Novel extended quadruplet induction regimens—challenging the need for upfront high-dose therapy in newly diagnosed all-risk multiple myeloma patients

Introduction

Multiple myeloma (MM), the second most common hematologic malignancy, is characterized by clonal expansion of malignant plasma cells within the bone marrow (BM) compartment, monoclonal antibodies in the blood and/or urine, bone lesions, renal compromise and immunodeficiency.

It is now well established that MM cells grow and evolve through continuous interactions with the surrounding microenvironment, cellular and extracellular matrix components as well as the liquid milieu in particular. Besides immune cells, cellular components include stroma cells, osteoclasts, osteoblasts and vascular endothelial cells. The liquid milieu consists of cytokines and growth factors including IL-6, VEGF, FGF, and IGF-1. For example, emerging evidence suggests that angiogenesis and immunosuppression often concur. Consequently, combining anti-angiogenic therapy with immunotherapy holds promise for normalizing dynamics of the tumor microenvironment and thereby enhancing treatment outcomes. Indeed, based on our increased knowledge of MM pathogenesis, derived therapeutic advances have achieved unprecedented deep and durable responses particularly in standard-risk MM patients, resulting in dramatic improvements of median overall survival (OS) rates above 10 years. In contrast, approximately 20% of high-risk MM patients, who experience early disease progression or death are underserved. The achievement and even more the durability of minimal residual disease (MRD) negativity (cut-off 10^-5 to 10^-6) have evolved as an early clinical end point to predict the clinical benefit of novel therapeutic agents and advantageous therapeutic MM regimens.

Several recent phase III trials demonstrated superior responses of CD38-targeted monoclonal antibody (CD38mAb)-containing quadruplet vs. CD38mAb-free triplet regimens in newly diagnosed (ND) MM patients who are eligible for high-dose melphalan followed by autologous stem cell transplantation (ASCT), both in standard- and high-risk patients. Specifically, besides a CD38mAb, these quadruplet regimens consist of a proteasome inhibitor, an immunomodulatory drug (IMiD) and dexamethasone.

Identified in 1980, CD38 is a 45-kDa type II transmembrane glycoprotein, which is highly expressed on MM cells, but also present on natural killer (NK) cells, regulatory B and T cells, myeloid-derived suppressor cells, and early osteoclast progenitors. Moreover, it interacts with the non-substrate ligand CD31 on endothelial cells. CD38 functions as a receptor, an adhesion molecule, as well as an immunomodulatory ectoenzyme, thereby contributing to MM cell proliferation, survival, angiogenesis, bone disease, and immune evasion. Due to its pleiotropic function within the deregulated BM microenvironment, CD38 has evolved as a prime target for MM therapy. Daratumumab (HuMax^®-CD38, Dara), a fully human IgG1-kappa CD38mAb was the first, the chimeric IgG1-kappa CD38mAb isatuximab-irfc (Isa), the second CD38mAb to be approved and commercialized. Both Dara as well as Isa act via Fc-dependent immune effector mechanisms, direct apoptotic activity and immunomodulatory effects. Fc-dependent immune effector mechanisms include complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent phagocytosis (ADCP) through their binding to activating Fcγ receptors (FcγRs) on immune effector cells. FcγR-mediated cross-linking additionally induces tumor cell apoptosis. CD38 ectoenzyme function results in increased NAD⁺ and reduced adenosine levels in the MM BM microenvironment. Together with their ability to eradicate immunosuppressive CD38-expressing regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), Dara and Isa promote the expansion of NK as well as CD4⁺ and CD8⁺ T cells and thereby restore anti-MM immune function within the BM microenvironment. Due to their multi-façeted activity within the MM BM microenvironment, CD38mAb-containing regimens reduce CD38 MM cells and thereby improve patient outcome.

Of note, Isa targets a CD38 epitope distinct from Dara. This may explain why Isa, but not Dara, induces direct programmed cell death of MM cells via lysosomal-associated and apoptotic pathways, without crosslinking. Differences in the epitope of these CD38mAbs may also explain their varying effectiveness to induce CDC, ADCC, ADCP, and apoptosis. However, based on our current knowledge the therapeutic relevance of this observation is unknown. A head-to-head clinical trial of Dara vs. Isa would be required to address this gap of knowledge.

This editorial commentary will discuss results of the phase II SKylaRk trial, which investigated the CD38mAb Isa in combination with once-weekly carfilzomib, lenalidomide (Revlimid^®), and dexamethasone (KRd) for patients with all-risk transplant-eligible (TE) NDMM patients in detail, put them into relation with other CD38mAb-containing quadruplet frontline therapies and debate the subject of early vs. deferred ASCT (1-12).

The SKylaRk trial

The SKylaRk trial is an investigator-initiated, open-label, single-arm phase II trial which investigated the addition of Isa (10 mg/kg IV, weekly for 8 weeks, then every other week for 16 weeks, and thereafter monthly) to weekly carfilzomib (56 mg/m² IV days 1, 8, 15), lenalidomide (25 mg p.o. days 1–21), and dexamethasone (20 mg p.o. days 1, 2, 8, 9, 15, 16) in all-risk TE NDMM patients and stratified maintenance by cytogenetic risk. Specifically, 50 all-risk TE NDMM patients received four 28-day cycles of Isa-KRd followed by the investigator’s choice of upfront vs. deferred ASCT. Patients who deferred ASCT received an additional 4 cycles of therapy; patients who underwent ASCT received 2 additional cycles of therapy, and then maintenance therapy for up to 2 years. The primary endpoint was complete response (CR) after four cycles of treatment. For maintenance therapy, patients were stratified by cytogenetics; those with standard-risk cytogenetics received lenalidomide (10 mg p.o. days 1–21), those with high-risk cytogenetics received Isa (10 mg/kg IV day 1), carfilzomib (56 mg/m² IV days 1, 8, 15), and lenalidomide (10 mg p.o. days 1–21). Median age at diagnosis of patients included in this study was 59 years (range, 40–70 years), and International Staging System (ISS) I 56%, ISS II 32%, and ISS III 12%. Twenty-three (46%) patients had high-risk factors (del17p, t(4;14), t(14;16), t(14;20), or 1q gain or amplification) (1).

Results

All patients received four cycles of the quadruplet therapy. Only 5 out of 50 patients chose to receive ASCT; the majority of patients chose a total of 8 cycles Isa-KRd. After a medium follow-up of 26 months [interquartile range (IQR), 20.7–30.1 months] the overall response rate (ORR) in the intention-to-treat (ITT) analysis after 4 cycles was 90%, with 78%≥ very good partial response (VGPR), and 32%≥ CR. Of the evaluable patients, ORR after 4 cycles was 100%, and 87%≥ VGPR. Of those patients receiving 8 cycles Isa-KRd without ASCT, ORR was 100%, 65% achieved a CR, and 98%≥ VGPR. MRD results were available for 28 out of 45 patients (62%), who achieved a ≥ VGPR after 4 cycles. Of those 43% (12/28) were MRD negative at 10⁻⁵, and 18% at 10⁻⁶. After completion of consolidation, MRD results were available for 41 patients, of who 66% were MRD negative at 10⁻⁵, and 17% at 10⁻⁶. Of those patients receiving 8 cycles Isa-KRd without ASCT, 72% were MRD negative at 10⁻⁵, and 19% at 10⁻⁶. Of the 5 patients receiving ASCT one patient became MRD negative at 10⁻⁵, and none at 10⁻⁶.

The most common grade 3 or 4 side-effects (≥2 patients) included neutropenia [13 (26%) of 50 patients], elevated alanine aminotransferase [6 (12%) patients], fatigue [3 (6%) patients], thrombocytopenia [3 (6%) patients], acute kidney injury [2 (4%) patients], anaemia [2 (4%) patients], and febrile neutropenia [2 (4%) patients]. In addition to these traditional efficacy and safety metrics, SKylaRk also explored novel endpoints such as treatment-induced changes of the T cell repertoire. Of note, no differences of the T cell repertoire were observed at baseline and at completion of the induction, or at achievement of MRD negativity. Similarly, no differences were also observed among standard- and high-risk patients (1).

The evolution of induction therapy in TE patients

After the introduction of a frontline proteasome inhibitor/IMiD/dexamethasone-containing triplet combination therapy {SWOG-S0007 trial [NCT00644228] (13); PETHEMA/GEM2012 [NCT01916252] trial (14)}, several clinical trials sought to determine the role of ASCT in the era of modern triplet regimens. An 8 year follow-up analysis of the phase III IFM/DFCI 2009 [NCT01191060] trial demonstrated superior progression free survival (PFS) of lenalidomide (Revlimid)/bortezomib (Velcade)/dexamethasone (RVd) before and after ASCT followed by lenalidomide-maintenance for 1 year vs. RVd alone, even in patients who did not achieve undetectable disease (MRD-negativity at 10⁻⁶) (15). However, there was no difference among these two strategies with respect to OS or PFS (16). Similar or even higher PFS data across all-risk patients were obtained in the IFM/DFCI 2009 partner DETERMINATION trial [NCT01208662] after a follow-up of 76 months, in which lenalidomide-maintenance was given until disease progression. Again no difference was observed in OS. Based on these results ASCT remains a cornerstone in frontline MM therapy. Causes for the lack of an OS advantage may include the design of the respective trial, the chronic nature of MM, and competing therapy harms and benefits (17).

The role of CD38mAb/bortezomib-containing regimens in frontline MM therapy

CD38mAb-containing quadruplet induction therapies have evolved as novel standard-of-care regimens, in both relapsed refractory (RR) but also in NDMM. Frontline trials, which investigated (I) Dara, include all-risk CASSIOPEIA (18), GRIFFIN (19), PERSEUS (20) and MASTER (21) trials, and high-risk OPTIMUM (22) and MANHATTAN (23) trials; and (II) Isa, include all-risk GMMG-HD7 (24), ISKIA (25), and the SKylaRk (1) trial, as well as high-risk GMMG-CONCEPT (26) and Intergroupe Francophone du Myelome (IFM) 2018-04 (27) trials. Importantly, confirming previous phase II clinical data of the GRIFFIN trial [NCT02874742] (19), which used IV Dara, the recently published open-label, multicenter, randomized phase III PERSEUS trial [NCT03710603] demonstrated high tolerability and a significant improvement of PFS and MRD negativity for SC Dara-VRd > ASCT > SC Dara -VRd consolidation and SC Dara -R maintenance vs. VRd > ASCT > VRd consolidation and R maintenance. Of note, in 64% of patients, Dara maintenance therapy could be discontinued due to persistent MRD negativity for ≥12 months (20). These results led to the recent approval of SC Dara-VRd by the US FDA on July 30, 2024, for induction and consolidation therapy in patients with TE-NDMM. Longer follow-up results are eagerly awaited, especially in high- and ultra-high-risk (≥2 high-risk factors, double-hit) NDMM patients. However, data on the high-risk cohort need to be interpreted with caution due to low numbers of high-risk patients in these trials.

Similar to Dara-containing quadruplet regimens, also quadruplet regimens including Isa demonstrated superior outcomes when compared to CD38mAb-free triplet regimens in frontline MM therapy. Specifically, first results (“part 1”) of the open label, multicenter, randomized, active-controlled phase III GMMG-HD7 trial [NCT01916252] (3×Isa-RVd vs. 3×RVd > ASCT > Isa/R maintenance vs. R maintenance) demonstrated a superior MRD negativity rate (cut-off 10⁻⁵) at the end of induction with 50% vs. 35.6% in the Isa-RVd vs. RVd arm in the all-risk ITT population. Moreover, although the rates of CR after induction therapy did not differ between Isa-RVd and RVd arms, there was a significant increase in ≥VGPR rates (77.3% vs. 60.5%, P<0.001) and ≥PR rates (90% vs. 83.6%, P=0.02) with Isa-RVd. The addition of Isa had no significant impact on the safety or dose intensity. Moreover, MRD negativity rate after Isa-RVd induction therapy was statistically superior to RVd also in TE NDMM patients with high-risk or ultra-high-risk cytogenetics, consistent with the benefit observed in the overall trial population. Results following the second randomization for maintenance therapy are eagerly awaited (24,28).

The role of CD38mAb/carfilzomib-containing regimens in frontline MM therapy: a challenge to ASCT?

Carfilzomib is a second-generation proteasome inhibitor, which irreversibly binds the β5 constitutive proteasome and the β5i immunoproteasome subunits. Initial preclinical studies indicated that carfilzomib, when compared to bortezomib, increases anti-MM activity and overcomes bortezomib resistance. In support of these preclinical data, the randomized phase III ENDEAVOR [NCT01568866] trial showed longer PFS and OS for Kd vs. Vd in RRMM patients (29). Moreover, several phase I-II clinical trials demonstrated high rates of CR and MRD negativity following KRd in NDMM patients, including high-risk patients. However, based on results of the randomized, multicenter, open-label phase III ENDURANCE trial [NCT01863550] (30) and a recent single-center, retrospective trial on KRd vs. VRd in NDMM patients without intention for immediate ASCT (31), data on the superiority of KRd vs. VRd remain controversial. Of note, a systematic review and meta-analysis demonstrated a significant PFS advantage for KRd over VRd in treating ND, particularly high-risk, MM patients (4). For final conclusions, the ongoing randomized, open-label phase III COBRA trial [NCT03729804] investigates the efficacy of extended KRd vs. VRd > 24×R maintenance vs. R maintenance until disease progression in a NDMM patient population without intention to immediate ASCT, and including high-risk patients. Whether novel CD38mAb-containing quadruplet therapies with the irreversible second-generation proteasome inhibitor carfilzomib may challenge the role of ASCT in TE NDMM patients is under debate. Indeed, ASCT-sparing approaches come with the promise to avoid its disadvantages, including acute toxicities as well as long-term adverse effects such as high rates of ≥ grade 3 hematologic toxicities, increased risk of infections and gastrointestinal disorders, increased mutational burden at relapse, elevated risk of second primary malignancies (i.e., MDS/AML), need for hospitalization, and a meaningful decrease of patients’ quality of life. Therapeutic approaches allowing to defer ASCT are therefore of highest interest.

Daratumumab-containing Kd combination regimens

The role of Dara-containing KRd regimens was investigated in the multicenter, single-arm, phase II MASTER [NCT03224507] trial (Dara-KRd > ASCT followed by up to two phases of consolidation with Dara-KRd) and the non-randomized clinical and correlative ASCT-free MANHATTAN trial (weekly Dara-KRd). Results of the MASTER trial [NCT03224507] demonstrated high efficacy of a CD38mAb-containing quadruplet therapy when used together with ASCT; and indicated the applicability of an MRD-based, response-adapted consolidation strategy in NDMM (21). Results of the ASCT-free MANHATTAN trial (weekly Dara-KRd) showed that extended treatment with KRd in NDMM patients (including 49% high-risk NDMM patients) leads to high MRD negativity rates (cut-off 10⁻⁵) of 71% (23). In support of these findings, a recently published phase II trial with extended Dara-KRd demonstrated sustained deep and durable responses (estimated 3-year PFS was 85%, the 3-year OS 95%) without the use of ASCT. Moreover, the high proportion of high-risk patients in this study provided a signal of efficacy in a population that is typically recommended to proceed with early ASCT, when possible. These data indicate that a CD38mAb-containing KRd regimen may lead to superior outcomes when compared to KRd with or without ASCT; and that Dara-KRd may replace ASCT (32). To further confirm these data, the ongoing large, multicenter, investigator-initiated phase II ADVANCE trial [NCT04268498] investigates the anti-MM activity of 8 cycles of KRd with or without Dara (i.e., Dara-KRd vs. KRd) in MM patients to whom ASCT is only offered when they remain MRD positive after 8 cycles. Another trial, the multicenter Dara-containing phase II OPTIMUM (MUK9) trial [NCT03188172] (Dara-cyclophosphamide (C)VRd > V-augmented HD-ASCT > Dara-VRd > Dara-VR > Dara-R maintenance) demonstrated superior PFS and OS (77% and 83.5% for OPTIMUM vs. 39.8% and 73.5% for MyeXI) in patients with molecularly defined ultra–high-risk NDMM or plasma cell leukemia when compared to the randomized phase III Myeloma XI (MyeXI) trial [NCT01554852] (KCRd or RCd > ASCT > R maintenance or observation) (22). Phase III clinical trials to verify this strategy, as a potential standard of care for this hard-to-treat patient population are needed. Whether patients with ≥2 high-risk cytogenetic abnormalities benefit from double ASCT was evaluated in another quadruplet induction/consolidation regimen with Dara-KRd, the phase II IFM 2018-04 trial [NCT03606577] (27).

Isatuximab-containing KRd combination regimens

Several trials, among them also the SKylaRk trial evaluated, whether the addition of Isa to carfilzomib-containing regimens may further improve treatment efficacy in all-risk NDMM patients. Together with the Dara-containing OPTIMUM (MUK9) and the IFM 2018-04 (see above) trial, the phase II GMMG-CONCEPT [NCT03104842] trial is the third study, which exclusively evaluated a CD38mAb in high-risk patients both in the TE and transplant-non-eligible (TNE) NDMM setting (6×Isa-KRd > ASCT > 4×Isa-KRd > Isa-KR maintenance or 6×Isa-KRd > 2×Isa-KRd > 4×Isa-KRd > Isa-KR maintenance). Excitingly, Isa-KRd achieved significant MRD negativity rates (67.7% for TE and 54.2% for TNE patients; cut-off 10⁻⁵) after consolidation; and sustained MRD negativity for ≥1 year of 62.6% and 46.2% (in TE and TNE patients, respectively). Median PFS and median OS were not reached in either arm after a median follow-up of 44 months for TE and 33 months for TNE NDMM patients, respectively (26). Early data of the randomized phase III IsKia trial (Isa-KRd > ASCT >Isa-KRd consolidation vs. KRd > ASCT > KRd consolidation) in NDMM patients similarly showed a promising reduction of MRD negativity post consolidation across all subgroups (67% vs. 48% at cut-off 10⁻⁶); and 65% vs. 48%, 69% vs. 53%, and 77% vs. 27% for patients with 0, 1, and 2+ high-risk cytogenetic factors, respectively. Longer follow-ups to correlate these data with PFS and OS are eagerly awaited (25). Moreover, the ongoing phase III 2020-02 MIDAS trial investigates the impact of MRD-guided single vs. double ASCT after induction with 6x Isa-KRd, followed by lenalidomide or Isa-iberdomide maintenance (Table 1).

Conclusions

Taken together, all of the above trials demonstrate the superior efficacy of CD38mAb-containing quadruplet vs. triplet regimens in the frontline setting. Despite being a single-arm, non-randomized clinical trial, the SKylaRk trial underscores the safety and efficacy of Isa-KRd not only in high-risk (as investigated in the GMMG-CONCEPT trial), but also in standard-risk NDMM patients. Indeed, after 4 cycles, the CR rate was 32% comparable with the CR rate of 36% achieved after 4 cycles Dara-KRd in the MASTER trial. A potential benefit of carfilzomib over bortezomib remains to be determined. It may be based on the irreversible vs. reversible mechanism-of-action of carfilzomib vs. bortezomib; and/or lower rates of carfilzomib-induced polyneuropathy, which allow extended treatment periods. Of note, although stem cells were collected for the ASCT in all patients, 45 of 50 patients in the SKylaRk trial chose the option to receive a total of 8 cycles Isa-KRd followed by maintenance. Indeed, in contrast to Europe, where practically all TE (young and medically fit) NDMM patients receive an ASCT, a shift of practice patterns towards deferring ASCT in the first remission is underway in the US. Excitingly, despite deferring ASCT (89%), the ORR in the SKylaRk trial after 8 cycles of therapy was an impressive 100%, with 95% of patients achieving ≥ VGPR and an unprecedented 74% of evaluable patients achieving MRD negativity. Expanding on the IsKia trial, which showed superiority of Isa-KRd with ASCT, results of the SKylaRk trial therefore demonstrate for the first time, deep and durable responses of Isa-KRd in all-risk NDMM patients with once-a-week carfilzomib dosing, also in the absence of ASCT. Nevertheless, a most recent post-hoc analysis of this study after a median follow-up of 37 months indicated the poorer outcomes of patients (N=5) with 2 or more high-risk cytogenetic abnormalities (HRCAs) who deferred ASCT. Therefore, while Isa-KRd in patients with 0–1 HRCAs who deferred ASCT demonstrated outcomes comparable to those seen in 4-drug combinations with upfront ASCT, there seems to be a need for further improvement in the ultra-high-risk patient population. Indeed, ASCT as well as other additional innovative strategies, such as CAR-T and/or bispecific therapies may be of more value in these patients (33).

Randomized clinical trials are needed to verify, whether extended quadruplet therapy in the absence of ASCT is superior to shorter courses of quadruplet therapy plus ASCT in all-risk NDMM patients. Furthermore, ongoing studies investigate whether CD38mAbs and/or carfilzomib together with antibody-drug-conjugate (ADC) belantamab mafodotin, CELMoDs iberdomide and mezigdomide, bispecific antibodies teclistamab and talquetamab, and CAR T cells idecabtagene vicleucel (ide-cel) and ciltacabtagene-autoleucel (cilta-cel) (e.g., DREAMM-7, MajesTEC-5, MASTER-2, GEM-TECTAL) achieve even deeper and longer responses through combined targeting of tumor cells and the tumor microenvironment.

In summary, results of the SKylaRk trial strongly support the translation of an ASCT-free Isa-KRd regimen from the clinical trial to the real-world setting, at least in some patients.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-191/prf

Funding: This study was supported by the Technopol grant (No. K3-F-730/003-2020).

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-191/coif). K.P. reports research support from Life Science grant (No. LSC18-010), Roche Pharmaceuticals; speaker’s honoraria from Celgene, Amgen Inc., and Janssen Pharmaceuticals; and consulting fees from Celgene, Takeda, and Janssen Pharmaceuticals. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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