Abstract
We performed real world evidence (RWE) analysis of daratumumab, lenalidomide and dexamethasone (Dara-Rd) versus lenalidomide and dexamethasone (Rd) treatment in relapsed/refractory multiple myeloma patients (RRMM). In total, 240 RRMM patients were treated with Dara-Rd from 2016 to 2022 outside of clinical trials in all major Czech hematology centers. As a reference, 531 RRMM patients treated with Rd were evaluated. Patients’ data were recorded in the Czech Registry of Monoclonal Gammopathies (RMG). Partial response (PR) or better response (ORR) was achieved in significantly more patients in Dara-Rd than in Rd group (91.2% vs. 69.9%; p < 0.001). The median progression free survival (PFS) was 26.9 months in the Dara-Rd and 12.8 months in the Rd group (p < 0.001). Median overall survival (OS) was not reached in the Dara-Rd compared to 27.2 months in the Rd group (p = 0.023). In patients with 1–3 previous treatment lines, there was significant PFS benefit of Dara-Rd compared to Rd (median PFS not reached vs. 13.2 months; p < 0.001). In patients with > 3 previous treatment lines, there was no significant PFS benefit of Dara-Rd treatment (7.8 months vs. 9.9 months; p = 0.874), similarly in patients refractory to PI + IMIDs (11.5 months vs. 9.2 months; p = 0.376). In RWE conditions, the median PFS in RRMM patients treated with Dara-Rd is shorter when compared to clinical trials. In heavily pretreated RRMM patients, efficacy of Dara-Rd treatment is limited; best possible outcomes of Dara-Rd are achieved in minimally pretreated patients.
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Introduction
In the last two decades, multiple myeloma (MM) treatment underwent significant progress [1]. The use of anti-CD38 monoclonal antibodies (mAbs) together with proteasome inhibitors (PI) and immunomodulatory drugs (IMIDs) became an emerging treatment modality with remarkable results. In clinical trials, anti-CD38 mAbs demonstrated high efficacy both in relapsed and newly diagnosed MM patients [2,3,4,5,6].
Daratumumab is the first widely used anti-CD38 mAb [7]. By binding to CD38 antigen on MM cells surface, daratumumab promotes apoptosis of MM cells and activates immune mechanisms (antibody-dependent cellular cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP) and complement dependent cytotoxicity (CDC)) leading to MM cell death [8, 9]. Immunomodulatory effect of daratumumab was also described to effect T-cells [10, 11]. In the first-in-human use, daratumumab monotherapy achieved response in 38% of heavily pretreated patients [12]. In preclinical tests, synergy of daratumumab and IMIDs was demonstrated [13]. Based on these results, in the phase III clinical trial POLLUX, daratumumab in combination with lenalidomide and dexamethasone (Dara-Rd) was compared to lenalidomide and dexamethasone (Rd). Dara-Rd regimen achieved deep responses (30.4% patients with negative minimal residual disease (MRD)) even in relapsed or refractory MM (RRMM) patients, and significantly prolonged median progression free survival (mPFS) to 45.5 months when compared to Rd alone (mPFS 17.5 months, p < 0.001) [2, 14]. Thus, Dara-Rd became a new standard-of-care for RRMM in many European countries [1, 15, 16].
However, randomized clinical trials (RCT) describe data different from real world evidence (RWE) conditions. In the RCT for MM, important subgroups of patients are often neglected. These subgroups are characterized with an aggressive disease course (extramedullary plasmacytoma, disease refractory to specific drugs, hyperviscosity with necessity of plasmapheresis, myeloma induced kidney failure, etc.) or significant comorbidities [17, 18].
With respect to these differences, we analyzed the outcomes of Dara-Rd regimen in real-world clinical conditions to define which patients benefit from Dara-Rd treatment the most.
Patients and methods
Our study is a multicentric real-life retrospective study carried out in major hematologic centers in the Czech Republic between 2016 and 2022. Patients represent real world RRMM population treated with best available treatment at the time.
Data from patients treated in Dara-Rd and Rd groups were collected from the Registry of Monoclonal Gammopathies (RMG) of the Czech Myeloma Group. In total, 240 RRMM patients treated with Dara-Rd and 531 RRMM patients treated with Rd were enrolled. Only one patient from the Dara-Rd group was enrolled in 2016, the rest of the cohort was enrolled from 2019 to 2022. Patients in the Rd group were enrolled from 2016 to 2019, when Rd was the golden standard for RRMM patients’ treatment. Patients treated with Rd before 2016 were excluded for historical lenalidomide reimbursement rules in the Czech Republic (after cumulative dose of 4200 mg, lenalidomide treatment had to be stopped). Patients treated with Rd after 2019 were also censored, as modern lenalidomide-based triplets (with daratumumab, ixazomib or carfilzomib) were used in the Czech Republic as a new golden standard. Thus, after 2019, patients treated in the Czech Republic only with Rd were mostly palliative. Enrolling them could seriously bias our results, favoring Dara-Rd group. All enrolled patients were treated outside of clinical trials. All patients provided informed consent for participation in the study according to the declaration of Helsinki.
Patients in Dara-Rd group received standard dosing of Daratumumab 16 mg/kg intravenous or 1800 mg subcutaneous equivalent [19] on day 1, 8, 15, 22 in cycle 1–2, day 1, 15 in cycles 3–6, and day 1 at cycles 7 and more; lenalidomide 25 mg on days 1 through 21, and dexamethasone 20–40 mg on days 1, 8, 15 and 22 in 28-day cycles. Patients in Rd group received lenalidomide 25 mg on days 1 through 21 and dexamethasone 20–40 mg on days 1, 8, 15 and 22 in 28-day cycles. Reduction of lenalidomide or dexamethasone was allowed according to physicians’ decision. Patients in Dara-Rd arm had corticosteroid-based premedication according to institutional guidelines before daratumumab administration.
All patients were required to use thromboprophylaxis and herpes zoster prophylaxis per institutional guidelines. Cytogenetic aberrations were evaluated at the time of newly diagnosed multiple myeloma (NDMM).
Assessments
All the data were recorded in the RMG. The endpoints were assessed based on the International Myeloma Working Group (IMWG) response criteria, incorporating an additional category of minimal response. Survival intervals progression free survival (PFS), duration of response (DOR) and overall survival (OS) were assessed from Dara Rd/Rd treatment beginning.
Statistical analysis
Depending on the nature of the data, suitable methods for description and statistical testing were selected. Categorical variables were described using absolute and relative frequencies and continuous variables by median complemented with 5th and 95th percentile. In accordance with data continuity (categorical x continuous), Pearson Chi-Square (resp. Fisher's exact test in case of non-meeting criteria) or Mann–Whitney U test was used to examine the association between selected variables and treatment regimen. Event-free survival (PFS, DOR and OS) was assessed using the Kaplan–Meier methodology, and statistical significance of differences in survival between subgroups was assessed using the log-rank test. All statistical tests were performed at a significance level of α = 0.05 (all tests two-sided). The analysis was performed in SPSS software (IBM Corp. Released 2016. IBM SPSS Statistics for Windows, Version 25Armonk, NY: IBM Corp.) and software R version 3.4.2 (www.r-project.org).
Results
Patients and treatment
Altogether, 240 patients were treated with Dara-Rd regimen and 531 patients with Rd regimen. Median age was 66.0 years (5th–95th percentile 45.9–77.7) in the Dara-Rd group and 71.1 years (5th–95th percentile 54.1–82.6) in the Rd group (p < 0.001). There was a comparable number of patients with high-risk cytogenetic aberrations (HR-CA; t(4;14), t(14;16), del(17p)) in both groups (28.0% (37/132) vs. 29.4% (60/204), p = 0.806).
The median of previous treatment lines was comparable between both groups (1 [95% CI: 1–4] vs. 1 [95% CI: 1–4], p = 0.090). There were significantly more patients exposed to PI + IMIDs (64.2% (154/240) vs. 45.8% (243/531), p < 0.001) in the Dara-Rd group. Number of PI + IMIDs refractory patients were comparable in both groups (29.6% (71/240) vs. 32.2% (171/531), p = 0.503. The median follow-up from Dara-Rd vs. Rd treatment initiation was 13.5 months [95% CI: 1.3–26.6] in the Dara-Rd group and 23.7 months [95% CI: 1.5–59.7] in the Rd group. Baseline characteristics of patients are summarized in Table 1.
Response to treatment
According to IMWG criteria, treatment response was evaluable in 181 patients in the Dara-Rd group and 429 patients in the Rd group. Complete response (CR) or stringent CR (sCR) was achieved in 4.4% (8/181) of patients in Dara-Rd group, compared to 3.3% (14/429) of patients in Rd group. Very good partial response (VGPR) or better response was achieved in 66.8% (121/181) of patients in Dara-Rd group, compared to 27.5% (118/429) of patients in Rd group. Partial response (PR) or better response (ORR) was achieved in significantly more patients in Dara-Rd group than in Rd group (91.2% vs. 69.9%). Differences in treatment responses were statistically significant (p < 0.001), favoring Dara-Rd regimen (Table 2).
Survival intervals
Median PFS was 26.9 months [95% CI: 20.6-NA] in the Dara-Rd group and 12.8 months [95% CI: 11.2–14.6] in the Rd group (HR: 1.81; [95% CI: 1.43–2.29]; p < 0.001) (Fig. 1A). Median OS was not reached in the Dara-Rd group compared to 27.2 months [95% CI: 24.0–31.3] in the Rd group (HR: 1.38; [95% CI: 1.05–1.83]; p = 0.023) (Fig. 1B).
Progression free survival—subgroup analysis
In the subgroup of patients with 1–3 previous treatment lines, Dara-Rd treatment significantly prolonged PFS, when compared to Rd (Not reached vs. 13.2 months [95% CI: 11.4–14.7], HR: 1.94; [95% CI: 1.51–2.48]; p < 0.001). In patients with > 3 previous treatment lines, there was no significant PFS benefit of Dara-Rd treatment (7.8 months [95% CI: 2.4–NA] vs. 9.9 months [95% CI: 7.6–22.1], HR: 0.94; [95% CI: 0.44–2.00]; p = 0.874) (Fig. 2).
In subgroup of patients who were refractory to PI + IMIDs, there was no significant PFS benefit of Dara-Rd treatment over Rd treatment (11.5 months [95% CI: 8.1–NA] vs. 9.2 months [95% CI: 6.4–12.7], HR: 1.18; [95% CI: 0.82–1.70]; p = 0.376) (Fig. 3).
In subgroup of patients who were refractory to lenalidomide, there was no significant PFS benefit of Dara-Rd treatment over Rd treatment (10.1 months [95% CI: 4.0–NA] vs. 12.7 months [95% CI: 4.9–NA], HR: 0.98; [95% CI: 0.39–2.45]; p = 0.961) (Supplementary Fig. 1).
In the subgroup of patients with HR-CA (t(4;14), t(14;16), del(17p)), there was no significant PFS benefit of Dara-Rd treatment (9.7 months [95% CI: 5.8–13.7] vs. 10.2 months [95% CI: 6.4–13.5], HR: 0.82; [95% CI: 0.51–1.33]; p = 0.428) (Supplementary Fig. 2), similarly to patients with gain(1q21) (13.8 months [95% CI: 9.9–20.7] vs. 10.2 months [95% CI: 6.9–12.8], HR: 1.33; [95% CI: 0.92–1.91); p = 0.129) (Supplementary Fig. 3). In the subgroup of RRMM patients with plasmacytoma found at the time of NDMM, Dara-Rd treatment prolonged PFS, when compared to Rd, but did not reach the level of statistical significance (23.6 months [95% CI: 10.8–NA] vs. 10.0 months [95% CI: 7.0–16.1], HR: 1.60; [95% CI: 0.95–2.69]; p = 0.080). In RRMM patients with plasmacytoma newly developed at disease relapse/progression, there was no significant PFS benefit of Dara-Rd treatment (9.9 months [95% CI: 3.9–16.5] vs. 6.4 months [95% CI: 4.4–12.8], HR: 0.85; [95% CI: 0.49–1.46]; p = 0.554) (Supplementary Fig. 4).
Dara-Rd treatment effect on PFS in different patients’ subgroups is summarized in Table 3.
Overall survival – subgroup analysis
In subgroup of patients who were refractory to PI + IMIDs, there was no significant OS benefit of Dara-Rd treatment over Rd treatment (19.6 months [95% CI: 13.7–NA] vs. 19.9 months [95% CI:14.6–24.4], HR: 1.07; [95% CI: 0.70–1.63]; p = 0.749). In the subgroup of patients with HR-CA, there was OS benefit of Dara-Rd treatment, but did not reach the level of statistical significance (13.7 months [95% CI: 10.1–NA] vs. 23.9 months [95% CI:15.3–29.6], HR: 0.72; [95% CI: 0.41–1.26]; p = 0.247). There was no significant OS benefit of Dara-Rd treatment over Rd in the subgroup of patients with gain(1q21) (not reached vs.24.6 months [95% CI: 17.8–31.4], HR: 1.10; [95% CI: 0.70–1.72); p = 0.690).
Dara-Rd treatment effect on OS in different patients’ subgroups is summarized in Table 4.
Adverse events
Infusion related reactions (IRRs) gr. 2–3 after daratumumab administration were present in 13.3% (32/240) of patients. Higher grades of IRRs were not observed. Serious (gr. 3–4) adverse events (AEs) of Dara-Rd regimen were dominantly hematologic—neutropenia (50.9% (80/157)), anemia (14.9% (23/154)) and thrombopenia (16.3% (25/153)). Other serious (gr.3–4) non-hematologic AEs was infections 16.2% (29/179), thromboembolic disease (4.5% (7/154)), diarrhea (2.9% (5/171)), fatigue (1.8% (3/169)), polyneuropathy (1.3% (2/157), nausea (1.3% (2/156), decompensation of diabetes mellitus (1.0% (1/101)), rash (0.6% (1/158)) and anorexia (0.6% (1/157)). In the Dara-Rd group, there were 5 deaths related to infection complications. Mild (gr.1–2) AEs and comparison with Rd group is summarized in supplementary Table 1.
Discussion
Novel drugs, such as daratumumab, isatuximab, carfilzomib and ixazomib, were carefully evaluated in RRMM patients in large multicentric RCT [2, 20]. Unluckily, population of MM patients eligible for RCT enrollment is significantly different from general MM patients’ population [17]. Therefore, there is a rapidly emerging importance of RWE analyses. Following a general trend of personalized medicine [21], in real-life conditions, it is necessary to differentiate which patients would benefit from specific treatment modality. Moreover, with various treatment options, proper timing of each treatment modality plays an important role [1]. Dealing with this issue, we performed a national RWE analysis of Dara-Rd treatment regimen.
Despite having an unselected patient population and not-evaluable treatment response in all patients, overall response to Dara-Rd treatment in our analysis was comparable to the POLLUX trial (91.2% vs. 92.9%) [14]. Low CR rate in our analysis is due to absence of routine BM evaluation in our RRMM patients, as the results would have had no practical impact on patients’ treatment course, and the treatment was until progression. On the other hand, survival intervals of Dara-Rd treatment were nearly half-time, when compared to the POLLUX trial. Main explanation is in the differences between the patients’ cohorts [14]. In our cohort, there was a higher proportion of patients with high-risk cytogenetic aberrations (28.0% vs. 15.0%), double refractory (PI + IMID) patients (29.6% vs 2.4%) and high proportion of patients with plasmacytomas (30.5%). In contrast with the POLLUX trial, we included 10% of lenalidomide refractory patients [14].
In our analysis, we found uncertain clinical benefit of Dara-Rd treatment in patients with more than 3 previous treatment lines. It is important to mention that our results may be influenced by low number of patients in this cohort. However, this finding was also shown in the POLLUX trial, when benefit from Dara-Rd was less pronounced in the more pretreated patients and vice versa (PFS: > 3 lines HR: 0.74 [CI 95% (0.24–2.26)] vs. HR: 0.42 [95% (0.30–0.58)]) [2]. Similarly, we found non-significant benefit of Dara-Rd treatment in patients refractory to PI, IMIDs or both. Our results are also unique for presence of lenalidomide refractory patients, while the POLLUX trial did not enroll them. These results show patients refractory to lenalidomide to have inferior outcome from the Dara-Rd treatment.
Overall, our analysis in accord with the POLLUX trial shows crucial role of Dara-Rd treatment timing, as the best effect is achieved in less pretreated patients [2]. These results are consistent with other RWE analysis, where the best results of daratumumab treatment were achieved in the first relapse (time to next treatment—25.9 months [22]). Similar results of Dara-Rd treatment in minimally pretreated patients were published by Italian [23, 24] or Spanish authors [25]. Results favoring the less pretreated patients were also shown in other triplet regimens, combining IMIDs and PI, like a pomalidomide-bortezomib-dexamethasone [26], or carfilzomib-lenalidomide-dexamethasone [27, 28]. These findings point to an actual unmet need for novel treatment strategies and molecular targets for multiple refractory MM patients instead of repeating of previously used drug classes [29,30,31].
In our analysis, we used HR-CA (del(17p), t(4;14) and t(14;16) based on the older classification from 2009 for better comparison with the POLLUX trial [32]. The benefit of Dara-Rd treatment in patients with HR-CA in our analysis was not significant, likewise in the patients with gain(1q21), nowadays recognized as a HR-CA [33]. This finding contrasts with the outcomes of the POLLUX trial where patients with HR-CA maintain PFS benefit by daratumumab treatment (HR: 0.43 [95% CI, 0.32–0. 57]) [2]. Similarly, there was PFS benefit in daratumumab with dexamethasone over bortezomib with dexamethasone (HR: 0.41 [95% CI, 0.21–0.83]) [34] and in combination of daratumumab—carfilzomib—dexamethasone over carfilzomib—dexamethasone alone (HR: 0.56 [95% CI, 0.34–0.93]) [35]. Interestingly, RCTs dealing with daratumumab in the front-line setting do not confirm clear benefit of daratumumab treatment in HR-CA patients [36,37,38]. This controversy only highlights necessity to consider HR-CA in a wider context of other high-risk factors, such as high LDH levels [39], extramedullary plasmacytomas [40] or circulating plasma cells [41]. Moreover, methods, such as FISH, may not reveal more complex aberrations (e.g., chromotrypsis or specific gene mutations), which have negative prognostic impact as well.
Daratumumab has limited efficiency in MM patients with plasmacytoma [42,43,44]. In our analysis, patients with plasmacytoma found at the time of NDMM had somehow better Dara-Rd treatment results than patients, who developed plasmacytoma in disease relapse or progression (RRMM). This interesting finding demonstrates different clinical course of these two entities, even in relapsed setting [45,46,47]. Our results were, however, influenced by relatively low number of patients with this form of MM.
Clear limitation of our study was a short follow-up of Dara-Rd cohort (median 13.5 months). Based on this limitation, we can more clearly point to patients with limited profit from Dara-Rd treatment than to patients who had the best outcomes. Another important limitation arises from the retrospective and non-randomized character of the analysis and limited cohorts size. For that reason, similarly to other non-randomized RWE studies, especially results in the subgroups should be assessed critically. Other limitation of our study was the absence of valid information of patients’ MRD status while BM evaluations was not routinely done in all patients, as previously described. According to POLLUX results, best treatment results of Dara-Rd regimen were shown in patients achieving CR (42-month PFS rates of 73.6%) [2]. Other study dealing with daratumumab treatment showed achievement of MRD negative status as a most important predictor of treatment success [48].
Taken together, our RWE results emphasize the importance of timing of modern treatment protocols. Dara-Rd treatment in relapsed/refractory setting should be used as soon as possible to maintain best possible effect. Use of this regimen in heavily pretreated or high-risk patients should be individually considered with respect to other treatment options.
Data availability
Data are available upon request from corresponding author.
References
Rajkumar SV (2022) Multiple myeloma: 2022 update on diagnosis, risk stratification, and management. Am J Hematol 97:1086–1107. https://doi.org/10.1002/ajh.26590
Bahlis NJ, Dimopoulos MA, White DJ et al (2020) Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended follow-up of POLLUX, a randomized, open-label, phase 3 study. Leukemia 34:1875–1884. https://doi.org/10.1038/s41375-020-0711-6
Avet-Loiseau H, San-Miguel J, Casneuf T et al (2021) Evaluation of Sustained Minimal Residual Disease Negativity With Daratumumab-Combination Regimens in Relapsed and/or Refractory Multiple Myeloma: Analysis of POLLUX and CASTOR. J Clin Oncol 39:1139–1149. https://doi.org/10.1200/JCO.20.01814
Voorhees PM, Rodriguez C, Reeves B et al (2021) Daratumumab plus RVd for newly diagnosed multiple myeloma: final analysis of the safety run-in cohort of GRIFFIN. Blood Adv 5:1092–1096. https://doi.org/10.1182/bloodadvances.2020003642
Facon T, Kumar S, Plesner T et al (2019) Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma. N Engl J Med 380:2104–2115. https://doi.org/10.1056/NEJMoa1817249
Attal M, Richardson PG, Rajkumar SV et al (2019) Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet 394:2096–2107. https://doi.org/10.1016/S0140-6736(19)32556-5
Usmani SZ, Nahi H, Plesner T et al (2020) Daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma: final results from the phase 2 GEN501 and SIRIUS trials. Lancet Haematol 7:e447–e455. https://doi.org/10.1016/S2352-3026(20)30081-8
Wang W, Erbe AK, Hank JA et al (2015) NK Cell-Mediated Antibody-Dependent Cellular Cytotoxicity in Cancer Immunotherapy. Front Immunol 6:368. https://doi.org/10.3389/fimmu.2015.00368
van de Donk NWCJ, Usmani SZ (2018) CD38 Antibodies in Multiple Myeloma: Mechanisms of Action and Modes of Resistance. Front Immunol 9:2134. https://doi.org/10.3389/fimmu.2018.02134
Krejcik J, Casneuf T, Nijhof IS et al (2016) Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood 128:384–394. https://doi.org/10.1182/blood-2015-12-687749
van de Donk NWCJ (2019) Reprint of “Immunomodulatory effects of CD38-targeting antibodies.” Immunol Lett 205:71–77. https://doi.org/10.1016/j.imlet.2019.02.002
Lokhorst HM, Plesner T, Laubach JP et al (2015) Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med 373:1207–1219. https://doi.org/10.1056/NEJMoa1506348
van der Veer MS, de Weers M, van Kessel B et al (2011) Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab. Haematologica 96:284–290. https://doi.org/10.3324/haematol.2010.030759
Dimopoulos MA, Oriol A, Nahi H et al (2016) Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med 375:1319–1331. https://doi.org/10.1056/NEJMoa1607751
Mateos M-V, Ludwig H, Bazarbachi A et al. (2018) Insights on Multiple Myeloma Treatment Strategies. Hemasphere 3:e163 https://doi.org/10.1097/HS9.0000000000000163
Terpos E, Engelhardt M, Cook G et al (2020) Management of patients with multiple myeloma in the era of COVID-19 pandemic: a consensus paper from the European Myeloma Network (EMN). Leukemia 34:2000–2011. https://doi.org/10.1038/s41375-020-0876-z
Chari A, Romanus D, Palumbo A et al (2020) Randomized Clinical Trial Representativeness and Outcomes in Real-World Patients: Comparison of 6 Hallmark Randomized Clinical Trials of Relapsed/Refractory Multiple Myeloma. Clin Lymphoma Myeloma Leuk 20:8-17.e16. https://doi.org/10.1016/j.clml.2019.09.625
Richardson PG, San Miguel JF, Moreau P et al (2018) Interpreting clinical trial data in multiple myeloma: translating findings to the real-world setting. Blood Cancer J 8:109. https://doi.org/10.1038/s41408-018-0141-0
Mateos M-V, Nahi H, Legiec W et al (2020) Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial. Lancet Haematol 7:e370–e380. https://doi.org/10.1016/S2352-3026(20)30070-3
Moreau P, Masszi T, Grzasko N et al (2016) Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med 374:1621–1634. https://doi.org/10.1056/NEJMoa1516282
Pawlyn C, Davies FE (2019) Toward personalized treatment in multiple myeloma based on molecular characteristics. Blood 133:660–675. https://doi.org/10.1182/blood-2018-09-825331
Szabo AG, Klausen TW, Levring MB et al. (2021) The real-world outcomes of multiple myeloma patients treated with daratumumab. PLoS One 16:e0258487. https://doi.org/10.1371/journal.pone.0258487
Fazio F, Franceschini L, Tomarchio V et al (2022) Daratumumab combined with dexamethasone and lenalidomide or bortezomib in relapsed/refractory multiple myeloma (RRMM) patients: Report from the multiple myeloma GIMEMA Lazio group. EJHaem 3:121–128. https://doi.org/10.1002/jha2.359
Antonioli E, Staderini M, Pilerci S et al (2020) Daratumumab, lenalidomide, and dexamethasone combination in relapsed/refractory myeloma patients: a real-life single-center experience. Leuk Lymphoma 61:3255–3258. https://doi.org/10.1080/10428194.2020.1802452
Fucci L, Gensini L, Coppetelli U et al. (2022) Daratumumab triplet therapies in patients with relapsed or refractory multiple myeloma: A “real world” experience. Leuk Res Rep 17:100330 https://doi.org/10.1016/j.lrr.2022.100330
Richardson PG, Oriol A, Beksac M et al (2019) Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial. Lancet Oncol 20:781–794. https://doi.org/10.1016/S1470-2045(19)30152-4
Stewart AK, Rajkumar SV, Dimopoulos MA et al (2015) Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 372:142–152. https://doi.org/10.1056/NEJMoa1411321
Rocchi S, Tacchetti P, Pantani L et al (2021) A real-world efficacy and safety analysis of combined carfilzomib, lenalidomide, and dexamethasone (KRd) in relapsed/refractory multiple myeloma. Hematol Oncol 39:41–50. https://doi.org/10.1002/hon.2820
van de Donk NWCJ, Usmani SZ, Yong K (2021) CAR T-cell therapy for multiple myeloma: state of the art and prospects. Lancet Haematol 8:e446–e461. https://doi.org/10.1016/S2352-3026(21)00057-0
Rodriguez-Otero P, Paiva B, San-Miguel JF (2021) Roadmap to cure multiple myeloma. Cancer Treat Rev 100:102284. https://doi.org/10.1016/j.ctrv.2021.102284
Lancman G, Sastow DL, Cho HJ et al (2021) Bispecific Antibodies in Multiple Myeloma: Present and Future. Blood Cancer Discov 2:423–433. https://doi.org/10.1158/2643-3230.BCD-21-0028
Fonseca R, Bergsagel P, Drach J et al (2009) International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia 23:2210–2221. https://doi.org/10.1038/leu.2009.174
Sonneveld P, Avet-Loiseau H, Lonial S et al (2016) Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group. Blood 127:2955–2962. https://doi.org/10.1182/blood-2016-01-631200
Weisel K, Spencer A, Lentzsch S et al (2020) Daratumumab, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma: subgroup analysis of CASTOR based on cytogenetic risk. J Hematol Oncol 13:115. https://doi.org/10.1186/s13045-020-00948-5
Landgren O, Weisel K, Rosinol L et al (2022) Subgroup analysis based on cytogenetic risk in patients with relapsed or refractory multiple myeloma in the CANDOR study. Br J Haematol 198:988–993. https://doi.org/10.1111/bjh.18233
Mateos M-V, Dimopoulos MA, Cavo M et al (2018) Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N Engl J Med 378:518–528. https://doi.org/10.1056/NEJMoa1714678
Bahlis N, Facon T, Usmani SZ et al (2019) Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Ineligible for Transplant: Updated Analysis of Maia. Blood 134:1875. https://doi.org/10.1182/blood-2019-123426
Moreau P, Attal M, Hulin C et al (2019) Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet 394:29–38. https://doi.org/10.1016/S0140-6736(19)31240-1
Palumbo A, Avet-Loiseau H, Oliva S et al (2015) Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. J Clin Oncol 33:2863–2869. https://doi.org/10.1200/JCO.2015.61.2267
Pour L, Sevcikova S, Greslikova H et al (2014) Soft-tissue extramedullary multiple myeloma prognosis is significantly worse in comparison to bone-related extramedullary relapse. Haematologica 99:360–364. https://doi.org/10.3324/haematol.2013.094409
Jelinek T, Bezdekova R, Zihala D et al. (2022) More Than 2% of Circulating Tumor Plasma Cells Defines Plasma Cell Leukemia-Like Multiple Myeloma. J Clin Oncol JCO2201226 https://doi.org/10.1200/JCO.22.01226
Jelinek T, Sevcikova T, Zihala D et al (2022) Limited efficacy of daratumumab in multiple myeloma with extramedullary disease. Leukemia 36:288–291. https://doi.org/10.1038/s41375-021-01343-w
Byun JM, Min C-K, Kim K et al (2022) Phase II trial of daratumumab with DCEP in relapsed/refractory multiple myeloma patients with extramedullary disease. J Hematol Oncol 15:150. https://doi.org/10.1186/s13045-022-01374-5
Beksac M, Spicka I, Hajek R et al. (2022) Evaluation of isatuximab in patients with soft-tissue plasmacytomas: An analysis from ICARIA-MM and IKEMA. Leuk Res 122:106948. https://doi.org/10.1016/j.leukres.2022.106948
Richardson PG, Perrot A, San-Miguel J, Beksac M, Spicka I, Leleu X, Schjesvold F, Moreau P, Dimopoulos MA, Shang-Yi Huang J, Minarik J, Cavo M, Prince HM, Malinge L, Dubin F, van de Velde H, Anderson KC (2022) Isatuximab plus pomalidomide and lowdose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refraktory multiple myeloma (ICARIA-MM): follow-up analysis of a randomised, phase 3 study. Lancet Oncol 23(3):416–427. https://doi.org/10.1016/S1470-2045(22)00019-5
Stork M, Sevcikova S, Jelinek T et al (2022) Unexpected Heterogeneity of Newly Diagnosed Multiple Myeloma Patients with Plasmacytomas. Biomedicines 10:2535. https://doi.org/10.3390/biomedicines10102535
Gagelmann N, Eikema D-J, Iacobelli S et al (2018) Impact of extramedullary disease in patients with newly diagnosed multiple myeloma undergoing autologous stem cell transplantation: a study from the Chronic Malignancies Working Party of the EBMT. Haematologica 103:890–897. https://doi.org/10.3324/haematol.2017.178434
Cavo M, San-Miguel J, Usmani SZ et al (2022) Prognostic value of minimal residual disease negativity in myeloma: combined analysis of POLLUX, CASTOR, ALCYONE, and MAIA. Blood 139:835–844. https://doi.org/10.1182/blood.2021011101
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The authors would like to thank all the patients involved in this study and their caregivers as well as data managers from participating centers in the Czech Republic.
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This work was supported by grant of the Ministry of Health of the Czech Republic NU21-03–00076, by grant of Ministry of Health DRO (FNBr, 65269705), by the project National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102)—Funded by the European Union – Next Generation EU.
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Stork, M., Spicka, I., Radocha, J. et al. Daratumumab with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma patients – real world evidence analysis. Ann Hematol 102, 1501–1511 (2023). https://doi.org/10.1007/s00277-023-05188-4
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DOI: https://doi.org/10.1007/s00277-023-05188-4