**2. Early mortality in the Connect MM Registry**

The Connect MM Registry reported on more than 3000 NDMM to identify and characterize EM. The first cohort included the first 1500 patients. Data was collected from an unselected patient population from routine clinical practices (81% community and 18% academic). Here a prognostic tool to assess the risk of EM based upon weighting of risk factors in elderly, SCT and non-SCT eligible patients was created to construct an Early Mortality Prediction Matrix (EMPM). See **Figure 1.**

For the 102 NDMM patients with EM, 39.2% (2.7% of total enrolled) were due to MM progression and 32.9% were related to non-causes. Common causes of death included heart failure, pneumonia, infections, and renal failure. The other


### **Figure 1.**

*A color-coded guide for the clinician identifies which patient (in red) who are at highest risk for EM within six months of diagnosis compared to green and yellow patients who are lowest risk.*

**11**

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

28.4% died of other causes or unknown. For those patients surviving more than six months causes of deaths were due to MM (58%) with 5% due to non-myeloma causes. The patients with EM received less triplet therapy (30% vs. 44.7%) and more radiation (24.5% vs. 15.3%) compared with longer surviving patients. EM

Prior to the era of novel agents, the incidence of EM in NDMM was 10–14% [1, 5, 17, 18]. Novel agents, supportive care, and SCT have improved PFS and OS. The promise of CAR-T therapy, monoclonal antibodies and unique agent BCMA directed against tumor necrosis super family member 17 suggest ongoing improvement for NDMM patients. Key management issues and controversies in EM patients in NDMM patients were passionately presented by Gonsalves [19]. Here the authors defined EM occurring in phase III trials and outlined key management issue strategies for NDMM to mitigate EM and summarizing those patients most at risk. The EMPM here describes parameters to identify NDMM patients at risk for EM, pitfalls

in treatment and opportunities to formally address EM in clinical trials.

combined has been used to predict NDMM patients at highest risk for EM.

and disease-specific risk-factors [24–29].

Prognostic studies provide clinicians with a better understanding of the relationship in NDMM patients between the aggressiveness of disease and survival. There are significant gaps in our understanding the optimum ways to risk-stratify NDMM patients when incorporating patient and disease-specific risk factors along with combining the relative contributions of individual risk factors. Existing point-based systems make it difficult to accurately predict outcomes in patients who have a combination of standard and high-risk characteristics [20–23]. Additionally, pointbased models are primarily based upon data from interventional clinical trials that may not be representative of Real World NDMM patient populations. The EMPM model here allows differential weighting of the impact of the individual patients

Patient co-morbidities have been associated with higher mortality in various clinical trials of patients with MM [4, 30–37]. For some NDMM patients, comorbiditites are both a direct cause of death and places patients at risk for early disease-related mortality by limiting their ability to tolerate therapy [4, 31, 33, 34]. Though the decline the EM to 6.8% reflects the benefit of novel agents and supportive care there are other considerations here. NDMM patients with EM tend to be older and poorer in health with higher rates of co-morbidities (especially diabetes), greater burden of disease, and high-risk features cytogenetics and Stage III disease. The EMPM demonstrates that a lower mobility score, age > 75, history of hypertension, thrombocytopenia, higher ECOG performance status, high ISS disease stage and renal insufficiency were associated with a higher likelihood of EM. Multivariate

The prognosis of NDMM patients depends upon staging, patient features, disease biology and treatment outcomes [3]. Risk stratification utilizes the Revised-International Staging System (R-ISS) as devised by the IMWG. The R-ISS is applicable for long-term prognosis but cannot identify those at risk for EM with NDMM [20]. Issues with the R-ISS include a point-based system which is disease specific factors which cannot assess the relative individual of each factor and does not account for patient-specific risk factors. The frailty score, as in the R-ISS, is a pointbased system that combines age, functional status and co-morbiditites to predict long-term survival and treatment feasibility in elderly patients with NDMM [20]. Combining the frailty score with the R-ISS stage improves the prognostic value for each score to predict long-term survival. However, neither score alone or when

patients were sicker and less likely to receive triplet therapy.

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

**3. Conclusions**

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

28.4% died of other causes or unknown. For those patients surviving more than six months causes of deaths were due to MM (58%) with 5% due to non-myeloma causes. The patients with EM received less triplet therapy (30% vs. 44.7%) and more radiation (24.5% vs. 15.3%) compared with longer surviving patients. EM patients were sicker and less likely to receive triplet therapy.
