2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Table 3. Rationale for Individualized, Risk-Adapted Therapy in Multiple Myeloma
Factor Individualized Approach to Initial Therapy Rationale
Age, performance status, co-morbidities Decision on Transplant Eligible versus Transplant Ineligible • The value of ASCT has been demonstrated in
• ASCT offered to patients age 65 (or up to age 75 in
USA) who have adequate performance status and
acceptable organ function
• Nature and duration of initial therapy varies
according to eligibility for ASCT
a judicious approach to the use of the available options.
Thus, given the dramatic variations in prognosis depending
on the various known prognostic factors, a “one-size-fits-all”
approach is both unreasonable and obsolete in multiple
myeloma. Even skeptics of risk-adapted or individualized
therapy do in reality practice such an approach, albeit
subconsciously. Table 3 shows how therapy can be tailored
by using host factors and markers of disease aggressiveness
and the rationale for such a risk-adapted strategy.
A risk-adapted strategy does not and should not mean
giving suboptimal (weak) therapy to patients with standard
risk and reserving the best therapy for patients at high risk.
To the contrary, it means not subjecting (or recommending
to) patients with standard risk regimens that have not been
proven to be useful in randomized trials. For example, VRD
has shown promise in newly diagnosed myeloma in a phase
II trial. That is sufficient to design phase III trials with this
regimen, but insufficient to recommend as an option outside
a clinical trial setting to patients with newly diagnosed
myeloma, especially to patients with standard-risk disease
in whom the value of this regimen, given its cost and
toxicity, requires data from randomized trials. One could
randomized trials only in this patient population
• Patient safety
Advanced age (�80 yr) Regimens with the least impact on quality of life • Although phase III data are not available, oral
Acute renal failure due to light chain
cast-nephropathy
•Rd
•MP
Rapidly acting regimens using drugs that are safe to use
in renal failure
regimens such as Rd or MP are well tolerated and
effective in patients with advanced age
• Rapid reversal of renal failure is possible with this
approach
• VTD • Persistent renal failure carries an adverse prognosis
• VCD • Patient safety dictates that in the presence of acute
Possible plasmapheresis
Possible hemodialysis
Goal of therapy is rapid reduction of involved serum-free
light chains to less than 50 mg/dL
Standard-risk myeloma Wide choice of induction regimens based on patient
preference, cost, toxicity, availability, etc.
•Rd
•VD
• VTD
• VCD
• Other
renal failure, drugs that are renally excreted, such as
lenalidomide, are best avoided particularly when
reversal of renal failure is a stated goal
• Little or no phase III data showing overall survival is
affected based on which of these induction regimens
are used as initial therapy
• Cost, toxicity, and availability concerns do matter and
should be taken into consideration in the absence of
compelling overall survival data dictating the use of
one specific regimen over the other, given the
estimated median survival of �7–10 yr
Intermediate-risk myeloma Bortezomib-based induction required Almost complete reversal of the poor prognostic impact
•VD
• VTD
• VCD
ASCT
Bortezomib-based maintenance therapy
of t4;14 has been noted with this strategy
High-risk myeloma Experimental approaches The median OS with approaches used in either
Plasma cell leukemia or multiple sites of
extramedullary disease at
presentation
Regimens with promising phase II data
• VRD
Initial therapy with multi-agent chemotherapy such as
VDT-PACE
standard- or intermediate-risk disease produce a
median survival of only 2–3 yr
The median OS is poor with approaches used in either
standard- or intermediaterisk disease
ASCT VDT-PACE can control disease rapidly and predictably
Maintenance therapy
Abbreviations: ASCT, autologous stem cell transplantation; MP, melphalan plus prednisone; Rd, lenalidomide plus low dose dexamethasone; VCD, bortezomib,
cyclophosphamide, dexamethasone; VD, bortezomib plus dexamethasone; VDT-PACE, bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide,
etoposide; VRD, bortezomib, lenalidomide, dexamethasone; VTD, bortezomib, thalidomide, dexamethasone.
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S. VINCENT RAJKUMAR
argue, however, that the outcome of patients with high-risk
myeloma is so poor with current available (phase III-vetted)
regimens that a new regimen with high activity such as VRD
is reasonable despite the added cost and toxicity. In other
words, the principle of risk-adapted therapy is to individualize
the treatment options for each patient in a manner
that carefully balances the risks and benefits depending on
prognosis and patient expectations. Patients with high risk
may be willing to take the added risks of unproven therapy
more often than patients with standard risk. Patients with
standard risk should be treated by using regimens that have
been tested and found effective in phase III trials.
More importantly, there is a critical ongoing “cure compared
with control” debate in the myeloma community on
whether we should treat the disease with an aggressive
multidrug strategy targeting complete response (CR) or a
sequential disease control approach that emphasizes quality
of life as well as OS. 6 A risk-adapted strategy allows patients
with standard-risk myeloma to have the choice
between pursuing either approach since there are no randomized
data demonstrating the clear superiority of one
approach over the other. It also highlights the need for such