Daratumumab with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma patients – real world evidence analysis

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. Supplementary Information The online version contains supplementary material available at 10.1007/s00277-023-05188-4.

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]  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 5 th and 95 th 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. Eventfree 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-proje ct. org).

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

Progression free survival-subgroup analysis
In the subgroup of patients with 1-3 previous treatment lines, Dara (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 (Fig. 3).
In subgroup of patients who were refractory to lenalidomide, there was no significant PFS benefit of Dara-Rd treatment over Rd treatment ( Fig. 1).
Dara-Rd treatment effect on PFS in different patients' subgroups is summarized in Table 3.

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 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 POL-LUX 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 highrisk 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.