Improvement in Survival of Multiple Myeloma Patients: A Long-Term Institutional Experience

Introduction-Multiple myeloma (MM) represents 1.8% of all new cancer cases in the U.S., with an estimated 32,110 new cases in 2019. While not curable, advances in treatment, including autologous stem cell transplant (ASCT) and maintenance therapy, have dramatically improved progression free survival (PFS) and overall survival (OS). The Ohio State University bone marrow transplant program began utilizing ASCT for newly diagnosed MM (NDMM) patients in 1992. With the introduction of new and more effective drugs used before and after ASCT, we performed survival analysis in NDMM patients from 1992-2016 receiving ASCT to examine our institutional progress.

Method-We performed a retrospective analysis of 1002 consecutive transplant eligible NDMM patients. Patients were split into five groups based on historic changes in novel agents for treatment of MM: 1992-1998 (vincristine/doxorubicin/dexamethasone-group 1), 1999-2002 (thalidomide/dexamethasone-group 2), 2003-2008 (bortezomib/lenalidomide/dexamethasone-group 3), 2009-2013 (carfilzomib/pomalidomide/dexamethasone, and maintenance therapy-group 4), and 2014-2016 (agents used for relapsed MM, including daratumumab/elotuzumab/ixazomib/dexamethasone, and maintenance therapy-group 5). Pre-ASCT conditioning regimen was melphalan 140-200 mg/m² in 94.4% of patients. Data were consistently obtained since 2003 for both standard and high-risk patients at diagnosis. High-risk patients had del17, t(4:14), t(14:16), hypodiploidy and/or 1q abnormality. Primary endpoints were PFS and OS. PFS was defined as time to progressive disease or death from any cause from the date of transplantation. OS was defined as time from transplantation to death from any cause, censoring those who were still alive at the last follow up. Kaplan Meier curves were used to calculate PFS and OS.

Results-The median age of all patients at transplant was 58 years (range: 18-81 years) and 58.5% were male. The median patient age increased significantly, from 54 to 60 years, over 1992-2016 (p<0.001). The majority of patients (53.6%) had IgG myeloma and 19.3% had light chain disease. 30% of patients with known cytogenetic data were high-risk. Melphalan 200 mg/m² was used in 80.5% of patients. It was noted that across the years (1992-2016), there was a statistically significant improvement in both PFS (p<0.01) and OS (p<0.01). Median PFS and OS of all patients was 1.3 and 2.0 years in group 1 (1992-1998); 1.0 and 3.2 years in group 2 (1999-2002); and 2.0 and 5.8 years in group 3 (2003-2008), respectively. This response was further improved to PFS and OS of 4.1 years and not reached (NR) in group 4 (2009-2013), and 3.8 years and NR in group 5 (2014-2016), respectively (Figure 1). The 3 year PFS of groups 1 through 5 was 26%, 25%, 35%, 57% and 58%, respectively. The 3 year OS of groups 1 through 5 was 45%, 54%, 74%, 82% and 80%, respectively. On subset analysis, across years, significant increases in PFS (p<0.01) and OS (p<0.01) were seen in patients ≤65 years of age. For patients >65 years old, there was a statistically significant improvement in PFS (p<0.01) but not in OS (p=0.054). For both standard and high-risk disease, there was significant improvement in PFS (p<0.01 and p<0.01), and OS (p=0.02 and p=0.02), respectively.

The rate of response both pre- and post-transplant showed statistically significant improvement across the years (p<0.01). The pre-transplant rate of very good partial response (VGPR), or better, increased from 5.3% in early 1990's (group 1), 15.3% (group 2), 39.8% (group 3) to 51.2% (group 4) and 54% (group 5). The post-transplant rate of response (VGPR or better) also increased from 31.5% (group 1), 28.8% (group 2), 65.6% (group 3), to 79.6% (group 4) and 76.3 % (group 5).

Conclusion-Our data show that NDMM patients' survival and response to standard of care treatment have improved dramatically since 1992, primarily due to inclusion of novel therapies and maintenance. For NDMM patients receiving ASCT, the 3 year overall survival rate has significantly improved from 45% in 1992-1998 to 80% in 2014-2016, which is similar to the post-ASCT OS shown in the 2012 study by McCarthy et al. The significantly increasing age of NDMM patients receiving ASCT over time suggests improving supportive care and expansion of standard of care therapies to more of the population, improving survival and quality of life.

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