**4. Three and five-year overall survival in NDMM**

Over the past 60 years, dramatic changes have been made in the treatment of multiple myeloma. These advances have radically altered the disease landscape and prognosis for newly diagnosed patients, turning a previously untreatable illness toward one of a chronic disease [42]. Here we discuss a brief history of treatments and prognostic features in NDMM, the development of novel treatment regimens, and the use of a prediction matrix in 3-year, and 5-year overall survival (OS).

### **4.1 Historical background of prognostic features**

In 1850, Dr. Henry Bence Jones described the first case of myeloma. His patient presented with fatigue, arthralgias, and polyuria. His urine was found to precipitate an unusual protein upon healing, now known as Bence Jones protein. In 1873, Rustizky was found to have multiple osseous masses in a similar patient, giving rise to the name multiple myeloma. In 1889, Kahler presented a large review of the disease, leading it to be called Kahler disease. Over the subsequent several decades, advances in x-ray imaging, microscopy, and electrophoresis allowed for further characterization of the disease. In 1953, immunoelectrophoresis identified excess monoclonal heavy and/or light chains as characteristic for the disease process seen in multiple myeloma [43].

Untreated, NDMM has a median overall survival of two years. In 1958, Blokhin introduced chemotherapy in MM with a mixture of racemic phenylalanine and nitrogen mustards like sacrosine. In 1962, Bergsagel pioneered the use of melphalan and glucocorticoids, creating the combination of melphalan with prednisone (MP), still in use today. However, complete remissions (CR) were rare. In 1983, McElwain and Powles introduced the use of high-dose therapy with melphalan, with CR achieved in a proportion of patients [44]. Those who achieved CR with MP had a median survival of eight years.

**13**

*Prognostic and Predictive Factors in Newly Diagnosed Multiple Myeloma Patients with Early…*

Despite the initial advances, the median OS remained at about three years. Remarkably, the current median OS now ranges from 8 to 12 years [45]. However, individual outcomes are varied, with 20% of patients surviving less than 2 years and 40% surviving more than 10 years after diagnosis [46]. Considerable advances in understanding of the pathobiology of multiple myeloma over this time have greatly aided in the ability to select prognostic factors in NDMM. Advances in treat-

For many years, the factors contributing to the highly variable prognosis in myeloma were unclear. Early on, immunoglobulin isotype was shown to play a role in prognosis, with monoclonal 1gA production (21%) associated with a worse prognosis [47]. The degree of plasma cell burden is only an issue in plasma cell

In 1975, the Durie-Salmon staging system was adopted, stratifying individuals by relative plasma cell burden (anemia), hypercalcemia, number of lytic lesions visible on x-ray, and serum urine M-protein levels [50]. However, the number of lytic lesions on x-ray is observer-dependent and created challenges with respect to

Thirty years later in 2005, Griepp and colleagues established the international staging system (ISS), utilizing the beta-2 microglobulin level and albumin level to appropriately risk-stratify patients. The ISS can predict EFS and OS regardless of age, geographic region, study site, standard-dose vs. high-dose therapy (HDT), or

Discovery of specific cytogenetic abnormalities correlates with prognosis in multiple myeloma and overall survival. Plasma cells typically have a low-proliferative index, and so cytogenetic abnormalities are detected in a small number of patients. Interphase FISH was found to be useful in identifying specific cytogenetic

As the heavy chain of the immunoglobulin molecule is constitutively activated on the 14th chromosome within plasma cells, translocations involving the immunoglobulin heavy chain haven been shown to play a strong role in myeloma pathogenesis and occur in up to half of NDMM patients. Among these 1gH translocations, five appear to be recurrent: t(4;14) and t(11;14), t(4;16) and t(14;20) [53]. The translocations t(4;14) and t(11;14) are not the most common abnormalities involving the 1gVH gene in myeloma, each seen in approximately 15% of patients. These translocations lead to overexpression of FGRF3 and BCL2, respectively. T(4;14) is regarded as high-risk abnormality with inferior median OS. t(11;14) and hyperdiploidy have been reported in some studies to predict a more favorable outcome. T(11;14) is observed in 16–24% of MM patients and has specifically gained interest with the use of the novel agent venetoclax, a BCL2 inhibitor. Currently, the use of venetoclax was stopped due to an early signal for increased death in early clinical trials due to a higher rate of infections [54]. A large, US, multicenter prospective observational cohort study did not demonstrate any impact of t(11;14) on PFS, or OS [55]. Further clinical trials investigating its use in myeloma are currently pending. T(14;16) and T(14;20) are relatively rare, seen in approximately 1.5–3% of patients and lead deregulation of the oncogenes c-MAF and MAFAB, respectively. Though a pivotal trial from the Mayo Clinic was suggestive of poor prognostic correlation with

ment that have been contributed greatly to survival are reviewed below.

*DOI: http://dx.doi.org/10.5772/intechopen.95819*

enrollment and reproducibility between trials.

the presence of t(14;16), larger series are uncertain [53].

**4.2 Prognosis in NDMM**

the use of novel agents [51].

**4.3 1gH rearrangements**

aberrations [52].

leukemia [48, 49].

Despite the initial advances, the median OS remained at about three years. Remarkably, the current median OS now ranges from 8 to 12 years [45]. However, individual outcomes are varied, with 20% of patients surviving less than 2 years and 40% surviving more than 10 years after diagnosis [46]. Considerable advances in understanding of the pathobiology of multiple myeloma over this time have greatly aided in the ability to select prognostic factors in NDMM. Advances in treatment that have been contributed greatly to survival are reviewed below.
