2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

CURRENT STATUS OF MYELOMA THERAPY
Trial Regimen
Table 5. Results of Recent Randomized Studies in Newly Diagnosed Myeloma
No. of
Patients
Overall
Response
Rate (%)
CR plus
VGPR (%)
comorbidities, the major options at present are either
alkylator- or bortezomib-based combination therapies given
for 9 to 18 months, or Rd. 1 With Rd, the optimum duration
of therapy is unclear; most patients continue therapy until
progression, provided the treatment is well tolerated. In
such patients, dexamethasone is usually lowered to a minimal
dose or discontinued after the first year. Results of a
randomized trial comparing Rd for 18 months compared
with Rd until progression are awaited. Thalidomide plus
dexamethasone is inferior to melphalan plus prednisone
(MP) in terms of overall survival and is not recommended.
The addition of lenalidomide to MP (MPR) does not improve
PFS compared with MP alone, and is also not recommended.
Standard risk. Six randomized studies have found that
melphalan, prednisone, thalidomide (MPT) improves response
rates with MP. 18-23 Four of these trials have shown a
prolongation of PFS with MPT, 18-20,22 and an OS advantage
has been observed in the two Intergroupe Francophone
Myelome (IFM) trials and in the trial by Wijermans and
colleagues. 18-22 Two meta-analyses of these randomized trials
have been conducted and they show a clear superiority
of MPT over MP. 24,25 Grade 3–4 adverse events occur in
approximately 55% of patients treated with MPT, compared
to 22% with MP. 20
Bortezomib-containing combinations serve as an alternative
to MPT as initial therapy in this patient population. In
a large phase III trial, bortezomib, melphalan, prednisone
(VMP) led to improved OS compared with MP. 26 Neuropathy
is an important risk with VMP therapy; grade 3 neuropathy
occurred in 13% of patients compared to 0% with MP. 26
Thus, as with transplant-eligible patients, the once-weekly,
subcutaneous schedule is preferred. There is no significant
Progression-free
Survival
(Median in Months)
P for Progression
Free Survival
3 yr Overall
Survival
Rate (%)*
Overall Survival
(Median in Months)
Rajkumar et al 7 RD 223 81 50 19.1 75 NR
Rd 222 70 40 25.3 0.026 74 NR 0.47
Harousseau et al 9 VAD 242 63 15 30 77 NR
VD 240 79 38 36 0.06 81 NR 0.46
Cavo et al 11 TD 238 79 28 40 84 NR
VTD 236 93 62 NR 0.006 86 NR 0.3
Moreau et al 12 VD 99 81 35 N/A N/A N/A
VTD 100 90 51 N/A N/A N/A
Facon et al 18 MP 196 35 7 17.8 48 33.2
Mel 100 126 65 43 19.4 52 38.3
MPT 125 76 47 27.5 �0.001 66 51.6 �0.001
Hulin et al 19 MP � Placebo 116 31 7 18.5 40 29.1
MPT 113 62 21 24.1 0.001 55 44 0.028
Wijermans et al 22 MP 168 45 10 9 43 31
MPT 165 66 27 13 �0.001 55 40 0.05
Palumbo et al 29 MP 164 48 11 14.5 65 47.6
MPT 167 69 29 21.8 0.004 65 45 0.79
Waage et al 21 MP � Placebo 175 33 7 14 43 32
MPT 182 34 23 15 NS 43 29 0.16
San Miguel et al** 26,30 MP 331 35 8 16.6 54 43
VMP 337 71 41 24 �0.001 69 NR �0.001
Reproduced from Rajkumar. 2
Abbreviations: CR, complete response; MP, melphalan plus prednisone; MPT, melphalan plus prednisone plus thalidomide; N/A, not available; NS, not significant; Rd,
lenalidomide plus dexamethasone; TD, thalidomide plus dexamethasone; VGPR, very good partial response; VMP, bortezomib plus melphalan plus prednisone; VTD,
bortezomib, thalidomide, dexamethasone.
* Estimated from survival curves when not reported.
** Progression-free survival not reported; numbers indicate time to progression.
P for
Overall
Survival
advantage of either bortezomib, thalidomide, prednisone
(VTP) or VTD over VMP. VCD is a minor variation of the
VMP combination that can be used in place of VMP to
minimize side effects.
Rd is also an attractive option for the treatment of elderly
patients with newly diagnosed myeloma because of its
excellent tolerability, convenience, and efficacy. The threeyear
OS rate with Rd in patients age 70 and older who did
not receive ASCT is 70%, and is comparable to results with
MPT and VMP. An ongoing phase III trial is currently
comparing MPT with Rd for 18 months compared with Rd
until progression.
No results from randomized trials are available yet comparing
Rd, MPT, VMP or VCD. Although MPT and VMP
have the strongest data, they are also less well-tolerated
than Rd and VCD, respectively. Based on cost and toxicity
considerations, Rd or VCD are probably the best options for
this patient population at present.
Intermediate risk. Bortezomib-containing regimens can
overcome to some extent the poor prognosis associated with
the t4;14 translocation. 11,17,27 As a result, in patients with
intermediate risk, bortezomib-containing initial therapy
such as VCD for approximately 24 months is preferred.
High risk, plasma cell leukemia, multiple extramedullary
plasmacytomas. Patients ineligible for ASCT with high-risk
disease, plasma cell leukemia or multiple extramedullary
plasmacytomas have poor prognosis. In these patients, depending
on tolerability, it would be reasonable to consider
VCD or VRD as initial therapy. The duration of therapy
will be dependent on the tolerability of these regimens in a
given patient. If possible, some form of continuous therapy is
probably needed.
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