Overall Survival of Transplant Eligible Patients with Newly Diagnosed Multiple Myeloma: Comparative Effectiveness Analysis of Modern Induction Regimens on Outcome

Aims: Overall survival (OS) of multiple myeloma (MM) has improved remarkably over time, with a recent study reporting a 4-year OS rate of approximately 81.5% with or without upfront autologous stem cell transplantation (ASCT) in patients receiving modern therapy (Attal M, et al. N Engl J Med 2017; 376:1311-1320). However, these results may overestimate the current OS of MM in this population, since patients enrolled in clinical trials represent a highly selected group, and may not reflect outcomes in a more generalizable population of MM patients. In order to remove the selection bias inherent in clinical trial enrollment, we studied the outcome of all newly diagnosed MM patients eligible for ASCT seen at the Mayo Clinic during the time period corresponding to the IFM trial. We also performed a comparative effectiveness analysis of bortezomib, lenalidomide, dexamethasone (VRD) (the regimen used in the IFM trial) and other induction regimens used during this period at our institution.

Methods: We reviewed electronic medical records to identify all patients with MM 65 years of age and younger who were seen at the Mayo Clinic between January 1, 2010 and August 31, 2015, and had a stem cell harvest performed within 12 months of initial diagnosis. We excluded patients with baseline serum creatinine >2gm/dL. Data on baseline characteristics, cytogenetics, initial therapy, ASCT, date of progression, and relevant prognostic variables were analyzed. OS was estimated using Kaplan Meier method. Differences between survival curves were tested for statistical significance using the two-sided log-rank test.

Results: 488 patients (267 men and 221 women) were studied. The estimated median follow-up duration was 46 months. Median age was 57.8 years (range, 32.8-64.9). Initial therapy consisted of VRD (n=126); bortezomib, cyclophosphamide, dexamethasone (VCD)(n=138); lenalidomide, dexamethasone (Rd)(n=142); bortezomib, dexamethasone (n=36); ixazomib, cyclophosphamide, dexamethasone (ICD) (n=15); carfilzomib, lenalidomide, dexamethasone (KRD)(n=8); ixazomib, lenalidomide, dexamethasone (IRD)(n=3); and other regimens (n=20). The median OS has not been reached. The 4 year OS rate of the whole cohort was 80.6%; 5 year OS rate was 74.1%. FISH results for mSMART risk stratification were available in 369 patients; 270 were standard risk (73.1%); 48 intermediate risk (13%); and 51 high risk (13.8%). The 4 year OS rates for standard, intermediate, and high risk MM were 83.7%, 58.2%, and 69.8%, respectively (P=0.008). The 4 year OS rate for the 3 most commonly used regimens VRD, VCD, and Rd were 77.4%, 78.6%, and 85.2%, respectively (P=0.14). However, the proportion of patients treated with VRD, VCD, and RD who had high risk disease was different; 32.7%, 9.4%, and 5.8%, respectively. Similarly, the proportion of patients treated with VRD, VCD, and RD who had intermediate risk disease was 11.2%, 18.7%, and 2.9%, respectively. Adjusting for mSMART risk, P value for the comparison of OS between the 3 regimens remained non-significant, P=0.21. OS was then compared after pooling similar regimens; the 4 year OS rates for VRD/IRD/KRD (IMid/PI combination)(n=137), VCD/ICD (PI/Alkylator combination)(n=153), and RD/VD (doublet regimen)(n=178) were 78.4%, 78.6%, and 82.4%, respectively, P=0.61. As expected, the use of regimens varied by risk stratification. The 4 year survival rates for the 3 regimens stratified by mSMART risk classification are shown in the Table. Among patients with high risk MM (n=50), 34 received IMiD/PI, 10 PI/Alkylator, and 6 doublet. Similarly, among patients with intermediate risk MM (n=44), 14 received IMiD/PI, 24 PI/Alkylator, and 6 doublet.

Conclusions: The 4 year OS rate of consecutive MM patients 65 years of age and younger eligible for ASCT treated at a single institution was 80.6%, and is comparable to results achieved in a contemporaneous randomized trial. This is a benchmark for this patient population; benchmark 4 year OS rates for standard, intermediate, and high risk MM are 83.7%, 58.2%, and 69.8%, respectively. Outcome of high risk MM has improved considerably during this time period. Comparative effectiveness analysis shows near identical outcomes (83-84% 4-year OS rate) in standard risk patients receiving common MM regimens.

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