The Evolving Impact on Survival Outcomes in Multiple Myeloma with Greater Access to Novel Treatment Regimens: Experience in a Real-World Cohort

Introduction: Novel agents (NA) are now established standards of care in the treatment of multiple myeloma (MM) in all lines of therapy. The use of proteosome inhibitors (PIs) and immunomodulatory drugs (IMiDs) has led to marked improvements in survival outcomes. Furthermore, these agents have evolved as the standard backbones for newer regimens incorporating novel approaches like monoclonal antibody-based (MAb) therapies and other targeted anti-plasma cell agents. Data is evolving with respect to patient outcome after exposure to standard PI and IMiD-based regimens in the real-world setting. We previously presented our provincial experience examining outcomes after subsequent lines of therapy in a setting where PI and IMiD-based approaches are routine. Herein, we update and expand the original series with a further 2 years of follow-up and with the cohort having greater access to newer more targeted agents.

Patients and methods: This series includes patients seen through the provincial myeloma program in Alberta, Canada. Only patients who initiated first line NA-based therapy between 2005-2015 were included to allow at least 2 years of follow-up. We examined double exposed (DE) patients, classified as those who had been treated with, but were not necessarily refractory to, both an IMiD and PI. We also examined patients who were double exposed by the end of their second line of treatment (DE2) as well as those who were double refractory (DR). Overall survival (OS) was measured from the time each line of therapy was started until death or last follow-up. Progression free survival (PFS) was from the time of therapy initiation to relapse, death or last follow-up. The category of MAb-based approaches was specifically examined given the unique mechanism of action of these agents. This category includes patients treated with daratumumab, elotuzumab, durvalumab and nivolumab-based combinations.

Results: Outcomes were examined after the 1st, 2nd, 3rd and 4th line therapy. Six hundred and nineteen patients have received upfront therapy of which, 311 and 308 were ASCT eligible and ineligible. The median follow-up for the whole cohort is 41 months. There was a statistically significant difference in favour of ASCT eligibility for frontline therapy with a median OS of 103 months vs 51 months (P < 0.001)) and a median PFS of 42 months vs 19 months (p < 0.001). Three hundred fifty five patients had relapsed. Survival outcomes between patients eligible and ineligible for frontline transplant were similar and thus were analyzed as a single cohort. Outcomes are presented in Table 1. From 2nd, 3rd and 4th line therapy the median OS were 36 months, 20 months, and 12 months and the median PFS were 12 months, 8 months and 6 months respectively. In the DE, DE2 and DR cohorts the median OS were 34 months, 36 months and 17 months and the median PFS were 11 months, 11 months and 4 months respectively. Forty-two patients received MAb based therapy for relapsed disease. Thirty-five patients received daratumumab, 4 received elotuzumab, 2 durvalumab, and 1 nivolumab. Forty-eight percent of patients in this cohort achieved a ≥PR (29% ≥VGPR). In this cohort the median OS and PFS from the time of first MAb exposure were 13 months and 3 months respectively. Focusing on the most widely used MAb daratumumab, 14% achieved ≥PR (9% ≥VGPR). In this cohort the median OS and PFS from the time of daratumumab exposure were 12 months and 4 months respectively. Of note, 71% of patients received their MAb in 4th line or later making this a heavily pretreated population.

Summary: In this updated series we continue to see remarkable survival outcomes for both transplant eligible and ineligible patients. In the former group, the median OS is approaching 10 years. In addition, we have seen gains in OS after each line of therapy likely owing to increased therapeutic options available for relapsed patients. This is notable given that patients are becoming double exposed to both traditional NA classes much earlier in their disease course. However, once double refractory the expected median PFS is only 4 months, again emphasizing that new approaches will be required to improve outcomes in this challenging population. The data presented here reveals a glimpse into the impact of MAb in a real-world setting; an important class of drugs owing to their entirely different mechanism of action. This data will help further benchmark expected outcomes as the therapeutic landscape in MM evolves.

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