2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Upfront Therapy for Myeloma: Tailoring
Therapy across the Disease Spectrum
Overview: The treatment of multiple myeloma is evolving
rapidly. Despite the number of regimens and combinations
available, there is lack of data from phase III trials demonstrating
superiority of one regimen over the other in terms of
overall survival and/or quality of life. The only clear survival
signals have come from studies that compared newer regimens
with historic ones such as melphalan-prednisone (MP)
or vincristine-doxorubicin hydrochloride-thalidomide (VAD).
Thus, the choice of therapy at present is often made based on
physician discretion, bias, and limited data from phase II
studies. Further, the regimens available have considerably
MULTIPLE MYELOMA is a malignant plasma-cell
proliferative disorder that accounts for approximately
10% of all hematologic malignancies. 1,2 Over 20,000
new cases are diagnosed annually in the United States, and
most patients continue to die of the disease. The risk of
multiple myeloma is two-fold higher in blacks compared
with whites. Multiple myeloma evolves from an asymptomatic
premalignant stage termed monoclonal gammopathy of
undetermined significance (MGUS). In the spectrum of
plasma cell disorders, there is an additional intermediate
arbitrary clinical stage–termed smoldering multiple myeloma
(SMM) that comprises of a mixture of patients with
premalignancy (i.e., MGUS) and malignancy (i.e., early
stage multiple myeloma). The SMM category is clinically
important because it is not possible in most instances to
determine which patient with SMM has premalignancy
compared with malignancy; therefore, these patients are
currently observed without therapy until overt signs or
malignancy develop. They are also candidates for clinical
trials, testing the value of early intervention. The diagnostic
criteria for multiple myeloma, MGUS, and SMM are given in
Table 1. 3
Prognosis and Risk-Stratification
Prognosis in myeloma depends on four major factors: host
characteristics (age, performance status, comorbidities),
stage, disease aggressiveness, and response to therapy. 4
Each of these four factors result in poor prognosis through
different mechanisms, and therefore the strategy to overcome
each of these factors will need to be quite different. For
example, it is not possible to overcome the poor prognosis
associated with host factors such as advanced age or multiple
comorbidities by increasing the aggressiveness of the
therapy used. Similarly, it is not possible to overcome the
poor prognostic effect conferred by acute renal failure without
taking into account the specific drugs than can be used
safely, and the specific dose modifications that may be
required. In other words, one needs to know precisely the
mechanism by which a given factor confers its adverse
prognostic value before we can develop strategies to overcome
such an effect.
Staging of myeloma by using the Durie-Salmon Staging
(DSS) or the International Staging System (ISS) both provide
prognostic information, but are typically not helpful in
making therapeutic choices because the risk groups are
508
By S. Vincent Rajkumar, MD
different profiles in terms of safety, convenience, and cost.
Given the dramatic variations in expected outcome depending
on the various known prognostic factors, a risk-adapted
strategy is required to provide the best available therapy to
each patient based on host factors as well as prognostic
markers of disease aggressiveness. This article reviews the
current status of myeloma therapy and risk stratification.
Results from major phase III trials are reviewed, and a
risk-adapted individualized approach to therapy is presented
and discussed.
heterogeneous and defy any rational uniform approach to
risk-adapted therapy. For instance, stage III ISS (defined on
the basis of a high beta-2 microglobulin level) consists of a
heterogeneous mix of patients, some of whom derive the
stage III label because of renal failure, whereas some meet
criteria for stage III because of a high tumor burden; both
renal failure and high tumor burden have the same effect on
beta-2 microglobulin. Thus staging, whereas useful for prognosis,
is not particularly useful in deciding choice of therapy
in multiple myeloma; the one exception to this rule is stage
I Durie-Salmon disease, which is a heterogeneous group of
patients with either SMM (no therapy needed) or solitary
plasmacytoma (typically treated with radiation alone).
Response to therapy is also not useful in determining
choice of therapy since this information is only available
post-hoc, and there are no good reliable tests that allow us
to predict response to specific drugs ahead of time. Thus
risk-adapted, individualized therapy for myeloma is currently
done primarily on the basis of two factors: host factors
and markers of disease aggressiveness.
Host factors are currently used in multiple myeloma
primarily to determine eligibility for autologous stem cell
transplantation (ASCT). In general, patients need to meet
minimum requirements for age, organ function, and performance
status to be considered eligible for ASCT. The initial
therapy varies according to eligibility for transplantation.
Disease aggressiveness has a major effect on prognosis and
can also be used to individualize therapy. Table 2 provides a
risk stratification model based on markers of disease aggressiveness
(mSMART). 5 This requires fluorescent in situ hybridization
(FISH) or similar studies be done on the bone
marrow at the time of initial diagnosis to detect t(11;14),
t(4;14), t(14;16), t(6;14), t(14;20), and deletion of 17p. 5 Gene
expression profiling (GEP), if available, can provide additional
prognostic value. Patients with standard-risk myeloma
(75% of myeloma) have a median overall survival (OS)
of an excess of 7 years whereas those with high-risk disease
From the Division of Hematology, Mayo Clinic, Rochester, MN.
Author’s disclosure of potential conflicts of interest are found at the end of this article.
Address reprint requests to S. Vincent Rajkumar, MD, Division of Hematology, Mayo
Clinic, 200 First Street SW, Rochester, MN 55905; email: rajkumar.vincent@mayo.edu.
© 2012 by American Society of Clinical Oncology.
1092-9118/10/1-10