**4.2 Prognosis in NDMM**

*Multiple Myeloma*

between trials.

areas of research.

in multiple myeloma [43].

median survival of eight years.

analysis did not independently find anemia, del(17q) mutation, low self-care score from EQ-SD, hypercalcemia, diabetes and R-ISS score, beta-2 microglobulin and albumin did not predict EM. NDMM patients with EM received more radiation therapy which delayed the initiation of therapy and limited their ability to receive triplet therapy. The EMPM has been validated by bootstrapping for internal crossvalidation [38–40]. A high degree of concordance was observed when applying the model using data from patients form the Phase 3 MM-015 trial and the phase 3

This matrix has the potential to be a clinically useful tool for NDMM patients who are at risk for EM and for analyses of specific patient populations, selection of therapy, identification of new targets for treatment and standardized comparisons

High-quality systematic research to identify patients at risk for EM have not been

studied prospectively. The EMPM is the first weight-based model that accounts for both patient and disease-specific risk factors. This model can facilitate early recognition for NDMM patients at high risk for EM to assist physician selection of personalized treatments, avoidance of nephrotoxic agents, monitoring of steroid dosing in diabetic patients, prompt initiation of doublet or triplet therapy and limiting radiation fields when applicable and the use of prophylactic antibiotics. The EMPM can be applied in routine clinical practice and considered in a risk-adaptive approach. Clinical trials of reducing EM patients in NDMM can be designed for new

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).

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

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

FIRST trial despite more rigorous eligibility criteria [41].

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

**4.1 Historical background of prognostic features**

**12**

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 leukemia [48, 49].

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 enrollment and reproducibility between trials.

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 the use of novel agents [51].

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 aberrations [52].

## **4.3 1gH rearrangements**

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

#### **4.4 del (13)**

Though commonly seen in association with other cytogenetic abnormalities in NDMM, del(13) alone does not predict poor outcomes. When occurring in MGUS and SMM it does not influence progression to myeloma. The finding has called into question the use of del(13) in NDMM prognostication [56]. However in the presence of concomitant t(4;14) or del17p, poor prognosis is suggested

del(17p).

The loss of the short term arm of chromosome 17, or del(17p), leads to loss of TP53 and appropriate DNA repair. 17p deletions occur in 8–10% of NDMM patients and has remained a poor risk feature not over by current use of novel therapies. Without adequate DNA repair function, the rate of clonal mutagenesis and subsequent treatment resistance rises more rapidly. Del(17p) is acquired at a median of 35.6 months after the time of diagnosis, with a median PFS of 5.4 months after acquisition. Consequently, as compared to non-del(17p) patients, median OS is significantly worse [57, 58].

#### **4.5 Hyperdiploidy and other cytogenetic abnormalities**

In recent years, high-throughput genomic studies using SNP or CGH arrays have accelerated our understanding of genetic changes within NDMM. Hyperdiploidy generally confers a more favorable prognosis in NDMM. The presence of certain trisomies, such as trisomy 3 and trisomy 5, may partially abrogate the negative prognostic features of other cytogenetic abnormalities. In contrast, the presence of trisomy 21 may potentiate the effects of negative prognostic features. Recently identified chromosomal abnormalities, such as gain of 1q and loss of 1q have also been shown to predict for poorer outcomes. One univariate analysis identified poorer prognosis with deletions of 1p, 2p, 14q, 16q, and 22q. Conversely, amplifications of chromosome 5, 11, 15 and 19 were associated with improved outcomes [56]. Chromosome 1q gain has become the most important chromosomal gain abnormality. In a recent update, high risk cytogenetics are presently considered to be del(17p), a p53 mutation, t(4;14), t(14;16),or gain 1q [59]. Similar to lymphoma, the presence of any two or three risk factors is considered 'double-hit' or 'triple-hit' myeloma, respectively.

In 2015, with the advent of cytogenetic profiles, a revised version of the ISS (R-ISS) was adopted, incorporating LDH and high-risk cytogenetics of t(4;14), t(14;16), and del(17p) into the scoring system [60, 61]. These objective systems have allowed for more reproducible results and the ability to more accurately compare patients within clinical trials [61].

However, establishment of baseline disease characteristics are critical for long term prognosis [62]. These newer staging systems do not account for several features that have been shown to correlate to long-term outcomes in myeloma, such as the use of novel myeloma therapies, triplet therapy, autologous stem cell transplant, patient performance status, renal function, a history of diabetes, or MRD status.

Novel agents in multiple myeloma have allowed for significant progress in the treatment of newly diagnosed patients, with more than doubling of the average survival with less toxicity [47].

#### a.Alkylating agents

In the early 1960's melphalan and cyclophosphamide were the first alkylating agents introduced in the treatment of NDMM demonstrated equivalent activity. In 1972, Harley evaluated other alkylating agents in NDMM, with the use

**15**

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

aggressive disease, as in plasma cell leukemia or refractory MM.

Glucocorticoids directly induce apoptosis of plasma cells. This is believed to occur via induction of IkB production that negatively regulates NFkB, resulting in downregulation of IL-6 and other pro-inflammatory cytokines, which facilitates apoptosis of the myeloma clones. In the late 1960's prednisone was added to melphalan, but adoption was slowed due to concerns over the known osteoporosis effect of chronic steroid therapy [44]. Since then, glucocorticoids (particularly dexamethasone) have remained a backbone of therapy. Singleagent dexamethasone is no longer advocated in the treatment of NDMM.

An international, randomized phase III trial demonstrated that thalidomide with dexamethasone was superior to dexamethasone alone, with an ORR or 63% vs. 46% and a PFS of 14.9 months vs. 6.5 months [59]. FDA approval in the USA in 1998 of Thalidomide was cautiously accepted due to historical concerns regarding the drug-associated phocomelia was displayed in infants 30 years earlier as antiemetic therapy in pregnancy. Thalidomide is used throughout Europe to date in the treatment of myeloma. Lenalidomide was FDA approved in 2005 based upon rate and lower toxicity profile on a retrospective single-institution case–control study of lenalidomide-dexamethasone vs. thalidomide dexamethasone demonstrated lenalidomide was better tolerated, had a higher ORR of 80% vs. 61%, higher VGPR rate 34 vs. 12%, and improved PFS of 27 months vs. 17 months, establishing lenalidomide with dexamethasone as an appropriate induction option [64]. In 2013, pomalidomide, a second-generation IMiD, was developed for use in relapsed/refractory disease. Though shown to have clear activity in NDMM via several immunomodulation pathways, the precise mechanism of action of these agents remain elusive. Irreversible peripheral neuropathy and increased thrombotic risk remain primary side effects of these agents. Prophylaxis with low-dose aspirin

The primary function of plasma cells is to produce immunoglobulin, which occurs on a constitutive basis and requires assembly within 26 s proteasome. Excess accrual of protein within the cell creates proteotoxic stress, leading to cell apoptosis and death. As a result, proteasome inhibitors have been shown to have potent efficacy within the treatment of myeloma. Bortezomib, a boroncontaining dipeptide, was the first proteasome inhibitor to be introduced for

of melphalan, carmustine, and cyclophosphamide, melphalan and prednisone. (MP) was established as the gold standard for treatment, paving the way to several decades of comparison against other combinations of agents, including cyclophosphamide, carmustine, vincristine, and adriamycin. Ultimately, combination therapies improved the response rate in NDMM but did not improve OS compared to MP. MP has a response rate of 50–60%, median PFS of 18 months, and an OS of 30–60 months [63]. To date, melphalan and cyclophosphamide remain effective treatment options and are commonly used in autologous stem-cell transplant conditioning. Combination alkylating agent regimens (such as VD-PACE or VDT-PACE) remain typically reserved for more

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

b.Glucocorticoids

c.IMiDs

daily is adequate prevention.

d.Proteasome inhibitors

*Prognostic and Predictive Factors in Newly Diagnosed Multiple Myeloma Patients with Early… DOI: http://dx.doi.org/10.5772/intechopen.95819*

of melphalan, carmustine, and cyclophosphamide, melphalan and prednisone. (MP) was established as the gold standard for treatment, paving the way to several decades of comparison against other combinations of agents, including cyclophosphamide, carmustine, vincristine, and adriamycin. Ultimately, combination therapies improved the response rate in NDMM but did not improve OS compared to MP. MP has a response rate of 50–60%, median PFS of 18 months, and an OS of 30–60 months [63]. To date, melphalan and cyclophosphamide remain effective treatment options and are commonly used in autologous stem-cell transplant conditioning. Combination alkylating agent regimens (such as VD-PACE or VDT-PACE) remain typically reserved for more aggressive disease, as in plasma cell leukemia or refractory MM.

#### b.Glucocorticoids

*Multiple Myeloma*

del(17p).

significantly worse [57, 58].

myeloma, respectively.

compare patients within clinical trials [61].

survival with less toxicity [47].

a.Alkylating agents

Though commonly seen in association with other cytogenetic abnormalities in NDMM, del(13) alone does not predict poor outcomes. When occurring in MGUS and SMM it does not influence progression to myeloma. The finding has called into question the use of del(13) in NDMM prognostication [56]. However in the

The loss of the short term arm of chromosome 17, or del(17p), leads to loss of TP53 and appropriate DNA repair. 17p deletions occur in 8–10% of NDMM patients and has remained a poor risk feature not over by current use of novel therapies. Without adequate DNA repair function, the rate of clonal mutagenesis and subsequent treatment resistance rises more rapidly. Del(17p) is acquired at a median of 35.6 months after the time of diagnosis, with a median PFS of 5.4 months after acquisition. Consequently, as compared to non-del(17p) patients, median OS is

In recent years, high-throughput genomic studies using SNP or CGH arrays have accelerated our understanding of genetic changes within NDMM. Hyperdiploidy generally confers a more favorable prognosis in NDMM. The presence of certain trisomies, such as trisomy 3 and trisomy 5, may partially abrogate the negative prognostic features of other cytogenetic abnormalities. In contrast, the presence of trisomy 21 may potentiate the effects of negative prognostic features. Recently identified chromosomal abnormalities, such as gain of 1q and loss of 1q have also been shown to predict for poorer outcomes. One univariate analysis identified poorer prognosis with deletions of 1p, 2p, 14q, 16q, and 22q. Conversely, amplifications of chromosome 5, 11, 15 and 19 were associated with improved outcomes [56]. Chromosome 1q gain has become the most important chromosomal gain abnormality. In a recent update, high risk cytogenetics are presently considered to be del(17p), a p53 mutation, t(4;14), t(14;16),or gain 1q [59]. Similar to lymphoma, the presence of any two or three risk factors is considered 'double-hit' or 'triple-hit'

In 2015, with the advent of cytogenetic profiles, a revised version of the ISS (R-ISS) was adopted, incorporating LDH and high-risk cytogenetics of t(4;14), t(14;16), and del(17p) into the scoring system [60, 61]. These objective systems have allowed for more reproducible results and the ability to more accurately

However, establishment of baseline disease characteristics are critical for long term prognosis [62]. These newer staging systems do not account for several features that have been shown to correlate to long-term outcomes in myeloma, such as the use of novel myeloma therapies, triplet therapy, autologous stem cell transplant, patient performance status, renal function, a history of diabetes, or MRD status. Novel agents in multiple myeloma have allowed for significant progress in the treatment of newly diagnosed patients, with more than doubling of the average

In the early 1960's melphalan and cyclophosphamide were the first alkylating agents introduced in the treatment of NDMM demonstrated equivalent activity. In 1972, Harley evaluated other alkylating agents in NDMM, with the use

presence of concomitant t(4;14) or del17p, poor prognosis is suggested

**4.5 Hyperdiploidy and other cytogenetic abnormalities**

**4.4 del (13)**

**14**

Glucocorticoids directly induce apoptosis of plasma cells. This is believed to occur via induction of IkB production that negatively regulates NFkB, resulting in downregulation of IL-6 and other pro-inflammatory cytokines, which facilitates apoptosis of the myeloma clones. In the late 1960's prednisone was added to melphalan, but adoption was slowed due to concerns over the known osteoporosis effect of chronic steroid therapy [44]. Since then, glucocorticoids (particularly dexamethasone) have remained a backbone of therapy. Singleagent dexamethasone is no longer advocated in the treatment of NDMM.

#### c.IMiDs

An international, randomized phase III trial demonstrated that thalidomide with dexamethasone was superior to dexamethasone alone, with an ORR or 63% vs. 46% and a PFS of 14.9 months vs. 6.5 months [59]. FDA approval in the USA in 1998 of Thalidomide was cautiously accepted due to historical concerns regarding the drug-associated phocomelia was displayed in infants 30 years earlier as antiemetic therapy in pregnancy. Thalidomide is used throughout Europe to date in the treatment of myeloma. Lenalidomide was FDA approved in 2005 based upon rate and lower toxicity profile on a retrospective single-institution case–control study of lenalidomide-dexamethasone vs. thalidomide dexamethasone demonstrated lenalidomide was better tolerated, had a higher ORR of 80% vs. 61%, higher VGPR rate 34 vs. 12%, and improved PFS of 27 months vs. 17 months, establishing lenalidomide with dexamethasone as an appropriate induction option [64]. In 2013, pomalidomide, a second-generation IMiD, was developed for use in relapsed/refractory disease. Though shown to have clear activity in NDMM via several immunomodulation pathways, the precise mechanism of action of these agents remain elusive. Irreversible peripheral neuropathy and increased thrombotic risk remain primary side effects of these agents. Prophylaxis with low-dose aspirin daily is adequate prevention.

#### d.Proteasome inhibitors

The primary function of plasma cells is to produce immunoglobulin, which occurs on a constitutive basis and requires assembly within 26 s proteasome. Excess accrual of protein within the cell creates proteotoxic stress, leading to cell apoptosis and death. As a result, proteasome inhibitors have been shown to have potent efficacy within the treatment of myeloma. Bortezomib, a boroncontaining dipeptide, was the first proteasome inhibitor to be introduced for

the treatment of multiple-myeloma. Monotherapy bortezomib FDA approval in 2003 demonstrated an ORR of 27% and a 10% CR rate. In combination with dexamethasone, ORR improved to 88% and CR + VGPR rate of 19%, with a 1-year OS of 87% [65]. Other proteasome inhibitors, including carfilzomib and ixazomib, have been developed and are FDA approved in the relapsedrefractory setting.

Emerging novel agents and therapies

e.Within the past 5 years, several agents have become available in the treatment of multiple myeloma. Notable agents, Dartumumab, a monoclonal antibody against CD-38, has displayed promising efficacy. Belantamab mafadotin, an antibodydrug conjugate between the B-cell maturation antigen (BCMA) and MMAF (a chemotherapy payload) was recently FDA approved for relapsed/refractory disease. BCMA CAR-T cell therapy also shows promise in the relapsed/refractory setting. Though not yet approved in NDMM, these agents, along with others, show promise in the treatment of newly-diagnosed and relapsed-refractory patients.

In 2005, OS in NDMM was 4.6 years, increasing to 6.1 years by 2010. Over the past decade, the adoption of immunomodulatory agents and proteasome inhibitors in triplet therapy extended median OS to greater than 7 years. These gains were predominantly driven by triplet therapy in the elderly and by reducing early mortality in the disease [53, 66].
