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maintenance therapy (Fig. 5.2.). In the first TT1 trial started in 1990 only conven­
tional chemotherapy was used, in TT2(a) consolidation therapy (after tandem
ASCT) and in TT2(b) trial thalidomide, and later on in TT3(a) bortezomib was
introduced (Fig. 5.2.). It was shown long time before novel agents were used that
long­term CR and cure is an achievable goal in myeloma patients [ 59 ]. After
14 years of follow­up in the TT1 trial where 231 patients were enrolled, 23 patients
remained alive without any progression with a 14­year plateau in OS [ 11 , 12 ]. The
incorporation of consolidation therapy in the post­transplant setting in TT2(a), tha­
lidomide in TT2(b), bortezomib in TT3(a) further improved the complete response
duration, EFS and OS rate, respectively (Fig. 5.2.) [ 60 ]. The TT clinical trials clearly
demonstrate that a certain portion of MM patients are curable. The 10­year PFS and
CR increased from 8.8% and 17.9% in TT1 to 15.5% and 28.2% in TT2(a) to 25.1
and 35.6% in TT2(b) and to 32.9% and 48.8% in TT3(a), respectively [ 22 ]. TT4,
TT5 and TT6 are ongoing clinical trials analyzing clinical outcome in low­risk,
high­risk and pretreated MM patients, respectively.

5.5 Allogeneic Stem Cell Transplantation

Allogeneic stem cell transplantation (Allo­SCT) is not a standard treatment option
for patients with MM because of its high treatment­related mortality rate [ 61 ].
However, because of the curative graft­versus­myeloma effects, it should be consid­
ered in selected patients with early relapse (<24 months) after primary therapy that
included ASCT, patients with high risk characteristics defined by cytogenetic/FISH,
presence of extramedullary disease and/or plasma cell leukemia, respectively [ 48 ,
62 ]. The Dutch myeloma research group has recently shown that Allo­SCT can
produce long­term favorable clinical outcome in HRMM patients with CR rate of
48.3%, PFS of 30.2 months and 10­year OS of 51%, respectively [ 63 ]. However, in
the relapsed/refractory setting the clinical outcome was poor, in particular in patients
who relapsed within 18 months after ASCT.
In recent years Allo­SCT with reduced­intensity conditioning (RIC) has been
increasingly used to treat patients with myeloma. This treatment option is associ­
ated with lower toxicity and substantial decrease in the incidence of transplant­
related mortality rates. However, in a recently published study by the European
Group for Blood and Marrow Transplantation (EBMT) in more than 400 relapsed
and progressive MM patients after prior ASCT (>2 ASCT: 44.6%) who underwent
related or unrelated RIC­Allo­SCT it was shown that median OS was 27.7% with a
PFS of 9.6% and a non­relapse mortality (NRM) rate of 21.5%. In a multivariate
analysis it was demonstrated that CMV seronegativity of both donor and patient was
associated with significantly better PFS, OS and NRM. Moreover, OS was better in
patients who had less than two prior ASCT, and NRM rate was lower in patients
who underwent RIC­Allo­SCT in shorter time from the first ASCT [ 64 ].
An evolving concept is the performance of an ASCT/Allo­SCT successively in a
tandem approach. In a recently performed large Japanese matched­pair analysis no

5 Stem Cell Transplantation for Multiple Myeloma