The majority of newly diagnosed myeloma patients do not fulfill the inclusion criteria in clinical phase III trials

Klausen, Tobias W.; Gregersen, Henrik; Abildgaard, Niels; Andersen, Niels Frost; Frølund, Ulf Christian; Gimsing, Peter; Helleberg, Carsten; Vangsted, Annette Juul

doi:10.1038/s41375-018-0272-0

Cited by 29 publications

(48 citation statements)

References 15 publications

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“…In patients receiving KRd in the ASPIRE trial, the median PFS over the 48-month trial duration was 26.3 months [25]. As already pointed out, there is a growing body of evidence that patient characteristics differ between this study of routine clinical practice and pivotal RCT [17][18][19][20]. An analysis of the representativeness of the RCT ASPIRE, TOURMALINE-MM1, POLLUX, and ELOQUENT-2 in real-world relapsed and/or refractory MM patients showed that the 3-year overall survival was longer for patients classified as RCT eligible compared to RCT ineligible patients [26].…”

Section: Discussion/conclusionmentioning

confidence: 80%

“…The advent of a wide array of new drugs and drug combinations for treating MM, especially in the relapse setting, has made it impossible to conduct head-to-head trials comparing each of these regimens with each other to derive a stringent treatment algorithm for these patients. Additionally, a growing body of research has raised awareness of the relative differences between patients eligible for randomized controlled trials (RCT) and those not eligible [2,[17][18][19][20][21], as well as the impact of conditional reimbursement on outcomes [19], triggering a debate on the applicability of pivotal trials to routine clinical practice [22]. Research based on real-world data, e.g., from registries, claims databases, or observational studies of daily practice has thus gained importance and has in some countries become a precondition for reimbursement.…”

Section: Discussion/conclusionmentioning

confidence: 99%

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Patient Characteristics and Outcomes of Relapsed/Refractory Multiple Myeloma in Patients Treated with Proteasome Inhibitors in Germany

et al. 2020

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Introduction: Real-world data reflects treatments and outcomes in clinical practice in contrast with controlled clinical trials. This study evaluates real-life multiple myeloma (MM) patients receiving proteasome inhibitor (PI)-based treatments in the second or third therapy line in 2017 in Germany. Methods: This is a retrospective chart review on adult relapsed/refractory MM patients treated with ≥1 dose of a PIbased regimen in either the second or the third line of therapy. Participating physicians had ≥3 years of clinical experience in treating symptomatic MM patients and used PI according to the label. Results: Distinct patient profiles for each PI-based regimen emerged. Younger, fitter, transplanteligible patients received novel PI triplets such as carfilzomib in combination with lenalidomide and dexamethasone (KRd) or IRd. Patients receiving lenalidomide in first-line therapy mostly received lenalidomide-free regimens in secondline therapy. In high-risk patients, no clear treatment patterns could be ascertained. The complete response rates were highest with KRd (13.0%), followed by carfilzomib in combination with dexamethasone (Kd) (5.7%) and bortezomib (4.8%). The very good partial response rates were highest with IRd (76.9%), followed by KRd (53.7%), Kd (25.7%), and bortezomib (20.5%). None of the KRd-or IRd-treated patients responded below a partial response. Discussion/Conclusion: Clear patient profiles for each PI type were observed. In second-line therapy, younger, fitter, transplant-eligible patients received novel-PI-based triplets, e.g., KRd or IRd. Patients treated with lenalidomide in first-line therapy mostly received lenalidomide-sparing regimens in second-line therapy. In high-risk patients no clear treatment patterns could be ascertained due to the limited sample size.

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Section: Discussion/conclusionmentioning

confidence: 80%

Section: Discussion/conclusionmentioning

confidence: 99%

Patient Characteristics and Outcomes of Relapsed/Refractory Multiple Myeloma in Patients Treated with Proteasome Inhibitors in Germany

et al. 2020

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“…Given the older age of patients with RRMM and the high comorbidity burden common to these real-world patients, these findings highlight the recognized limited generalizability of RCT results to the general population of patients with RRMM who are more heterogeneous. 17,20,21 RCT eligibility for patients with newly diagnosed multiple myeloma (NDMM) has been evaluated in previous research of 23 As patients progress through the natural course of their disease, the comorbidities that can exclude patients from an RCT have been shown to increase. 24 Our data point to a greater risk of RCT ineligibility for our RRMM population (up to 72.3%) than has been reported in NDMM, even further limiting the generalizability of trial results in the increasing RRMM population.…”

Section: Discussionmentioning

confidence: 99%

Randomized Clinical Trial Representativeness and Outcomes in Real-World Patients: Comparison of 6 Hallmark Randomized Clinical Trials of Relapsed/Refractory Multiple Myeloma

Chari

Romanus

Palumbo

et al. 2020

Clinical Lymphoma Myeloma and Leukemia

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Despite randomized clinical trials (RCTs) of novel agents showing prolonged survival for patients with relapsed/refractory multiple myeloma (RRMM), we have found that most patients with RRMM receiving routine care will not be eligible for these trials. Furthermore, survival has been significantly worse for patients with RRMM not meeting the eligibility criteria, resulting in a gap between RCT efficacy and real-world effectiveness. Background: Concern has been increasing in oncology regarding randomized clinical trial (RCT) eligibility limiting the generalizability of the findings to real-world populations. Using a large US electronic health record database, we investigated the real-world generalizability of the findings from recent RCTs for relapsed and/or refractory multiple myeloma (RRMM). Patients and Methods: Patients with RRMM initiating second-to fourth-line therapy with the control arm of the following RCTs were retrospectively identified and categorized as "RCT eligible" or "RCT ineligible" according to the eligibility criteria: (1) Rd (lenalidomide, dexamethasone)-ASPIRE, TOURMALINE-MM1, POLLUX, and ELOQUENT-2; and (2) Vd (bortezomib, dexamethasone)-CASTOR and ENDEAVOR. Predictors of RCT ineligibility and overall survival were analyzed using logistic regression and Cox regression analysis. Results: Variations in the individual trial ineligibility rates were noted, with up to 72.3% (range, 47.9%-72.3%) of patients not meeting the eligibility criteria for 1 of the 6 hallmark RCTs (n ¼ 788 for Rd; n ¼ 477 for Vd). Other malignancies, cardiovascular disease, acute infection, and renal dysfunction were the common reasons for ineligibility. Advanced age, Charlson comorbidity score of ! 2, later therapy lines (3-4), and refractory status to the previous line were independently predictive of RCT ineligibility. RCT-ineligible versus RCT-eligible patients had a significantly greater mortality risk (hazard ratio, Rd, 1.46; Vd, 1.51). Conclusion: Most real-world patients with RRMM were ineligible for the hallmark RCTs. The eligibility rates varied across the RCTs, underlining the flawed nature of cross-study comparisons without RCT validation. Overall survival was significantly affected by the inability to meet the criteria, highlighting the limited generalizability of the RCT results. Greater efforts are required to broaden the eligibility criteria to reflect real-world clinical characteristics and narrow the gap between RCT efficacy and the observed effectiveness in real-world patients with RRMM.

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“…The definition of bortezomib-, lenalidomide-, pomalidomide-, daratumumab-, and carfilzomib-refractory myeloma was fulfilled in 137, 135, 81, 63, and 38 patients, respectively. The median survival of patients with bortezomib-, lenalidomide-, pomalidomide-, daratumumab-, and carfilzomib-refractory myeloma (95% CI) was 22 (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28), 19 (15-29), 17 (10-29), 19 (12-33), and 10 (4 to NR) months, respectively. The definition of double-refractory myeloma (refractory to bortezomib and lenalidomide) was fulfilled in 100 patients.…”

Section: Life Expectancy Of Patients With Myeloma Refractory To Novelmentioning

confidence: 99%

“…Clinical trials test the clinical performance of drugs in selected study populations, but it is unclear how these drugs work under real-world circumstances, where patients often have higher age, higher burden of comorbidities, more advanced disease, and lower incentive for treatment [11]. Clinical practice guidelines and expert recommendations concerning the management of MM focus primarily on patients with newly diagnosed disease and those with a first or a second relapse [12][13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

The Clinical Course of Multiple Myeloma in the Era of Novel Agents: A Retrospective, Single-Center, Real-World Study

Szabo

Iversen

Möller³

et al. 2019

CHI

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In this retrospective study we reviewed the clinical course of every patient with multiple myeloma treated from 2006 to 2016 at Vejle Hospital: 303 patients with a median age of 69 years at diagnosis received a median of four (range 1-18) lines of therapy; 149 in a 2006-2010 cohort and 154 in a 2011-2016 cohort. After initiation of treatment, the median decrease in the number of patients per each subsequent line of therapy was 22%. Lenalidomide-dexamethasone (n = 156), bortezomib-dexamethasone (n = 107), and bortezomib-lenalidomide-dexamethasone (n = 84) were the most commonly used regimens. The partial response or better rate was 78%, 58%, 55%, and 44% in lines of therapy one to four, respectively. The median (95% confidence interval [CI]) progression-free survival was 18 (15-22), 10 (8-13), 8 (7-10), and 6 (4-8) months in lines of therapy one to four, respectively. The median (95% CI) overall survival (OS) was 4.1 (3.7-4.8) years. Compared with the 2006-2010 cohort, patients in the 2011-2016 cohort had longer OS; 5.3 (4.7 to not reached) versus 3.4 (2.7-4.0) years, p < 0.0001. This was especially true in patients not treated with high-dose therapy and autologous stem cell transplantation; 4.7 (3.2-5.9) versus 2.6 (2.0-3.3) years, p = 0.0052. Patients in the 2011-2016 cohort were on treatment during a greater part of their life and had higher exposure to high-dose melphalan with autologous stem cell transplantation, lenalidomide, pomalidomide, daratumumab, and carfilzomib.

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The majority of newly diagnosed myeloma patients do not fulfill the inclusion criteria in clinical phase III trials

Cited by 29 publications

References 15 publications

Patient Characteristics and Outcomes of Relapsed/Refractory Multiple Myeloma in Patients Treated with Proteasome Inhibitors in Germany

Patient Characteristics and Outcomes of Relapsed/Refractory Multiple Myeloma in Patients Treated with Proteasome Inhibitors in Germany

Randomized Clinical Trial Representativeness and Outcomes in Real-World Patients: Comparison of 6 Hallmark Randomized Clinical Trials of Relapsed/Refractory Multiple Myeloma

The Clinical Course of Multiple Myeloma in the Era of Novel Agents: A Retrospective, Single-Center, Real-World Study

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