Clinical Report: Real-World Carfilzomib Dosing and Outcomes in RRMM

Overview

This retrospective study analyzed real-world prescribing patterns and clinical outcomes of carfilzomib in relapsed or refractory multiple myeloma (RRMM). It highlights the variability in dosing schedules and the lack of consensus on optimal dosing to balance efficacy and toxicity.

Background

Multiple myeloma is a plasma cell malignancy treated commonly with proteasome inhibitors (PIs) such as bortezomib and carfilzomib. Carfilzomib, a second-generation PI, offers sustained proteasome inhibition with less neuropathy but potential cardiac and renal toxicities. Clinical trials have used various dosing schedules, including twice-weekly and once-weekly regimens at doses ranging from 27 mg/m2 to 70 mg/m2, but no definitive consensus exists on the optimal regimen. Real-world data are needed to understand prescribing patterns and outcomes outside clinical trials.

Data Highlights

The study utilized the Flatiron Health EHR-derived database from 280 US cancer clinics, including patients aged 18-70 treated with carfilzomib-containing regimens in second or later lines from 2012 to 2023. Carfilzomib dosing was categorized by mg/m2 and weekly frequency, with partner drugs grouped into CD38 monoclonal antibodies, immunomodulatory drugs, and others. Patient characteristics included demographics, ECOG performance status, ISS stage, cytogenetic risk, renal function, and prior therapies.

Key Findings

• Carfilzomib dosing varied widely in real-world practice, with common regimens including 56 mg/m2 twice weekly (K56-2x), 70 mg/m2 once weekly (K70-1x), and 56 mg/m2 once weekly (K56-1x).
• Randomized trials showed K70-1x improved progression-free survival (PFS) over 27 mg/m2 twice weekly (K27-2x), but comparisons with other dosing schedules like K56-2x or K56-1x remain unknown.
• The ARROW2 trial demonstrated comparable PFS between K56-1x and K27-2x when combined with lenalidomide, though non-inferiority was not formally met.
• Carfilzomib doublet therapy (Kd) without CD38 mAbs or IMiDs was the basis for many pivotal trials, but real-world regimens often include triplets or quadruplets with these agents.
• Renal function and cytogenetic risk factors were important considerations in dosing and outcomes, with renal insufficiency and high-risk cytogenetics impacting treatment decisions.

Clinical Implications

Clinicians should recognize the heterogeneity in carfilzomib dosing schedules and tailor therapy based on patient-specific factors including renal function and prior treatments. While higher once-weekly doses may improve PFS, toxicity profiles and patient convenience must be balanced. Incorporation of partner agents such as CD38 monoclonal antibodies and IMiDs is common in practice and may influence optimal dosing strategies.

Conclusion

Real-world data reveal significant variability in carfilzomib dosing for RRMM, underscoring the need for further comparative studies to define optimal regimens that maximize efficacy while minimizing toxicity. Personalized treatment approaches remain essential in this heterogeneous patient population.

References

1. Kumar et al. 2008 -- Bortezomib in Relapsed Multiple Myeloma
2. Demo et al. 2007 -- Carfilzomib Preclinical Studies
3. O'Connor et al. 2010 -- Proteasome Inhibition Mechanisms
4. Kuhn et al. 2007 -- Carfilzomib Selectivity
5. Siegel et al. 2012 -- Carfilzomib Safety Profile
6. Dimopoulos et al. 2016 -- ENDEAVOR Trial Results
7. Stewart et al. 2015 -- Carfilzomib vs Bortezomib
8. Stewart et al. 2015 -- ASPIRE Trial
9. Dimopoulos et al. 2019 -- CANDOR Trial
10. Moreau et al. 2020 -- IKEMA Trial
11. Richardson et al. 2019 -- SELECT Trial
12. Siegel et al. 2012 -- Phase I Carfilzomib Dosing
13. Siegel et al. 2013 -- Carfilzomib Dose Escalation
14. Kumar et al. 2018 -- SWOG S1304 Trial
15. Dimopoulos et al. 2021 -- ARROW Trial
16. Kumar et al. 2023 -- ARROW2 Trial
17. Rajkumar et al. 2014 -- IMWG Cytogenetic Criteria