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Imbalances between efficacy benefits reported in phase 3 clinical trials in relapsed/refractory multiple myeloma and real-world setting

An analysis of real-world data in patients with relapsed, or refractory multiple myeloma (RRMM) indicates that the efficacy benefits reported in phase 3 clinical trials in RRMM do not translate equally into the daily clinical practice. In fact, there is evidence for substantially shorter outcomes in the real-world versus the clinical trial settings. This effect was regimen-based and was particularly pronounced with carfilzomib-based regimens and injectable PI-immunomodulatory drug-based triplet regimens. The main explanation for these differences can be found in the discrepancies in patient characteristics between patients treated in real-world and in clinical trials. Additionally, there is a discrepancy between duration of therapy achieved in the real-world vs.clinical trial setting. The investigators concluded that it is therefore important to better understand the factors affecting the translation of clinical trial efficacy into real-world effectiveness in RRMM and to design clinical trials that are more reflective of real-world scenarios.

Toxicity management in the real-world setting is critical

The introduction of novel agents into the treatment arsenal for patients with RRMM significantly improved the survival of patients. The protocols of these large randomized trials create a rigorously controlled treatment environment and the results obtained in this setting are difficult to duplicate in real-world. This is partly related to the patient selection in clinical trials, but is also influenced by the higher toxicity burden, a lower patient and physician motivation, a different distribution of academic versus community centres and healthcare access issues outside of clinical studies. Notably, the duration of treatment (DoT) has also been shown to be important with regards to long-term outcomes, with shorter treatment associated with shorter progression-free (PFS) and overall survival (OS). Due to rigorous selection criteria in clinical trials, and due to protocol-driven dose modifications, patients in a controlled clinical trial setting may be able to tolerate a novel drug better than patients in the real-world setting, leading to longer treatment durations in clinical trials. Thus, toxicity management in the real-world setting is critical, with the aim of keeping patients on treatment.

Importance of patient selection

Coming back to the patient selection in clinical trials, it is important to note that a substantial proportion of real-world patients would not be eligible for clinical trials, driving discrepancies in outcomes. In fact, data reported by Shah et al. (Clin Lymphoma Myeloma Leuk 2017;17:575–83) indicate that up to 40% of MM patients enrolled in observational registries would not be eligible for interventional phase 3 studies. As such, clinical trial findings may not reflect the overall RRMM population.

Gap between PFS and TTNT in clinical trials and in real-world narrows in later lines of therapy

In the presented analysis, Richardson et al. conducted a PubMed search for publications containing real-world RRMM data published in the past 10 years. Abstracts from the past 3 annual meetings of ASH, ASCO, and EHA, and from the past 2 IMW meetings were similarly reviewed. In total, 7 relevant publications and 15 abstracts, focusing on reports of real-world data in RRMM patients with 1–3 prior therapies treated with proteasome inhibitor (PI), or immunomodulatory drug-based regimens, were used for the analysis.

The analysis showed disparities in the outcomes seen in clinical trials and in the real-world setting. The ranges of median PFS and time to next treatment (TTNT) values in real-world reports were generally shorter than those reported in phase 3 clinical studies in RRMM patients with 1–3 prior therapies (Slide 2, see ‘Keyslides’ on this website). Interestingly, real-world data on carfilzomib-based regimens (median PFS/TTNT: 14.9-22.2 months in trials vs. 3.2-9.4 months in real-world reports) and injectable PI-immunomodulatory drug-based triplet regimens (median PFS/TTNT: 18.3-29.6 months in trials vs. 9.4-12.7 months in real-world reports) appeared to show a notably shorter range of median PFS/TTNT than respective clinical study data. Conversely, PFS/TTNT in clinical and real-world studies appeared more closely aligned with all-oral regimens (median PFS/TTNT: 17.5-20.6 months in trials vs. 19.2 months in real-world reports). Also the ranges of median DoT values in the real-world reports were generally shorter than what was reported in phase 3 clinical studies in RRMM patients with 1–3 prior therapies (Slide 3). Although reasons for discontinuations were not consistently reported, treatment toxicity is anticipated to have contributed to patients discontinuing therapy, and thus tolerability may be an important factor for a number of regimens in the real-world setting. Of note, the ranges of median DoT and median PFS/TTNT in clinical trials and real-world analyses appeared to be more similar with bortezomib-based regimens. This might possibly be associated with the fixed DoT utilized in bortezomib phase 3 studies closely mirroring the drug exposure that is tolerated in the real world.

Finally, the researchers focussed on regimens used in more heavily pre-treated patients (>3 prior therapies) (Slide 4). This analysis showed that both the DoT and the outcomes appeared to be more similar for pomalidomide-dexamethasone and daratumumab-based regimens in clinical trials and in the real-world setting. This may be associated with the heavily pre-treated nature of the RRMM patients being treated with these regimens, and their associated general poor prognosis. As a result, the gap between PFS and TTNT in clinical trials and in real-world narrows in later lines of therapy. However, addition of an injectable PI to the pomalidomide/dexamethasone regimen was associated with a longer DoT and PFS/TTNT in the clinical trial compared to the real-world setting, reflecting the data seen for injectable PI-immunomodulatory drug combinations in the overall analysis and suggesting a regimen-based effect.

In conclusion, the efficacy benefits reported in phase 3 clinical trials in RRMM do not always translate equally to the real-world setting, with evidence for specific regimens of substantially shorter outcomes in the real-world versus clinical trial settings. A key driver of these disparities may be stringency of eligibility criteria in various clinical trials leading to discrepancies in patient characteristics between enrolled populations and real-world patients. Tolerability may also be an important issue associated with the gap in efficacy and effectiveness. As such, keeping patients on treatment through optimal toxicity management in the real-world setting is critical.

Reference

Richardson, P, San Miguel J, Moreau P, et al. Real-World and Clinical Trial Data in Relapsed/Refractory Multiple Myeloma (RRMM): Evaluating Treatment Duration and Comparing Effectiveness and Efficacy. Presented at ASH 2017; Abstract 3149.

Speaker Paul Richardson

Richardson

Paul G Richardson, MD,PhD, Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

 

See: Keyslides

 

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