Prognostic factors and tools for monitoring treatment efficacy

Prognostic factors and tools for monitoring treatment
efficacy
Table 1 summarizes the most important prognostic factors for
identifying high-risk MM based on the tumor clone, the host, and
the interaction between the tumor and the host (represented by
tumor burden and disease complications). Particular interest is being
paid to performance status (frailty) and comorbidities because they
clearly affect treatment options and cause a risk of toxicity, drug
discontinuation, and shorter survival. Cytogenetic/FISH evaluation
on purified PCs is essential in all patients with newly diagnosed MM
because of its impact on disease outcome.15 Moreover, as indicated
in Table 1, the association between genetic lesions and the other
prognostic features identifies an ultra-high-risk population.16 Novel
drugs can improve but not overcome the adverse prognosis of
high-risk patients. The most positive results are being reported for
bortezomib in patients with t(4;14).17 Pomalidomide in the relapse
setting has been effective in patients with del(17p), whereas
carfilzomib appears to be more useful for t(4;14). However, the
significance of cytogenetic abnormalities at relapse is not so well
established. Finally, the recently reported positive results for
tandem autologous stem cell transplantation (ASCT), particularly in
patients with t(4;14), should be highlighted.18
Treatment monitoring
Response to frontline therapy is one of the most important
prognostic factors in most hematological malignancies, myeloma
being no exception, whereby the better the quality of the response
the longer the survival. However, the definition of complete
response (CR) is far from optimal and more sensitive techniques for
evaluating MRD both outside the BM (eg, imaging techniques such
as MRI or PET) and inside the BM [eg, immunophenotyping by
multiparametric flow cytometry (MFC) or molecular analysis by
allele-specific oligonucleotide-PCR or next-generation sequencing]
are needed. The Italian and Arkansas groups have shown that failure
to achieve complete fludeoxyglucose-PET suppression after trans-
plantation is associated with shorter survival.19 Using MFC, the
Spanish and UK groups have both shown that, in transplanted and
elderly MM patients, persistence of MRD is associated with
significantly poorer outcome and this parameter is of significantly
more prognostic power than negative immunofixation14,20; however,
further standardization of MFC is still required. Allele-specific
oligonucleotide-PCR also predicts outcome and is probably one log
more sensitive than MFC, but is significantly less applicable (50%
vs 95%). Preliminary data from next-generation sequencing indicate
high applicability and sensitivity (90%), making the technique a
possible alternative to MFC.21 It should be noted that, due to the
patchy pattern of myeloma BM infiltration, a negative MRD result
may not be indicative of disease eradication, but rather the result of
a nonrepresentative BM sample.
Treatment
Since the introduction of melphalan–prednisone (MP) in the late 1960s,
the only significant innovation in the subsequent 30 years was the use
of high-dose melphalan followed by stem cell support (ASCT) for
young myeloma patients, whereas for elderly patients, MP remained
the standard treatment. In contrast, since 2000, a revolution in the
treatment of MM has been made possible by the availability of new
agents with distinct mechanisms of action: the IMiDs thalidomide and
lenalidomide and the proteasome inhibitor bortezomib.22