (panobinostat
34
and daratumumab
35-37
and ixazomib32 ) and drugs with
33
) and antibodies (elotuzumab
) Reviews on the treatment of relapsed MM have been recently published
39-41
but
they do not include the most recent results , specially those with daratumumab.
GENERAL CONSIDERATIONS
1) Available therapies
Clinical efficacy of second-line new agents given alone or with dexamethasone in Phase II trials
23-35
is
summarized in Table 1. Rate and duration of response, and PFS depend on the inclusion criteria (number of
prior lines of treatment, resistance to lenalidomide/bortezomib). However, these trials have shown the
efficacy of pomalidomide, carfilzomib, ixazomib and daratumumab in heavily pretreated patients, including
patients refractory to bortezomib, lenalidomide or both. Efficacy of panobinostat and elotuzumab has been
evaluated directly in combination after Phase I trials
31, 32
. Safety data
33-35, 40-47
are shown in Table 2.
These new agents have also been tested in combination with older ones in Phase II trials (Table 3)
48-54
. We
now have several therapeutic classes which can be combined in multiple ways, leading to a large variety of
possibilities
at
each
stage
of
the
disease.
Moreover
high-dose
therapy
plus
autologous
stem-cell
4
From www.bloodjournal.org by guest on July 5, 2017. For personal use only.
transplantation (HDT/ASCT) and allogeneic stem-cell transplantation can still be proposed for relapsed MM
therapy. Their indications have been recentlly reviewed
31, 55
.
Randomized trials in relapsed MM have shown the superiority of triple combinations (triplets) containing
two new agents compared to double combinations (doublets) with only one new agent. The first of these
trials
showed that in
first
relapse
after HDT/ASCT,
superior to TD in terms of response rate, PFS and OS
bortezomib-thalidomide-dexamethasone
(VTD)
was
56.
More recently, seven large randomized trials compared triplets with the addition of one new agent to one
57-60
of the back-bone combinations, either RD
or VD
61-64
. These trials are summarized in Table 4.
The triplet was always superior to the standard doublet in terms of response rate and PFS. However the
follow-up of these studies was generally short and at time of publication the benefit in terms of OS was not
always significant. This may be partly due to the multiple possibilities of salvage treatment at the time of
subsequent relapses.
2) Parameters to consider at relapse
Relapse MM is a heterogeneous situation and there are multiple parameters that can impact the result of
relapsed MM treatment. They have been listed in recent reviews
36, 37
and are summarized in Table 5.
Disease-associated parameters are mostly prognostic factors and have currently little impact on the choice
of treatment. Compared to RD or VD, triplets improve PFS both in standard-risk and in high-risk patients as
defined by beta2-microglobulin
57-60
or ISS
57,59,64
, and by cytogenetics
poor prognosis associated with high-risk cytogenetics
which
might
be
more
active
in
specific
prognostic
65
57-59
, although they do not abrogate the
. Moreover, there is currently no targeted-therapy
subgroups.
Therefore
triplets
should
be
preferred
whatever the prognostic factors, including cytogenetics. Some patients have very aggressive relapse with
5
From www.bloodjournal.org by guest on July 5, 2017. For personal use only.
rapid onset and for instance hypercalcemia, renal insufficiency or extra medullary disease. These patients
require immediate treatment, usually with a triplet including one IMID and one PI
37,39
.
Patients’ characteristics are important for determining the benefit/risk ratio of a given treatment. Age and
comorbidities are major factors to consider at the time of choosing relapse treatment. Again triplets were
superior to standard doublets even in older patients and in patients with renal dysfunction
57-60,64,66
. However
clinical trials do not reflect real life since frail patients and patients with end-stage renal failure are usually
excluded.
ECOG
performance
status
or
frailty
index
67
should
be
considered
in
elderly
patients.
Comorbidities and adverse events of previous treatments can serve to exclude one of these agents because
of its specific toxicity. All-oral combinations may be preferred by some patients, particularly those living far
from the hospital.
Previous treatments parameters
-
A previous ASCT and the interval between ASCT and relapse define the indication of ASCT at
relapse
-
37, 55
.
The number of prior lines of treatment is an important prognostic factor and an inclusion factor
in clinical trials. Pomalidomide has been developed mostly in heavily pretreated patients
panobinostat is more active in patients with 2 prior lines or more
62
and
Carfilzomib, Ixazomib and
Daratumumab combinations are superior whatever the number of lines (1 to 3)
-
40
58,68,69
.
The prior use and results of IMIDs and PIs are becoming important issues. Patients with prior
treatment are bortezomib or lenalidomide-exposed, others are bortezomib or lenalidomide-
naive. A
patient who previously responded to a given agent without major toxicity can be
retreated at relapse with the same agent or with an agent of the same class
37
. More difficult is
the treatment of refractory patients. According to IMWG criteria refractoriness is defined by
progression occurring on therapy or
