Age (≤75 years) and Not Choice of First-Line Therapy Improves Overall Survival in Transplant Ineligible NDMM Patients: Results from a Large UK Real-World Dataset

Background

UK standard of care for transplant-ineligible (TNE) newly diagnosed multiple myeloma (NDMM) patients is fixed duration therapy (FDT) for the first two lines of treatment, which usually consists of 6-8 cycles of either a bortezomib (BOR) or thalidomide (THAL) based regimen. Treatment objective for this patient group is disease control whilst maintaining quality of life (QoL), which translates into improved survival. QoL is often reported to be better during treatment free intervals (TFI). TNE MM patients are under-represented in clinical trials owing to a combination of personal choice, poor performance status (PS), and co-morbidities. We performed a retrospective analysis in TNE NDMM patients to evaluate the influence of age and choice of upfront therapy on clinical outcomes. We quantified treatment free interval (TFI), in real world practice where FDT is used.

Methods

218 TNE NDMM patients treated between 2009-2017 within Thames Valley Cancer Network (UK) were eligible for inclusion. Data was collected from the chemotherapy database and patient records. Primary outcome was overall survival (OS) and the secondary outcomes were progression-free survival (PFS), time to next treatment (TTNT), TFI and response rates for the total cohort. Subgroup analyses were performed based on first line treatment: thalidomide-based (THAL) vs. proteasome inhibitor-based (PI), and age at presentation: ≤75 yrs vs. >75 yrs. Differences between subgroups were tested using an unstratified log-rank test. Medians and Cox hazard ratios (HR), with 95% confidence intervals (CIs) were calculated and Kaplan-Meier survival estimates are presented. Response rates were recorded as per IMWG consensus criteria.

Results

At start of first line therapy, median age was 75.2 years (IQR: 68-81), ≤75: n=106, >75: n=112, male 60%, and ISS stage (I: 17%, II: 16%, III: 48%, unknown: 19%), serum creatinine ≥ 140micromol/L was recorded in 30% of patients. Upfront therapy was THAL: 58%, PI: 22%, alkylator-based: 12%, lenalidomide-based: 8%. Treatment was delivered as a triplet regimen in 62.4% of the total cohort of patients, and as a doublet in 37.6%. Patient numbers within treatment subgroups were: THAL: n=126, PI: n=49. Median follow-up for the total cohort was 23months (IQR 10.8-44.4). Median length of upfront FDT was 4.6 months (IQR: 2.7-5.7). Overall response rate (ORR) for first-line therapy in all patients was 69%, with responses categorised as CR: 24%, VGPR: 14%, PR: 31%, SD: 12%, PD: 8% and unknown 11%. No difference in OS and PFS was noted between sexes. Both gender distribution and therapy proportions (doublet, triplet) were comparable across the 2 age groups: ≤75 (61% M, 39% F, doublet 34%, triplet 65%), >75 (59% M, 41% F, doublet 35%, triplet 65%). THAL group (58% M, 42% F), PI group (55% M, 45% F). ORR between subgroups was as follows: (THAL: 75% vs. PI: 80%) and (≤75: 76% vs. >75: 63%). Patients aged ≤75 showed a statistically significant improvement in OS and PFS compared to those >75: OS (49.0 vs. 22.5 months, p<0.0001, HR: 2.19, 95% CI: 1.53-3.14), PFS (10.8 vs. 7.6 months, p<0.001, HR: 1.66, 95% CI: 1.23-2.24). Survival rates at 1 year and 2 years between ≤75 and >75 were (80.9% vs. 77.4%) and (66.8% vs. 44.6%) respectively. Differences in OS and PFS were not statistically significant between the THAL and PI subgroups: OS (33.0 vs. 31.3 months, p=0.957, HR 1.01, 95% CI: 0.66-1.56), PFS (9.2 vs. 8.7 months, p=0.366, HR 1.18, 95% CI: 0.82-1.70). Difference in TTNT was not statistically significant between ≤75 vs. >75 (18.6 vs. 18.3 months, HR: 1.29, 95% CI: 0.91-1.82) and between THAL vs. PI (18.6 vs. 20.2 months, HR 0.91, 95% CI: 0.61-1.38). The longest TFI during FDT was following first-line therapy with a median of 6.9 months (IQR: 1.4-18.0, n=141), reducing after second line therapy to 2.3 (IQR: 0.7-6.6, n=71), and after third line therapy to 0.7 (IQR: 0.2-2.1, n=26).

Conclusion

This large real-world data study showed significantly improved OS and PFS for patients aged ≤75 compared to those >75 yrs, whilst choice of therapy (THAL or PI) had limited impact, when evaluated as individual factors. Survival benefit in <75 yr olds emerges after the first year suggesting that relapse related morbidity/mortality has an impact on survival. Clinically meaningful TFI was only recorded after first line FDT. This data suggests that a continuous therapeutic approach with manageable toxicities may be more appropriate in TNE myeloma patients.

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