Improving Outcomes for Patients with Multiple Myeloma through the Optimization of Treatment Sequences
Authors: Petrucci Maria Teresa , Mendes João , Boer Jennifer H. , Casamassima Gabriele , Willis Anna , Wadlund Astrid Ottosson , Matthijsse Suzette , Armeni Patrizio 
Published: November 2021

Abstract
Introduction: Multiple myeloma (MM) is an incurable disease characterized by the proliferation of malignant plasma cells within the bone marrow, causing a wide range of burdensome symptoms. Patients initiating treatment typically receive a combination of drugs across various classes with or without autologous stem cell transplantation (ASCT). However, patients will invariably relapse following initial treatment, and often require many lines of drug treatment over the course of their disease. Real-word data showed that a significant proportion of newly diagnosed MM patients that receive frontline (FL) treatment did not receive subsequent treatment. These high attrition rates suggest that using the best treatment upfront is crucial in delaying disease progression.
The CASSIOPEIA (transplant-eligible [TE] setting), MAIA and ALCYONE (transplant-ineligible [TIE] setting) trials demonstrate that the addition of daratumumab (DARA) to standard of care treatments in FL significantly improves patient outcomes. Based on data from these trials, the European marketing authorization for DARA has been extended to the FL setting. To ensure the best possible long-term patient outcomes in clinical practice, the availability of new FL treatment options requires a redefinition of treatment patterns. Thus, we aim to investigate whether the adoption of DARA as a FL, as opposed to later-line, treatment of MM leads to better outcomes and improved clinical practice.
Methods: In the absence of real-world sequencing data, we developed a clinical sequencing simulation using individual patient data from the DARA trials and indirect comparative evidence, across all indications in MM. We used progression-free survival curves to simulate health state transition probabilities across four lines of active treatment, to capture the efficacy of treatment sequences in MM. Patients start with initiation of FL treatment, and ASCT eligibility determines the sequences patients receive. Clinical expert opinion was sought to determine 1) the full range of meaningful treatment sequences and 2) which of these are used most in Italian clinical practice. Based on the clinical simulation outcomes, we calculated average time spent in each line of treatment, percentage of patients alive at different timepoints, and the total survival for patients initiating a sequence. This analysis included conservative attrition rates from trial data, 14% for TE (CASSIOPEIA) and 24% for TIE (MAIA/ALCYONE), assumed as similar across regimens in each setting.
Results: In the TE setting, the best outcomes were achieved when using the DARA-based regimen (DVTd) as FL treatment, followed by either a LEN-based regimen (KRd) or a BOR-based regimen (PVd), resulting in a total survival of 14.2 and 14.1 years, respectively. In the TIE setting, the best outcomes were achieved when DRd or DVMP were used as FL treatment, followed by either a BOR-based regimen (PVd, for DRd) or a LEN-based regimen (KRd, for DVMP), resulting in a total survival of 11.7 and 10.9 years, respectively.
In both the FL and second line (2L) settings, there was a clear survival benefit of using DARA. When comparing the DARA-based sequence with the current FL TE benchmark sequence (DVTd + KRd + Pd + Vd versus VTd + DRd + Kd + Pd), an additional survival of 1.5 years was observed in TE patients. When DARA was added to the current FL TIE benchmark sequence (DRd + PVd + Kd + Vd versus VMP + DRd + Kd + Pd), TIE patients lived on average 2.8 years longer. For TE patients, time spent progression-free ranged from an average of 4.83 to 7.99 years at FL, 1.42 to 5.40 years in 2L, 0.23 to 2.24 years in 3L and 0.17 to 1.53 years on 4L. For TIE patients, the variation was higher, leaving more room for optimization: 1.97 to 7.31 years at FL, 0.68 to 4.76 years in 2L, 0.17 to 3.25 years in 3L and 0.19 to 0.51 years in 4L.
Conclusion: To our knowledge, this is the first sequencing simulation to consider optimal patient outcomes across several lines of MM treatment. The results show that the longest time in remission is achieved with the use of DARA-based regimens as FL treatment, significantly improving patient outcomes.
Time spent progression free decreases with each subsequent line of treatment and the magnitude of the effect seen in the third and fourth treatment lines is not as significant as that of the effect seen in earlier treatment lines. Therefore, patients should be treated with the most effective treatment upfront.

Disclosures
Petrucci: Celgene: Honoraria, Other: Advisory Board; Janssen-Cilag: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; GSK: Honoraria, Other: Advisory Board; Karyopharm: Honoraria, Other: Advisory Board. Mendes: Janssen-Cilag Farmacêutica: Current Employment. Boer: Janssen: Consultancy. Casamassima: Janssen: Current Employment. Willis: Janssen: Consultancy. Wadlund: Janssen: Current Employment. Matthijsse: Janssen: Consultancy. Armeni: Astrazeneca: Consultancy; Boehringer Ingelheim: Consultancy; Novartis: Consultancy; Sanofi: Consultancy; Johnson & Johnson: Consultancy; Amgen: Consultancy; Janssen: Consultancy.