**3. Emerging role of magnetic resonance imaging & 18-Flouro-Deoxy-Glucose (FDG) positron emission tomography**

Imaging techniques are also considered as important prognostic tools. The metastatic bone survey (MBS), a whole body x-ray, has been used as a standard for evaluating bone disease (osteolytic lesions or osteopenia). Unfortunately, the MBS does not detect bone destruction until more than 70% of the bone has decalcified [60]. The DSS1 has associated poor prognosis to patients with > 2 MBS osteolytic lesions, a feature seen in 33% of newly diagnosed MM patients [61]. It also appears that the MBS related poor prognosis still holds true in the era of novel agents [62], [63].

Magnetic resonance imaging (MRI) and more recently, positron emission tomography integrated with computed tomography (PET/CT) using radionuclide18F labeled with fluoro‐ deoxyglucose (18F-FDG) have demonstrated effective detection of bone lesions, marrow involvement and in the case of the latter; demonstrating active or inactive disease and their use can provide vital prognostic information (See Figure 5). Studies utilizing the PET/CT and MRI by the Arkansas group [61]- [63] and the Italian group [64] have looked at the prognostic implications of the number of focal lesions (FL), the uptake of FDG expressed as standardized uptake value (SUV), presence of extramedullary disease (EMD), at baseline and after treatment in previously untreated myeloma patients. The results from these studies showed that FL number adversely affected over survival (OS) and event free survival (EFS) independently, as did presence of EMD and failure of FDG suppression. Higher SUV of the most active FL (SUVmax) on PET/CT is also associated with poor outcomes(SUVmax >3.9 [62] or SUVmax >4.2 [64]).

The prognostic validity of the GEP-70 high risk signature has been confirmed in several independent patient cohorts (IFM 99 trial [55], ECOG E4A03 trial [55], HOVON-65 trial [57]). The Intergroupe Francophone du Myélome (IFM) have developed a 15-gene model [55], which described a set of genes that control proliferation and chromosomal instability. This model was able to identify high risk group in UAMS population but with less statistical significance. It was also interesting to note that IFM-15 and UAMS GEP-70 gene models do not share any common genes, which likely reflects the redundancy in the genes and pathways with prog‐ nostic significance in MM. Recently, the EMC-92 gene model has been reported on the HOVON65 clinical trial patients, with no overlapping genes compared with UAMS 70-gene signature and it identifies an additional 3-4% high risk MM patients to the existing GEP

Patients with low risk disease usually survive on a median about 6-7 years or longer when compared to those with high risk disease, who survive on a median ~ 3 years. On the other hand those with intermediate risk have been shown to have comparable survival to low risk patients in studies where there was early use of bortezomib plus ASCT [58]. The disease subset with GEP70 high risk signature, translocation (14; 16), translocation (14; 20), and deletion 17p remains a challenge. Clinical trials addressing this difficult group of newly diagnosed patients are now being conducted, such as the SWOG-1211(NCT01668719) study [59], to establish

**3. Emerging role of magnetic resonance imaging & 18-Flouro-Deoxy-**

Imaging techniques are also considered as important prognostic tools. The metastatic bone survey (MBS), a whole body x-ray, has been used as a standard for evaluating bone disease (osteolytic lesions or osteopenia). Unfortunately, the MBS does not detect bone destruction

to patients with > 2 MBS osteolytic lesions, a feature seen in 33% of newly diagnosed MM patients [61]. It also appears that the MBS related poor prognosis still holds true in the era of

Magnetic resonance imaging (MRI) and more recently, positron emission tomography integrated with computed tomography (PET/CT) using radionuclide18F labeled with fluoro‐ deoxyglucose (18F-FDG) have demonstrated effective detection of bone lesions, marrow involvement and in the case of the latter; demonstrating active or inactive disease and their use can provide vital prognostic information (See Figure 5). Studies utilizing the PET/CT and MRI by the Arkansas group [61]- [63] and the Italian group [64] have looked at the prognostic implications of the number of focal lesions (FL), the uptake of FDG expressed as standardized uptake value (SUV), presence of extramedullary disease (EMD), at baseline and after treatment in previously untreated myeloma patients. The results from these studies showed that FL number adversely affected over survival (OS) and event free survival (EFS) independently, as

has associated poor prognosis

**Glucose (FDG) positron emission tomography**

until more than 70% of the bone has decalcified [60]. The DSS1

signatures [57].

guiding posts for future trials.

208 Multiple Myeloma - A Quick Reflection on the Fast Progress

novel agents [62], [63].

**Figure 5.** Left panel shows MRI focal lesion on sagittal STIR images; right panel shows AP FDG uptake on PET

Specifically, baseline PET focal lesions > 3 (32% of newly diagnosed MM) and baseline MRI focal lesions > 7 (36% of newly diagnosed MM) were associated with shorter EFS and OS in Total Therapy 3 trials. It was also observed seen that complete suppression of FDG before the first autologous stem cell transplant (ASCT) conferred a favorable affect on outcome especially seen in the GEP 70 – defined high risk patients [61], [62]. More recently, it has also shown that absence of PET suppression by Day 7 of first induction cycle in MM patients treated on the Total therapy 3 trials have shorter progression free survival (PFS) and OS [65]. These obser‐ vations have important implications and would need further validation in the era of novel therapy induction regimens. One could potentially identification of high risk patients based on imaging response that would require change in therapeutic strategy, similar in fashion to how PET is employed in aggressive lymphomas.

PET/CT and MRI are not yet established as a standard for diagnosis and disease evaluation, as concerns have arisen due to heterogeneity of visual criteria and inconsistency in interpre‐ tation of results [66]. In current practice, the PET/CT can be employed in patients presenting with solitary plasmacytomas where the clinical suspicion for systemic disease is high, or when patients are relapsing biochemically but bone marrow biopsy provides ambiguous results. The use of MRI and PET/CT is presently limited to clinical investigations, partly due to the economic implications of broader usage in clinical practice. These concerns may be alleviated may be in the future with development of more efficient and cost-effective technologies.

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Novel Prognostic Modalities in Multiple Myeloma

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#### **4. Conclusion and future directions**

Our understanding of MM has grown many folds over the last 2 decades with a better understanding of the genomic heterogeneity associated with this disease. We are just begin‐ ning to combine the clinical and biologic prognostic markers in newly diagnosed multiple myeloma patients in efforts to better stratify patients and choosing appropriate therapies. There are multinational efforts, such as the CoMMpass study, aiming to provide for a com‐ prehensive understanding of the disease in the era of novel agents [66]. With the advances in drug development, we are getting closer to developing a risk-adaptive therapeutic strategy for majority of MM patients. There is a robust pipeline of novel targeted agents on the horizon for MM. It appears that there will be enough effective and tolerable therapeutic agents in the oncologist's armamentarium that the treatment strategy will take in to account both the clinical and biologic risk factors for a truly personalized medicine experience. The advances in diagnostic and prognostic tools will also provide impetus for a response-adaptive strategy which will likely be incorporated in the therapeutic matrix as the data emerges over the next decade.
