Evolving Treatment Trends in Relapsed/Refractory Multiple Myeloma (RRMM) in Europe from 2016 to 2018: Analysis of a Multi-National Survey

Abstract

Background Recently, treatment options for RRMM have increased substantially with multiple approvals of novel agents/combination, making the treatment algorithm increasingly complex, with changes driven chiefly by access to novel agents/regimens. Furthermore, patient (pt) and disease characteristics have a profound impact on treatment decisions. To understand the impact of recently approved novel regimens on real-world (RW) treatment patterns, we conducted a multi-national survey to investigate the management of RRMM across Europe. Methods Retrospective, anonymized data from RRMM pts, treated in academic or community hospitals/clinics in 8 countries were extracted from Jan 2016 to Dec 2018. Data were analyzed overall and for Germany, Austria, and Switzerland (DACH) vs other countries (Belgium, France, Greece, Spain and UK) due to differences in treatment access. Results The cumulative number of pts included was 2782 in 2016, 3902 in 2017, and 4658 in 2018. Of the pts enrolled in 2016, 2017 and 2018, 40%, 49% and 51%, respectively, were in 3rd+ line (≥3L), potentially reflecting the increasing availability of treatment options for RRMM and extended survival in MM. Median age at diagnosis in pts enrolling in 2016, 2017, and 2018, was 68, 69, and 70 years, respectively, with 23%, 24%, 26% aged >75 years, underlining the fact that MM remains a disease of the elderly. The data revealed a difficult-to-treat RW population: 31%-36% of pts had an ECOG PS ≥2 at 2nd line (2L) in 2016-2018; increasing to 44%-49% at 4th+ lines (≥4L). At 2L, 42%-45% of pts presented ≥1 treatment-dependent comorbidity in 2016-2018, including hypertension (23-27%) and renal impairment (9-10%). Cytogenetic risk, evaluated in 38%-42% of pts at initial diagnosis, was reported as high in 8%-10% of the total population. Treatment initiation due to biochemical relapse was reported in 33%/36% of pts at 2L/3L in 2016, and in 30%/28% in 2018, indicating that ~1/3 of pts manifested an asymptomatic rather than clinical relapse. The proportion of pts treated with triplet regimens increased from 26%, 26%, and 30% at 2L, 3L and ≥4L in 2016 to 43%, 40%, and 38% in 2018, reflecting the adoption of newly approved triplets in RRMM, particularly in DACH countries. Use of proteasome inhibitor (PI)-based regimens increased from 35%, 30% and 34% at 2L, 3L and ≥4L in 2016, to 43%, 37% and 37% in 2018, driven by increased/earlier use of novel PIs (carfilzomib and ixazomib). These trends were more obvious in DACH, highlighting the impact of earlier access to modern treatment in these countries. Similarly, the proportion of pts on daratumumab-based regimens increased from 0, 5%, and 20% at 2L, 3L and ≥4L in 2016, to 10%, 24% and 31% in 2018. From 2016 to 2018, prior IMiD exposure at 2L increased from 11% to 20% in DACH, but remained stable at 42% in other countries; at 3L, there was an increase from 77% to 82% in all countries reflecting the uptake of novel triplet combinations. Most pts were IMiD-exposed or IMiD-refractory at ≥4L. Regarding the treatment algorithm, the rate of PI-based treatment at 1L was 74%-75%. PI- to IMiD-based therapy was the commonest treatment sequence from 1L to 2L, at 64%-66%, while PI- to PI-based therapy at 1L to 2L increased from 22% in 2016 to 30% in 2018. Key disease/pt characteristics associated with the selection of regimens at 2L and 3L are summarized in the Table. Prior IMiD treatment limited the use of IMiD-based therapy in subsequent lines. The use of KRd, IRd and DRd was mostly associated with ISS stage III, while the use of KRd was less frequently reported in pts with cardiac comorbidities. In pts with prior PI treatment, KRd and IRd (but not Kd) were more common at 2L, while DRd was preferred at 3L. A higher proportion of fit, young, or prior-SCT pts were treated with KRd or DRd, while IRd was the preferred treatment in pts with biochemical relapse. Conclusions Multiple drug approvals for RRMM in Europe have resulted in marked changes in the treatment algorithm, with a more immediate impact in countries with earlier access to new treatment options. Multiple decision drivers such as age, fitness, comorbidities and prior treatment are associated with uptake of different novel regimens at 2L and 3L. The increasing range of treatment options has resulted in pts receiving more lines of therapy for RRMM, highlighting the need for cautious planning of treatment sequencing to optimize the use of available combinations according to pt characteristics and disease factors. Disclosures Merz: Janssen: Other: Travel grants; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Abbvie: Other: Travel grants; Celgene: Other: Travel grants; Takeda Vertrieb GmbH: Other: Travel grants, Research Funding. Pérez:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees. Kolb:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: travel and registration for my participation to international medical congres (ASH). Symeonidis:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zomas:Takeda: Employment. Gonzalez:Takeda: Employment. Kellermann:Amgen: Research Funding; BMS: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Sanofi: Research Funding; Takeda: Research Funding. Goldschmidt:Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; John Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; ArtTempi: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; MSD: Research Funding; Molecular Partners: Research Funding; Mundipharma: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product.

Management of Patients with Relapsed and/or Refractory Multiple Myeloma Treated with Novel Combination Therapies in Routine Clinical Practice in Germany

“…Although in both Europe and the USA bortezomib is the most commonly used proteasome inhibitor in the first-line setting, and in combination with novel agents in second and later lines [ 36 , 37 ], in our study, it was prescribed mainly in combination with daratumumab in second and third lines (9% and 11%, respectively). Overall, there are clear differences in treatment practice between countries [ 20 , 21 , 37 – 39 ], with no standard of care for patients with RRMM in later lines of treatment, and treatment algorithms evolving over time [ 21 , 36 , 37 , 39 ]. The changing landscape and treatment practice differences between countries are related to the introduction of various novel therapies over recent years, as the timings of regulatory approvals and reimbursement differ between Europe and the USA, and the time taken for such agents to become available after approval varies across Europe [ 36 ].…”

“…The changing landscape and treatment practice differences between countries are related to the introduction of various novel therapies over recent years, as the timings of regulatory approvals and reimbursement differ between Europe and the USA, and the time taken for such agents to become available after approval varies across Europe [ 36 ]. Of note, in Germany, novel treatments are available/reimbursed immediately after regulatory approval, meaning that these agents are often available earlier in Germany than elsewhere [ 36 , 39 ]. Data from the present German study, therefore, provide useful insights into the uptake of novel agents in this rapidly changing treatment landscape.…”

Survival and treatment patterns of patients with relapsed or refractory multiple myeloma in France — a cohort study using the French National Healthcare database (SNDS)

“…Although there continues to be no standard of care for RRMM in Europe [32], recent studies show that lenalidomide is often the most common treatment, and PI-based regimens, including triplets, are increasingly being prescribed [21,33]. Practice patterns in France differ from the rest of Europe, and only a few studies have reported on recent treatment patterns in RRMM that are specific to the French population [19,20].…”

“…The European Society for Medical Oncology (ESMO) guidelines mainly recommend using these novel agents in doublet and triplet combination regimens that include a corticosteroid (dexamethasone or prednisone) [4,18]. However, it remains unclear to what extent guideline recommendations translate into clinical practice [17], and there is relatively little current evidence on real-world treatment patterns for RRMM in France [19,20], Europe [1,[21][22][23][24], or indeed elsewhere [17,25].…”

Adjusted Comparison of Outcomes between Patients from CARTITUDE-1 versus Multiple Myeloma Patients with Prior Exposure to PI, Imid and Anti-CD-38 from a German Registry

“…In the current study, patient outcomes with cilta-cel, as observed in CARTITUDE-1, were compared with outcomes from similar patients treated with RWCP, as observed in Therapie Monitor in Germany. Therapie Monitor provides a representative sample of patients from German routine clinical practice and has excellent variable coverage, ensuring reliable comparisons [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. This is further illustrated by the observed median OS and TTNT in Therapie Monitor of 9.89 and 6.21 months, respectively, consistent with outcomes in other sources and geographies [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ].…”