2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

CURRENT STATUS OF MYELOMA THERAPY
Fig 1. Approach to the treatment of newly diagnosed myeloma (A)
and in newly diagnosed patients with myeloma with special circumstances
(B).
Abbreviations: ASCT, autologous stem cell transplantation; CR,
complete response; Dex, dexamethasone; Rd, lenalidomide plus
low-dose dexamethasone; VCD, bortezomib, cyclophosphamide,
dexamethasone; VDT-PACE, bortezomib, dexamethasone, thalidomide,
cisplatin, doxorubicin, cyclophosphamide, etoposide; VGPR,
very good partial response; VRD, bortezomib, lenalidomide, dexamethasone;
VTD, bortezomib, thalidomide, dexamethasone.
* For patients who choose delayed ASCT, continue Rd.
† When continuing Rd, dexamethasone usually discontinued after
12 months, and continued long-term lenalidomide is an option for
patients who are tolerating treatment well.
trials. On the other hand, patients with high-risk require a
complete response for long-term survival and hence clearly
need an aggressive strategy designed to eradicate all plasma
cells, if possible.
Approach to Initial Therapy
The approach to treatment of symptomatic newly diagnosed
multiple myeloma is outlined in Fig. 1 and is dictated
by host factors that govern eligibility for ASCT and markers
of disease aggressiveness that determine risk-stratification.
1 The major regimens used for therapy and the data to
support their use are listed in Tables 4 and 5. In general,
all patients are probably best served by participation in
clinical trials, and every effort should be made to encourage
participation in such studies. The algorithms outlined in
this review are to be considered primarily when a suitable
clinical trial is unavailable or impractical.
Initial Treatment in Patients Eligible for ASCT
Typically, patients eligible for ASCT are treated with
approximately two to four cycles of induction therapy before
stem cell harvest. In general, regardless of the regimen
used, once weekly subcutaneous bortezomib and dexamethasone
at a 40-mg once-a-week schedule (low-dose dexamethasone)
is preferred in most patients for initial therapy,
unless there is an urgent need for rapid disease control.
Several other regimens besides the ones discussed in this
review have been tested in newly diagnosed multiple myeloma,
but there are no clear data from randomized controlled
trials that they have an effect on long-term
endpoints.
Standard risk. Patients with standard risk who are eligible
for ASCT can be treated with a variety of active regimens.
The main options for initial therapy are lenalidomide
plus low-dose dexamethasone (Rd) or one of several
bortezomib-based regimens. Lenalidomide plus dexamethasone
is active in newly diagnosed myeloma. Rd, which uses
low-dose dexamethasone, has less toxicity and better overall
survival than lenalidomide plus high-dose dexamethasone. 7
One caveat is that Rd may impair collection of peripheral
blood stem cells for transplant in some patients when
mobilized with granulocyte–colony stimulating factor (G-
CSF) alone. Thus, patients over the age of 65 and those who
have received more than four cycles of Rd) stem cells must be
mobilized with either cyclophosphamide plus G-CSF or with
plerixafor. All patients require antithrombosis prophylaxis
with aspirin; low molecular–weight heparin or coumadin is
needed in patients at high risk of DVT. 8
Several bortezomib-containing regimens can also be used
as initial therapy instead of Rd. Harousseau and colleagues
compared bortezomib plus dexamethasone (VD) with vincristine,
doxorubicin hydrochloride, dexamethasone (VAD)
as pre-transplant–induction therapy. 9 Post-induction verygood-partial-response
(VGPR) was superior with VD compared
with VAD, 38% compared with 15%, respectively.
However, progression-free survival (PFS) improvement was
modest, 36 months compared with 30 months, respectively,
and did not reach statistical significance. No overall survival
benefit was noted. Three-drug regimens such as bortezomibcyclophosphamide-dexamethasone
(VCD), and bortezomibthalidomide-dexamethasone
(VTD), and bortezomiblenalidomide-dexamethasone
(VRD) are in various stages
of development. 10 In randomized trials, VTD has shown
better response rates and PFS compared with TD, 11 as well
as VD. 12 VCD has impressive activity in newly diagnosed
multiple myeloma and is less expensive than either VTD or
VRD. Preliminary studies indicate that VCD is well tolerated
and has similar activity compared with VRD, making
it an excellent choice when considering a bortezomibcontaining
regimen for frontline use. 13
There are no data so far comparing Rd with any of the
bortezomib-containing regimens. Results from a Southwest
Oncology Group (SWOG) randomized trial that compared
VRD to Rd are awaited. One drawback of bortezomibcontaining
regimens is the risk of neurotoxicity early in the
disease course. However, recent studies show that the neurotoxicity
of bortezomib can be greatly diminished by administering
bortezomib using a once-weekly schedule, 14,15 and
by administering the drug subcutaneously. 16 Unlike lenalidomide,
bortezomib does not appear to have any adverse
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