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New Treatments for Multiple Myeloma

New Treatments for Multiple Myeloma

ABSTRACT: In 2004, multiple myeloma was diagnosed in more than 15,000 people in the United States and will account for approximately 20% of deaths due to hematologic malignancies. Although traditional therapies such as melphalan (Alkeran)/prednisone, combination chemotherapy with VAD (vincristine, doxorubicin [Adriamycin], and dexamethasone), and high-dose chemotherapy with stem cell transplantation have shown some success, median survival remains between 3 to 5 years. Treatment options for patients with multiple myeloma have increased in recent years, with the promise of improvement in survival. New agents, such as the proteasome inhibitor bortezomib (Velcade), the antiangiogenic and immunomodulator thalidomide (Thalomid) and its analogs, such as lenalidomide (Revlimid), together with other small molecules, including arsenic trioxide (Trisenox), and other targeted therapies, have been studied alone and in combination with other antineoplastic therapies, either as induction therapy prior to stem cell transplantation or in patients with relapsed disease. Bortezomib recently was approved in the United States for the treatment of multiple myeloma in patients who have received at least one prior therapy. The use of bortezomibbased regimens as front-line therapy as well as the use of other agents in multiple myeloma remain under investigation, and approvals for both thalidomide and lenalidomide are hoped for soon, with the overall prospect of patient outcome continuing to be increasingly positive.

In 2004, multiple myeloma was diagnosed
in more than 15,000 people
and accounted for approximately
11,000 deaths, representing 20% of
fatalities due to hematologic malignancies
in the United States.[1] Multiple
myeloma is a hematologic B-cell malignancy
associated with elevated serum
and urine immunoglobulins, plasma
cell infiltration of the bone marrow,
soft-tissue plasmacytomas, and skeletal
complications. Traditional therapies
for multiple myeloma have included the
combination of the alkylating agent melphalan
(Alkeran) with the steroid prednisone;
combination chemotherapy
with VAD (vincristine, doxorubicin
[Adriamycin], and dexamethasone);
high-dose chemotherapy with autologous
stem cell transplantation (SCT);
and nonmyeloablative or fully ablative
allogeneic transplantation.[2,3]

Although many patients respond
to treatment, relapse is inevitable and
median survival remains between 3
and 5 years[3,4]; hence, the need for
new approaches is critical.[3] Multiple
new agents for the treatment of multiple
myeloma are under clinical examination,
including the proteasome
inhibitor bortezomib (Velcade), thalidomide
(Thalomid) and its analogs such
as lenalidomide (Revlimid), and arsenic
trioxide (Trisenox), as well as a variety
of other therapeutic strategies. This
review briefly covers these emerging
therapeutics and discusses their potential
in myeloma therapy.

It is important to note that clinical
trials have applied different criteria to
measure response to treatment.
Commonly used response criteria
and modified versions include those
of the Southwest Oncology Group
(SWOG),[5] the Eastern Cooperative
Oncology Group (ECOG),[6] and the
European Group for Blood and Marrow
Transplantation (EBMT),[7]
which all share certain outcome measures
(eg, paraprotein reduction).
However, the EBMT criteria define
response more stringently and are now
accepted as the most rigorous standard
in drug development. Nevertheless,
response rates from various
agents should be compared with caution,
because the criteria to measure
response differ between trials.

Bortezomib

The proteasome, a multisubunit
protease complex, plays an essential
role in protein homeostasis in both
normal and neoplastic cells. The proteasome
is critical to regulated degradation
of proteins involved in essential
cellular functions, including protein
turnover, cell adhesion, cell-cycle progression,
antigen presentation, and
inflammation.[8-10] Inhibition of proteasome
function offers encouraging
possibilities for the treatment of cancer,
and various natural and synthetic
molecules have been used to study
proteasome inhibition in neoplastic
cells.[11] However, only bortezomib
(formerly known as PS-341), a boronic
acid peptide derivative and
potent (Ki = 0.6 nM), selective, reversible
proteasome inhibitor,[12] has
entered trials and been approved for
clinical use.

Mechanisms of Action
Several mechanisms by which bortezomib
elicits antitumor effects in
multiple myeloma have been identified.
Inhibition of the proteasome with
bortezomib has been shown to decrease
myeloma cell proliferation
through stabilization of the tumor suppressor
p53 and the cyclin-dependent
kinase inhibitors p21 and p27.[13,14]
Bortezomib also promotes apoptosis
via stabilization of the proapoptotic
Bid and Bax proteins and inhibitor-
κBα (IκBα), as well as activation of
the c-Jun NH2-terminal kinase (JNK),
as illustrated in Figure 1.[14-16]

Stabilization of IκBα has been
shown to result in inhibition of nuclear
factor κB (NF-κB) activation and
to prevent upregulation of the antiapoptotic
Bcl-2, Bcl-xL, and XIAP
proteins.[17,18] These effects produce
an increase in caspase-9-mediated
apoptosis.[19] Activated JNK also increases
AP-1-mediated upregulation
of Fas protein (CD95), which promotes
caspase-8-mediated apoptosis.[
19] Therefore, treatment with
bortezomib may ultimately restore an
apoptotic phenotype to myeloma cells
through increased activation of both
the intrinsic and extrinsic pathways.

The antitumor activity of bortezomib
also occurs in part through indirect effects
on the bone marrow microenvironment
(Figure 2). Bortezomib has
been shown to inhibit the adhesion of
myeloma cells with bone marrow stromal
cells (BMSCs), thereby preventing
the release of cytokines such as
interleukin (IL)-6, vascular endothelial
growth factor (VEGF), and insulin
growth factor-1 (IGF-1).[13] Bortezomib-
mediated inhibition of these cytokines,
which promote proliferation,
survival, and angiogenesis, has resulted
in decreased viability of myeloma
cells, as well as sensitization to antineoplastic
agents.[20]

This chemosensitization may also
result from inhibition of NF-κB-
mediated release of VEGF and IL-6
production by the BMSCs. NF-κB activity
also has been associated with
chemoresistance, and loss of NF-κB-
mediated protection may result in
chemosensitization.[21] Importantly,
evidence has shown that normal cells
are less sensitive to proteasome inhibition
than neoplastic cells and that
proteasome activity has recovered in
normal tissues within 24 hours following
treatment.[12,21]

Relapsed, Refractory
Multiple Myeloma

The results of a number of clinical
studies of bortezomib in relapsed
and/or refractory multiple myeloma
are summarized in Table 1.[22-34]
Phase I trials suggested that multiple
myeloma is sensitive to proteasome
inhibition and that a dosing schedule allowing for a 72-hour interval between
individual doses and a drugfree
rest period every third week has
manageable toxicities.[35,36]

  • SUMMIT-Based in part on the
    results of these studies, as well as highly
    supportive and provocative preclinical
    data in in vitro and in vivo models
    of multiple myeloma, SUMMIT,[22] a
    phase II trial, focused on patients with
    multiple myeloma that had both
    relapsed after prior therapy and was
    refractory to the last therapy. Patients
    (N = 202) received bortezomib,
    1.3 mg/m2 twice weekly for 2 weeks,
    with a 1-week rest between cycles.

    Responses were determined using
    modified EBMT criteria.[7] Complete
    response (CR) was defined as absence
    of paraprotein (undetectable by both
    electrophoresis and immunofixation),
    normal serum calcium concentration,
    and stable skeletal disease. To better
    define the range of responses classified
    as partial response (PR) by EBMT criteria,
    SUMMIT and CREST (described
    below) investigators included a new
    response category-near CR (nCR)-
    defined as 100% disappearance of
    paraprotein by electrophoresis but retention
    of positive immunofixation
    profile, with stable bone disease and a
    normal serum calcium concentration.

    Overall, 27% of the 193 evaluable
    patients demonstrated a major response
    (PR or better), with 4% achieving CR,
    an additional 6% achieving nCR, and
    18% PR.[22] A landmark analysis demonstrated
    that patients who achieved a
    major response to bortezomib after two
    cycles survived significantly longer than
    those who did not (P = .007). Median
    survival with or without extended treatment
    was 17 months.[37] Data from an
    extension study with 63 patients showed
    that extended treatment with bortezomib
    for up to 32 cycles was associated
    with a manageable safety profile.[38]

    Bortezomib was effective in improving
    aspects of patient care such as improvement
    in global quality of life and
    reduction in disease symptoms. When
    patients who achieved major responses
    were analyzed apart from the remainder
    of the population, bortezomib treatment
    improved the overall quality of
    life and resulted in clinical benefits such
    as increased hemoglobin levels and
    platelet counts. Response rates were
    independent of number or type of prior
    therapies and other prognostic factors
    such as chromosome 13 deletion and
    β2-microglobulin levels. Responses
    were, however, significantly associated
    with the percentage of plasma cells
    in the bone marrow and patient age.
    The most frequently reported toxicities
    of bortezomib were gastrointestinal,
    with nausea and diarrhea being most
    prevalent, along with fatigue, cyclical
    thrombocytopenia that recovered by the
    first day of the subsequent cycle, and
    peripheral neuropathy that resolved or
    improved in the majority of patients
    following discontinuation of treatment.

  • CREST-The CREST study examined
    bortezomib in multiple myeloma
    patients who had relapsed after
    first-line therapy.[23] In this study of
    54 patients with relapsed or refractory
    disease, two dosing schedules-bortezomib
    at 1.0 mg/m2, and 1.3 mg/m2,
    administered on days 1, 4, 8, and 11
    with a 1-week rest each 3-week
    cycle-were assessed. The response
    rates (CR + PR) were 30% and 38%
    for patients who received bortezomib
    alone at 1.0 or 1.3 mg/m2, respectively.
    The toxicities observed were similar
    to those reported in SUMMIT.
  • APEX-APEX, an international,
    multicenter phase III study, compared
    bortezomib with high-dose dexamethasone
    in 669 patients with relapsed or
    refractory multiple myeloma.[24] The
    dexamethasone arm of the trial was
    stopped after a preplanned interim
    analysis revealed significant clinical
    benefits in survival and time to disease
    progression for patients receiving bortezomib.
    Dexamethasone patients were
    allowed to cross over to receive bortezomib
    in a companion study.
  • Bortezomib/Dexamethasone-
    Preclinical evidence supports the concept
    that the effectiveness of bortezomib
    could be enhanced through combination
    with antineoplastic therapy. The
    combination of bortezomib with
    dexamethasone has resulted in at least
    additive anticancer effects in multiple
    myeloma cells.[13] Bortezomib has
    also markedly sensitized multiple
    myeloma cell lines to chemotherapeutic
    agents such as melphalan, mitoxantrone (Novantrone), and doxorubicin,
    and these combinations have yielded
    synergistic effects.[20,21]

    Based on these preclinical data in
    multiple myeloma models,[13] the addition
    of dexamethasone was permitted
    in both the SUMMIT and CREST
    phase II studies if patients presented
    with suboptimal responses to bortezomib
    monotherapy (progressive
    disease after two cycles or stable
    disease after the first four cycles).
    In SUMMIT, responses were observed
    in 13 (18%) of 74 evaluable
    patients who received dexamethasone
    with bortezomib after having demonstrated
    stable or progressive disease
    with single-agent bortezomib.[22] In
    CREST, the combination of bortezomib
    with dexamethasone also resulted
    in additional responses, with
    response rates (CR + PR) of 37% and
    50% at the two dose levels.[23] Furthermore,
    responses to bortezomib
    plus dexamethasone were seen in patients
    previously documented as having
    refractory disease.[39]

    Results from a phase I study assessing
    combination therapy with pegylated
    liposomal doxorubicin (Doxil) in a variety
    of refractory hematologic malignancies,
    including multiple myeloma,
    have been reported. Patients (N = 42,
    including 24 with multiple myeloma)
    received doses of bortezomib ranging
    from 0.90 to 1.5 mg/m2 on days 1, 4, 8,
    and 11, with liposomal doxorubicin
    (30 mg/m2) on day 4 of the 3-week
    cycle. In patients with multiple myeloma
    (n = 22 evaluable), this combination
    resulted in 5 CRs, 3 nCRs, and 8
    PRs (72% CR or PR), while five patients
    had either a minor response or
    stable disease. Cycle 1 grade 3/4 doselimiting
    toxicities included diarrhea,
    constipation, hyponatremia, hypotension,
    confusion, neutropenia, and syncope.
    Clinically relevant (grade 3/4)
    toxicity related to drug treatment observed
    after cycle 1 included constipation,
    cytopenias, diarrhea, fatigue,
    impotence, palmar-plantar erythrodysesthesia,
    and peripheral neuropathy.
    More than 60% of patients who were
    resistant to or who relapsed from prior
    anthracycline therapy responded.[25]

  • Bortezomib/Melphalan-Based
    on preclinical evidence of synergy between
    bortezomib and melphalan in
    multiple myeloma,[20,21] Berenson
    and colleagues examined combination
    bortezomib and melphalan in patients
    (N = 28) with relapsed or refractory
    multiple myeloma in a dose-escalation
    study.[26] In a preliminary report, bortezomib
    was given at an initial low
    dose of 0.7 to 1.0 mg/m2 twice weekly
    for 2 weeks every 4 weeks, in conjunction
    with melphalan ranging from
    0.025 to 0.25 mg/kg on days 1 to 4
    every 4 weeks. Initial responses at this
    dose of bortezomib were encouraging,
    with over 40% of patients showing a
    clinical response (CR or PR). Grade 3
    toxicities in this study were primarily
    hematologic. The majority of patients
    (> 75%) with baseline low-grade peripheral
    neuropathy (n = 8) exhibited
    stable neuropathy, but neuropathy in
    two patients worsened transiently.
  • Bortezomib/Thalidomide-In an
    initial report of 56 multiple myeloma
    patients who had relapsed following
    autologous transplantation, treatment
    with a combination of bortezomib (1.0
    or 1.3 mg/m2) and thalidomide (50 to
    200 mg) with or without dexamethasone
    was examined.[28] Neither chromosomal
    abnormalities nor drug doses
    appeared to affect responses, although
    survival tended to be higher in patients
    without compared to those with chromosomal
    abnormalities. Grade 3/4 cumulative
    neurotoxicity was not seen in
    cycles 1 to 4. The preliminary results of
    a phase II study of bortezomib
    (1.3 mg/m2) in combination with thalidomide
    (100 mg) and liposomal doxorubicin
    (20 mg) suggested that this
    combination could induce major responses
    with manageable toxicities in
    patients with relapsed or refractory
    disease.[27]

Newly Diagnosed
Multiple Myeloma

Bortezomib has also demonstrated
activity as monotherapy or in combination
regimens in the treatment of patients
with newly diagnosed multiple
myeloma in a number of preliminary
reports (Table 1).[29-34] Although we
have shown that single-agent bortezomib
on the standard dose and schedule
produced an overall response rate
of 45% with manageable toxicities in
newly diagnosed patients and less peripheral
neuropathy compared with
other studies,[29] clinical trials of bortezomib-
based combinations in this setting
appear more promising, with
particularly high CR/nCR rates.[30-34]

Jagannath et al found that bortezomib
with dexamethasone (40 mg on
the day of and after bortezomib administration)
with less than PR after two
cycles, or less than CR after four cycles,
yielded CR, nCR, or PR in the majority of patients with newly diagnosed
multiple myeloma.[30] The
combination of bortezomib with dexamethasone
also appeared to serve as
an appropriate induction therapy prior
to stem cell transplantation, because
the combination was well tolerated
and SCT was feasible.[31] Cavenagh
et al conducted a trial of bortezomib,
1.3 mg/m2, on days 1, 4, 8, and 11 for
up to four 3-week cycles, with dexamethasone,
40 mg, on days 1 to 4, 8
to 11, and 15 to 18 of cycle 1 and on
days 1 to 4 of subsequent cycles and
doxorubicin, 0, 4.5, or 9.0 mg/m2, on
days 1 to 4 in the front-line setting.[32]
In this study, over 20% of patients
achieved CR, the vast majority had PR,
and stem cell collection was feasible in
all but one of 21 patients.

The regimen of bortezomib, 1.0 to
1.3 mg/m2 on days 1, 4, 8, 11, 22, 25,
29, and 32 of up to four 6-week cycles
or on days 1, 8, 15, and 22 of up to five
5-week cycles, with melphalan,
9.0 mg/m2, and prednisone, 60 mg/m2,
on days 1 to 4 also demonstrated impressive
activity with manageable toxicity.[
33] In this phase I/II study, no
dose-limiting toxicities were observed
with bortezomib treatment for up to
49 weeks. Preliminary data from another
study also have demonstrated very
encouraging results with the use of
bortezomib, thalidomide, and dexamethasone[
34] in the front-line setting.

Thalidomide

After its introduction in the 1950s
as a sedative, thalidomide was linked
to serious birth defects and was consequently
removed from the marketplace
in the 1960s.[3] It regained its
position as a viable therapeutic agent
when it was discovered to be efficacious
in the treatment of erythema nodosum
leprosum and has since been
investigated in a variety of conditions.[
40] Most importantly, although
still considered experimental, thalidomide
is now commonly used to treat
multiple myeloma either as monotherapy
or in combination with dexamethasone.
Specifically, the efficacy
and toxicity of thalidomide have been
extensively studied in patients with relapsed,
refractory, and newly diagnosed
multiple myeloma.

Mechanisms of Action
Although the antitumor mechanisms
of thalidomide have not been
fully defined, evidence suggests that
induction of apoptosis, inhibition of
cytokine production and angiogenesis,
and immune modulation of
T cells and natural killer cells are involved.[
41-43] Thalidomide has been
shown to promote apoptosis through
the extrinsic pathway via activation of
caspase-8 and inhibition of caspase inhibitor
of apoptosis protein-2 (cIAP-2)
(Figure 1).[43] The antimyeloma activity
of thalidomide is also partially
attributable to inhibition of the interaction
of multiple myeloma cells with
BMSCs (Figure 2). The reduced adhesion
results in reduced secretion of cytokines,
including IL-6, VEGF, and
IGF-1, decreased cell viability and angiogenesis,
and chemosensitization of
multiple myeloma cells.[42]

Inhibition of angiogenesis may
be important, because microvessel
density-a marker for angiogenesis-
increases as multiple myeloma
progresses, and a high level of angiogenesis
is associated with decreased
survival.[44] However, because paraprotein
responses to thalidomide have
not always correlated with differences
in microvessel density, other mechanisms
such as immunomodulation and
effects of adhesion may be key.[45]
Importantly, immune modulation by
thalidomide appears to involve activation
of phosphatidylinositol 3-kinase
and increased IL-2 secretion of
T lymphocytes as well as natural killer
cell-mediated tumor cell lysis.[46]

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