Multiple myeloma (MM) is a cancer of the B-cell lineage resulting from the hyperproliferation of malignant plasma cells in the bone marrow, which is largely due to the dysregulation of oncogenic signaling pathways and abnormal immune function [1]. Most patients with MM experience relapse and eventually develop disease that is refractory to available treatments [1, 2]. Refractory disease can result from the presence of drug-resistant cells caused by multiple mechanisms, including mutations, reduced target expression, and changes in the tumor microenvironment [1,2,3]. Patient prognosis worsens with each relapse, and most high-risk patients, particularly elderly patients, will not receive a third line of therapy [4, 5]. Therefore, early-line treatments that provide disease control, delay relapse, prolong survival, are tolerable, and do not compromise the quality of life are critical.

The treatment landscape for MM continues to evolve, leading to improved outcomes. Data are still lacking, however, on how best to sequence regimens in relapsed/refractory MM (RRMM) [4, 6,7,8]. In this narrative review based on our expert opinion and an assessment of our clinical practice, we discuss the current treatment landscape for early-line treatment of MM, with a focus on immune-based agents, and associated clinical investigations.

The standard of care for MM includes combinations of drugs with different mechanisms of action, such as immunomodulatory drugs, monoclonal antibodies (mAbs), corticosteroids, proteasome inhibitors (PIs), and alkylating agents (Table 1). Almost all therapy combinations include a corticosteroid (dexamethasone or prednisone) and a PI (bortezomib, carfilzomib, or ixazomib), which induces apoptosis of malignant cells [2, 4, 6, 7, 9]. Immunomodulatory drugs currently recommended in MM are thalidomide, lenalidomide, and pomalidomide [2, 6, 7, 9]. Immunomodulatory drugs have a dual mechanism of action—direct tumor cell killing and enhancement of immune function [10, 11]. Specifically, they bind to cereblon, a component of the E3 ubiquitin ligase complex, leading to the degradation of the transcription factors Ikaros and Aiolos and resulting in the reactivation of apoptotic pathways in MM cells and enhancement of innate and adaptive immune cell function [10, 11]. mAbs targeting CD38 have also emerged as an important class of drugs in MM [12]. Daratumumab and isatuximab bind to CD38, a cell surface receptor highly expressed in myeloma cells and several types of immune cells, and exert their action through Fc-dependent mechanisms and immunomodulatory effects [3, 13]. Fc-dependent mechanisms involve antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity, which lead to lysis or phagocytosis of myeloma cells. The immunomodulatory effects of anti-CD38 mAbs promote T-cell proliferation and effector function through inhibition of CD38 enzymatic activity, which reduces adenosine immunosuppressive activity and elimination of CD38+ immunosuppressive cells [14]. mAbs targeting other myeloma cell epitopes have also been developed [15, 16]. Elotuzumab, a humanized IgG1 mAb targeting the SLAMF7 protein that is expressed on myeloma cells independent of cytogenetic abnormalities, mediates myeloma cell killing through mechanisms similar to those of the aforementioned anti-CD38 mAbs [15, 16]. Additional drugs considered within combination regimens are alkylating agents (e.g., cyclophosphamide), which cause DNA damage, and panobinostat, an inhibitor of the enzyme histone deacetylase, which activates the expression of tumor suppressor genes through the opening of chromatin structures initially silenced through histone acetylation [17]. Selinexor, an exportin-1 inhibitor, is an approved drug in MM that inhibits the nuclear export of tumor suppressor proteins and oncoproteins [18, 19]. Antibody-drug conjugates (ADCs) and chimeric antigen receptor (CAR) T-cell-directed therapies that target B-cell maturation antigen (BCMA), such as idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), are also emerging as standard of care regimens in MM and are detailed later in this review, as well as cereblon E3 ligase modulators (CELMoD® agents).

For patients with newly diagnosed MM (NDMM), immunomodulatory drugs combined with PIs and a steroid are widely used, and more recently, daratumumab-based combinations have been recommended [6, 9]. Initial therapy can vary across countries depending on drug availability and patient eligibility for autologous stem cell transplant (ASCT). For those who are transplant eligible (TE), the most common standard treatment is lenalidomide, thalidomide, or cyclophosphamide added to a bortezomib-dexamethasone backbone as induction therapy prior to ASCT, followed by continuous lenalidomide maintenance therapy until disease progression (Table 1) [6, 9, 20]. Chemotherapy with high-dose melphalan (200 mg/m2 intravenous) is the standard conditioning regimen before ASCT [6, 9]. Among these combinations, lenalidomide-bortezomib-dexamethasone has been suggested to offer the best risk-benefit profile [9]. If an immunomodulatory drug is not available in certain countries, cyclophosphamide may be substituted [6, 9]. The inclusion of daratumumab or isatuximab as an early-line option is changing the treatment landscape, owing to the approval of combination regimens such as daratumumab-bortezomib-thalidomide-dexamethasone in TE patients, daratumumab- or isatuximab-carfilzomib-dexamethasone in patients with RRMM who have received 1 to 3 prior lines of therapy; and daratumumab-bortezomib-melphalan-prednisone or daratumumab-lenalidomide-dexamethasone in those who are transplant ineligible (TI) [2, 21,22,23]. The phase 3 CASSIOPEIA study demonstrated that the addition of daratumumab to thalidomide-bortezomib-dexamethasone increased the depth of response and improved rates of progression-free survival (PFS) in patients with TE NDMM [24]. The addition of daratumumab to lenalidomide-bortezomib-dexamethasone regimens also improved the depth of response in patients with TE NDMM in the phase 2 GRIFFIN study, a finding that is being evaluated further in the phase 3 PERSEUS study [21, 25, 26]. Daratumumab was approved by the US Food and Drug Administration (FDA), European Commission (EC), and Health Canada in 2019 in combination with thalidomide-bortezomib-dexamethasone; [21,22,23] to date, studies are ongoing for the combination with lenalidomide-bortezomib-dexamethasone.

In TI patients, standard treatments include lenalidomide-bortezomib-dexamethasone or lenalidomide-daratumumab-dexamethasone for fit patients and lenalidomide–low-dose dexamethasone for unfit patients (Table 1) [2, 6, 9, 27, 28]. The effectiveness of these regimens may partially depend on the characteristics of the patient population. For example, compared with lenalidomide-dexamethasone, lenalidomide-bortezomib-dexamethasone resulted in significant improvements in PFS and OS only in patients aged <65 and <75 years, respectively, in phase 3 SWOG S0777 trial [29]. In the phase 3 MAIA trial, the PFS benefit with daratumumab-lenalidomide-dexamethasone vs lenalidomide-dexamethasone was maintained in the subgroup of patients aged >75 years (median PFS, not reached [NR] vs 31.9 months, respectively), although inferential statistical testing was not performed for these data [30]. The bortezomib dosing frequency can also be modified without compromising the efficacy of this regimen, as evidenced by the robust PFS benefit observed in a phase 2 study of lenalidomide, bortezomib and dexamethasone (RVd) lite (administered over a 35-day cycle: oral [PO] lenalidomide 15 mg on days 1–21; subcutaneous bortezomib 1.3 mg/m2 on days 1, 8, 15, and 22; and PO dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23) in patients with TI NDMM (median PFS, 41.9 months) [31]. Lenalidomide is an important component of these regimens, as it has been shown to delay initiation of second-line therapy for >3 years [27]. Daratumumab is also recommended for use without lenalidomide when added to bortezomib-melphalan-prednisone [6, 9, 21, 22]. The inclusion of daratumumab within these combinations was based on results from the phase 3 MAIA and ALCYONE studies, which demonstrated longer PFS when combined with lenalidomide-dexamethasone or bortezomib-melphalan-prednisone, respectively [30, 32]. The authors consider the current standard of care in this setting to be daratumumab-lenalidomide-dexamethasone, based on more recently reported survival data from the MAIA trial, which showed longer PFS (daratumumab-lenalidomide-dexamethasone vs lenalidomide-dexamethasone: NR vs 34.4 months) in patients with TI NDMM [33]. An additional lenalidomide-free recommended regimen in the United States is cyclophosphamide-bortezomib-dexamethasone [6].

As lenalidomide-based therapies have become common in frontline therapy in NDMM, pomalidomide- and daratumumab-based regimens as next-line options have been studied in recent clinical trials. The following triplet combinations are currently recommended based on ASCO/CCO, IMWG, and EHA-ESMO guidelines for patients with RRMM previously exposed to lenalidomide (Table 1): pomalidomide-dexamethasone plus a PI (bortezomib, ixazomib, or carfilzomib), an anti-CD38 mAb (daratumumab or isatuximab), or an anti-SLAMF7 mAb (elotuzumab); daratumumab-dexamethasone plus a PI (bortezomib or carfilzomib); and isatuximab-carfilzomib-dexamethasone [6, 7, 9]. The approval of daratumumab-based combinations in the frontline setting has introduced additional complexity in the selection of next-line options [9]. For patients previously exposed to daratumumab, next-line options may include PIs and immunomodulatory agents, particularly pomalidomide-bortezomib-dexamethasone for patients previously also exposed to lenalidomide [6, 7, 9]. Isatuximab, which received approval from the FDA, EC, and Health Canada in 2020 for use in combination with pomalidomide-dexamethasone and carfilzomib-dexamethasone [34, 35], may be an option since the epitopes of daratumumab and isatuximab do not overlap, and they induce different structural changes within the CD38 protein that may lead to differential tumor cell killing; evidence-based data, however, are lacking in this regard [7, 36]. In a phase 2 study of isatuximab monotherapy in patients with RRMM and daratumumab-refractory disease, the primary endpoint of overall response rate (ORR) was not met; the disease control rate was 37.5% but was greater in patients with daratumumab washout periods of ≥6 months vs <3 months (58.3 vs 28.6%, respectively) [37]. Further study will be necessary to determine the potential of isatuximab monotherapy or combination therapy for patients who have developed the daratumumab-refractory disease. Additionally, based on its approval by the FDA and EC, elotuzumab may be used in combination with pomalidomide-dexamethasone or lenalidomide-dexamethasone [2, 9, 15, 38].

An alternative to pomalidomide or daratumumab is switching from bortezomib to carfilzomib within a triplet-combination that also includes cyclophosphamide, as PI sensitivity is often retained following bortezomib exposure. Carfilzomib has been shown to induce apoptosis in bortezomib-resistant MM cell lines and in patient samples [39]. However, the clinical benefit of treatment with carfilzomib or bortezomib may depend on the patient population. In the phase 3 ENDURANCE trial of carfilzomib vs bortezomib in combination with lenalidomide-dexamethasone in patients with NDMM, the median PFS was similar between groups (34.6 vs 34.4 months, respectively) [40]. However, the composite rates of grade ≥3 cardiac, pulmonary, and renal toxicities were greater with carfilzomib-lenalidomide-dexamethasone than with bortezomib-lenalidomide-dexamethasone (16 vs 5%, respectively), whereas the rates of grade ≥3 peripheral neuropathy were lower (1% vs 8%). Consequently, the toxicologic profile associated with carfilzomib may limit the use of this agent in patients with underlying cardiopulmonary or renal comorbidities, and the peripheral neuropathy associated with bortezomib may limit its use in patients with neurological comorbidities. However, carfilzomib has also shown a survival benefit in patients with RRMM, as evidenced in the phase 3 ENDEAVOR trial, in which patients who had received 1 to 3 prior lines of treatment had an increased median overall survival (OS) with carfilzomib-dexamethasone vs bortezomib-dexamethasone (47.8 vs 38.8 months, respectively; hazard ratio, 0.76; 95% CI, 0.63–0.92) [41]. Furthermore, cyclophosphamide added to carfilzomib-dexamethasone has demonstrated clinical benefit in patients with the lenalidomide-refractory disease [42]. Another option in this setting is the combination of selinexor with bortezomib-dexamethasone, as evaluated in the phase 3 BOSTON trial [43]. Pomalidomide has also been shown to inhibit the proliferation of lenalidomide-resistant MM cell lines [16]. This observed in vitro efficacy is supported by the results of the phase 3 OPTIMISMM trial, which found that treatment with pomalidomide, bortezomib, and low-dose dexamethasone improved PFS compared with bortezomib and low-dose dexamethasone in patients with RRMM and lenalidomide-refractory disease (median PFS, 9.5 vs 5.6 months, respectively) [44, 45]. Immunophenotypic profiling of peripheral blood samples from patients treated with daratumumab, pomalidomide, and low-dose dexamethasone in arm B of phase 2 MM-014 trial further supported the efficacy of pomalidomide in patients with the lenalidomide-refractory disease [46]. Pomalidomide mediated increases in proliferating T cells, increases in HLA-DR+ activated T cells, and expansion in the effector memory T-cell compartment in patients with the lenalidomide-refractory disease and the total population, suggesting that the efficacy of pomalidomide is maintained in patients with the lenalidomide-refractory disease [46]. A more detailed review of the treatment of patients with lenalidomide exposure, including lenalidomide-refractory disease, can be found in Moreau et al. [8] and the International Myeloma Working Group guidelines [7].

The phase 3 FIRST, SWOG, Myeloma XI, and CALGB studies collectively established the role of frontline lenalidomide until disease progression for patients with TE or TI NDMM [28, 29, 47, 48]. Additionally, with daratumumab being increasingly prescribed in the frontline setting due to its recent approval in many countries [21,22,23], it has become critical to study regimens that can be given to patients with MM refractory to lenalidomide or daratumumab early in their disease course, especially at first relapse. Despite the multitude of therapeutic options available for patients with RRMM, evidence of effectiveness in early lines of therapy and in patients who experienced lenalidomide treatment failure is limited [7, 8, 29]. This is, in part, because many of the recent phase 3 trials were designed prior to frontline lenalidomide becoming a frequently used treatment strategy. Additionally, evidence of treatment efficacy following the failure of early-line daratumumab is limited by the relatively low clinical trial enrollment of patients with daratumumab-refractory or -relapsed disease. Currently, pomalidomide-, carfilzomib- and anti-CD38–based regimens are options considered for next-line therapy after either lenalidomide or daratumumab and will be the focus of this review.

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