Strengths and Bias of the Different Therapeutic Strategies for the Treatment of Multiple Myeloma Patients Who Progress after Front-Line use of Lenalidomide: A Systematic Review of Available Clinical Trials

Purpose: Patients with Multiple Myeloma (MM) who relapse after exposure to lenalidomide in the context of their first line therapeutic strategy are becoming a growing and clinically relevant population. We performed a systematic review of available clinical trials evaluating the efficacy, in terms of Progression-Free Survival (PFS), of different therapeutic strategies for the treatment of MM patients at first relapse after front-line use of lenalidomide.

Methods: Publications of interest were searched on the PubMed database. The following search terms were employed: relapsed multiple myeloma, refractory multiple myeloma, first relapse, second line therapy, and lenalidomide-refractory, lenalidomide-exposed.

Results: Triplets including anti-CD38 antibodies, carfilzomib and dexamethasone obtained more significant PFS regardless of the number of prior therapies. Other trials also demonstrated a not negligible benefit with combinations containing pomalidomide, particularly in early lines of therapy. However, the variable amount of Len-Exp/Len-R patients enrolled in these studies and the limited number of those analyzed after progression following front-line lenalidomide, makes it difficult to select an “optimal” choice for the treatment of these MM patients at first relapse. Promising results have been more recently obtained by using combo therapies including belantamab-mafodotin and immunotherapies with CAR-T cells.

Conclusion: In absence of clear-cut data regarding specifically the effects of currently available regimens in MM patients refractory or relapsed after first-line therapies including lenalidomide, novel approaches based on immune-therapies and focused on this specific population of MM patients would warrant further specific investigation.

Lenalidomide, an Immunomodulatory-Drug (IMID) that has CBRL (cereblon) protein as the target for its anti-neoplastic activities, remains a fundamental component of the large majority of multi-agent treatments recommended in the first line therapy of either Transplant-Eligible (TE) or Not Transplant Eligible (NTE) patients with Multiple Myeloma (MM) [1]. Therefore, resistance to lenalidomide has become, during the last years, a relevant issue for the choice of appropriate approaches in the setting of Relapsed/Refractory MM (RRMM) patients, particularly at first relapse. Aiming to better clarify this issue, we conducted herein a systematic literature review to provide an updated focus on the optimal positioning and selection of different therapeutic strategies that are now available in this specific setting, mainly according to Progression-Free Survival (PFS) results reported in the most relevant clinical trials.

Publications of interest were searched on the PubMed database. The following search terms were employed in the research: multiple myeloma, first relapse, second line therapy, lenalidomide-refractory patients, and lenalidomide-exposed patients. Abstracts published by international conferences [American Society of Clinical Oncology (ASCO), American Society of Hematology (ASH) and European Hematology Association (EHA)] a, as well as meta-analyses were also searched for further relevant studies. The pivotal randomized phase 3 clinical trials identified in the systematic literature review were supplemented with more recent analyses that provided longer follow-up time. Our analysis does not contain information on toxicities or comments on the safety profile of each regimen.

In the past decade, the combinations of carfilzomib plus dexamethasone (Kd) (ENDEAVOR phase 3 trial - NCT01568866) [2] and that of daratumumab plus bortezomib and Dexamethasone (DaraVd) (CASTOR phase 3 trial - NCT02136134) [3] were investigated in comparison with bortezomib and dexamethasone (Vd), both in NTE MM patients who had received lenalidomide plus Dexamethasone (Rd) upfront or in patients who had received lenalidomide maintenance after Autologous Stem Cell Transplantation (ASCT). Specifically, in the ENDEAVOR trial [2], 464 patients with RRMM, who had received a median number of 2 previous Lines of Therapy (LOT) (range 1-2), were assigned to receive Kd. In this group, the number of lenalidomide-refractory (Len-R) patients was 113 (24%), regardless of the number of previous LOT. In the Intention-To-Treat (ITT) population, the median PFS was 18.7 months, but, in Len-R patients, it was only 8.6 months. In the CASTOR trial [3], 251 patients with more heavily treated RRMM, who had received a median number of 2 previous LOT (range 1-9), were assigned to receive DaraVd. In this study, the number of Len-R patients was 60 (24%), regardless of prior LOT. After a median follow-up of 47 months, the median PFS was 16.7 months in the ITT population, while in Len-R patients it was was significantly lower (7.8 months) [4]. In both these initial studies, however, only a limited fraction of lenalidomide ¬pretreated [Len-Exp] (19-38%) or Len-R patients (24%) was included [2-6]. Furthermore, another major limitation was the number of patients who had progressed on front-line lenalidomide that was not specified.

More recently, the IKEMA (NCT032275285) [7-9] and CANDOR (NCT03158688) [10-12] phase 3 trials included MM patients with one or two previous LOT, with higher percentages of Len-R patients (32%), although very few were the Len-R patients following a single LOT. Notably, the OPTIMISMM (NCT01734928) [13] and APOLLO (NCT03180736) [14] phase 3 trials were instead specifically designed to include the growing and clinically relevant population of patients with Len-R disease (from 71% to 80%). Overall, these studies demonstrated that the combination of pomalidomide with bortezomib and dexamethasone (PVd), daratumumab with pomalidomide and dexamethasone (DaraPd) and daratumumab or isatuximab with carfilzomib and dexamethasone (DaraKd or IsaKd, respectively) may represent effective options for RRMM patients.

In the IKEMA phase 3 trial [7,8], 179 patients with RRMM, who had received a median number of 2 previous LOT (range 1-2), were assigned to receive IsaKd vs., Kd. Forty-percent of patients (n. 72) were Len-Exp and 57 patients (32%) were Len-R; the number of patients who had progressed on front-line lenalidomide was, indeed, very small (n = 8; 4.4%). In a following update of the study, after a follow-up of 44 months, in ITT population the median PFS was 35.7 months [9]. Median PFS for Len-R patients progressing on front-line lenalidomide was not evaluated, due to very small number of patients, but HR for PFS benefit in Len-R patients, regardless of the number of previous LOT, was similar to HR in ITT population (0.59 vs., 0.58 respectively). Therefore, IsaKd might be considered an important treatment option for myeloma patients with Len-R disease. However, limitations of this study were: i) the small number of Len-R patients enrolled; ii) the very limited amount of patients progressing on front-line lenalidomide; iii) the fact that PFS of Len-R patients was unknown (Table 1).

In the CANDOR phase 3 trial [10,11], DaraKd was administered in 312 RRMM patients who had received 1-3 prior LOT and, again, compared with Kd; 123 patients (39%) were Len-Exp and 99 patients (32%) were Len-R to any previous lenalidomide-including regimen. Median PFS was 28.4 months in the entire DaraKd group, while it was not reached for patients who were Len-Exp and 28 months for patients who were Len-R. DaraKd resulted in a PFS benefit both among Len-Exp and Len-R patients, regardless of the number of previous LOT [12]. However, again, the exact number of patients progressing on front-line lenalidomide was unspecified (Table 1).

In the OPTIMISMM phase 3 trial [13], 281 Len-Exp patients with RRMM, who had received a median number of 2 LOT (range 1-3), were assigned to receive PVd and compared with Vd. Forty percent of patients (n = 111) had received one previous LOT, while 60% (n = 170) had undergone more than one treatment. After a median follow-up of 16 months, the median PFS was 11.2 months in the ITT population. Median PFS for the subset of Len-R patients was 9.5 months. Notably, the median PFS of Len-R patients who had progressed after front-line lenalidomide-based therapy was 17.8 months (Table 1).

In the APOLLO phase 3 trial [14], DaraPd was tested, and compared with pomalidomide plus dexamethasone (Pd), in 151 Len-Exp patients, 120 of whom (79%) had Len-R disease; only 16 of these patients (11%), however, had received a single previous treatment. Indeed, the large majority of patients (89%; n = 135) was more heavily pre-treated and had undergone a median of 2 previous LOT (range 1-5). After a median follow-up of 16.9 months, in the ITT population, the median PFS was 12.4 months, while median PFS for Len-R patients was 9.9 months, regardless of the number of LOT previously received. Important limitations of the study were: i) a significant number of prior treatments; ii) a very small number of Len-R patients who had progressed on front-line lenalidomide; iii) the median PFS of Len-R patients who had progressed on front-line lenalidomide was unknown (Table 1).

The same DaraPd combination was investigated in the MM-014 phase 2 trial (NCT01946477) [15]. This study included 112 Len-Exp, 84 of whom (75%) had Len-R disease and 70 (62.5%) have received only one previous therapy. This phase 2 trial was therefore predominantly designed for Len-R patients with disease in relapse after front-line therapy [ASCT followed by consolidation and lenalidomide maintenance until progression or DaraRd/VRd (daratumumab + lenalidomide + dexamethasone/bortezomib + lenalidomide + dexamethasone) for patients with NTE, newly diagnosed MM]. According to ITT, the median PFS was 30.8 months, while the median PFS in Len-R patients was 23.7 months, independently upon the number of prior LOT (Table 1).

Both these studies with DaraPD show, however, limitations; in particular, the median PFS of patients progressing on front-line lenalidomide was not specified. Notably, the promising results presented in the phase II, non-randomized MM-014 trial are in line with real-world data obtained examining patients progressing on lenalidomide following one prior line of treatment, where DaraPd was associated with a median PFS of 18.9 months in a population that had relapsed on lenalidomide maintenance post ASCT [16].

Interestingly, Weisel K, et al. [17] recently performed a MAIC (matching-adjusted indirect comparison) analysis of the lenalidomide-sparing CANDOR vs., OPTIMISMM and APOLLO phase 3 trials. They demonstrated that the DaraKd performed significantly better than PVd and DaraPd in terms of PFS (PFS: 22.6 months DaraKd vs., 11.2 months PVd; PFS: 21.7 months DaraKd vs., 12.1 months DaraPd) in patients with Len-Exp RRMM, the majority of whom were Len-R. Unfortunately, in this indirect comparison, sample sizes were insufficient to perform robust analyses in patients who received one prior line of therapy.

Looking at novel drugs, Selinexor in combination with bortezomib and dexamethasone (SVd), was compared to Vd in 195 RRMM patients who had received from 1 to 3 prior therapies in the BOSTON phase 3 trial (NCT03110562); 77 patients (39%) were Len-Exp and 53 (27%) were Len-R. In a subgroup analysis of the study, after a median follow-up of approximately 29 months, Mateos MV, et al. [18]; showed that the median PFS was 10.2 months in the SVd group for patients who were Len-R at any previous LOT [19], but, again, the number of patients who had progressed after front-line lenalidomide was unknown (Table 1).

The pivotal, randomized, phase 3 trials DREAMM-7 (NCT04246047) [20] [belantamab, bortezomib and desamethasone (BVd) vs., DaraVd] and DREAMM-8 (NCT04484623) [21] [belantamab, pomalidomide and dexamethasone (BPd) vs., PVd] investigated combinations containing the drug-conjugated, anti-BCMA monoclonal antibody belantamab-mafodotin and were mainly designed for Len-Exp and Len-R RRMM patients after 1 to more than 4 previous LOT. In the DREAMM-7 [20] study 127 RRMM patients (52%) enrolled in the BVd arm had previously received lenalidomide (Len-Exp) and 79 (33%) were Len-R. Twenty-two patients had undergone a single treatment before enrollment in the study. After a median follow-up of 28.2 months, the study demonstrated the superiority of BVd, regardless of the number of previous LOT (PFS 36.6 months in ITT population, 25.0 months in Len-R patients) [20]. In the DREAMM-8 study [21] 155 patients were assigned to the BPd group: all of them were Len-Exp and 81% were Len-R. At a median follow-up of 21.8 months, the 12-month estimated PFS with BPd was 71%, significantly better respect to PVd. Unfortunately, also these studies have limitations: in DREAMM-7 trial, the PFS of patients who had progressed on front-line lenalidomide was unknown [20,22]; in DREAMM-8 study, the percentage of Len-R patients following only one LOT and PFS of Len-R patients were not reported [21] (Table 1).

Regarding T-cell redirecting immune-therapies, there are, to the best of our knowledge, no published trials with the use of bispecific antibodies as treatment of MM patients at first relapse. Looking instead at the use of CAR-T cells, the randomized CARTITUDE-4 phase 3 trial (Cilta-cel versus standard of care) demonstrated an impressive superiority of CAR-T in Len-R patients who had received from 1 to 3 prior LOT therapies [23], including DaraPd and PVd [24]. At 12 months, in fact, median PFS was not reached in the Cilta-cell group, both in patients in first progression after front-line lenalidomide-based therapy and in those who have received more than one previous LOT.

Possible criticisms to this type of study design and uncertainties in the analysis of statistics and trial concepts are probably appropriate. Notwithstanding, it is a fact that no phase 3 pivotal studies have been so far exclusively conducted in Len-Exp/Len-R RRMM patients following only one LOT. This makes it difficult to select an “optimal” choice for the treatment of these patients at first relapse, though triplets including anti-CD38 antibodies, carfilzomib and dexamethasone have obtained more significant PFS regardless of the number of prior therapies. This observation would support the idea that a switch in class of agent could be preferable following lenalidomide failure, though OPTIMISMM [13] and MM014 [15] trials also demonstrated a not negligible benefit with combinations containing pomalidomide, particularly in early lines of therapy in RRMM. Indeed, available data should be interpreted with caution, due to differences in trial designs, schedules and doses of lenalidomide, numerical differences in patient population selection, particularly regarding the variable amount (including appropriate definition) of Len-Exp/Len-R patients enrolled and the limited number of those analyzed after progression following front-line lenalidomide. In this last setting, the possible positive effects of combo therapies including belantamab-mafodotin should be deeply analyzed, particularly in the growing population of patients relapsed after both daratumumab and lenalidomide employed as frontline therapy. Indeed, immunotherapies with CAR-T cells would seem to be the most promising approach for these patients, while the role of bispecific antibodies also would warrant to be extensively investigated.

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