Multiple Myeloma in the Era of Novel Agents and Stem Cell Therapies

Abstract

The recent availability of several lines of novel therapeutic agents such as immunomodulatory agents, proteasome inhibitors, and monoclonal antibodies; the widespread utilization of hematopoietic stem cell transplantation; the use of advanced diagnostic techniques that allow risk stratification and monitoring of treatment responses; and the general improvement in health care have revolutionized treatment of patients with multiple myeloma and this has translated into significant improvements in survival outcomes. Monitoring of minimal residual disease can guide the intensity of treatment, and the efficient application of modern diagnostic tools in monitoring treatment responses in real-world clinical practice can hopefully be achieved in the near future. The recent use of quadruplet regimens in the treatment of patients with multiple myeloma has translated into unprecedented treatment responses and survival outcomes. Also, chimeric antigen receptor T-cell therapy and bispecific antibodies represent a new dimension in the precision medicine in MM. Additionally, our ability to induce deep responses has improved, and the treatment goal in myeloma patients tolerating the recommended therapy has moved from delay of disease progression to induction of the deepest possible response.

1. Introduction

Multiple myeloma (MM), which accounts for 10–15% of all hematologic malignancies, arises from a terminally differentiated postgerminal center plasma cells in the bone marrow (BM) and is characterized by a monoclonal proliferation of plasma cells resulting in the production of monoclonal antibodies and end-organ damage [1, 2, 3, 4]. MM is a disease of old age with the median age at diagnosis ranging between 65 and 74 years in western countries [1, 2, 3, 5]. The risk factors for MM include old age; certain races such as African Americans and living in certain geographic locations such as Australia, Western Europe, and the United States of America (USA); male gender; and family history [1, 3, 5]. However, ionizing radiation, pesticides and benzene, obesity and chronic infection, genetic factors, chronic antigenic stimulation, and environmental as well as occupational factors play a role in the pathogenesis of MM [5, 6, 7, 8]. The recent advances in diagnostics and therapeutics have translated into an increase in the median survival of patients with MM by approximately 6 years [1, 9]. The global 5 years survival is more than double over the past decades due to the availability of several lines of novel therapeutic agents and hematopoietic stem cell transplantation (HSCT), the recent advancements in diagnostic techniques, and the general improvement in health care [3, 10, 11].

2. Diagnosis and staging of MM

The diagnosis of MM requires: (1) ≥10% clonal BM plasma cells or a biopsy proven plasmacytoma; and (2) evidence of one or more of MM defining events namely: [A] CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) features felt related to the plasma cell disorder, [B] BM clonal plasmacytosis ≥ 60%, [C] serum involved/uninvolved free light chain ratio (FLC) ≥ 100 (provided involved FLC is ≥ 100 mg/L), or [D] >1 focal lesion on magnetic resonance imaging (MRI) [1, 2, 3]. Based on the revised international staging system (RISS), MM is usually classified into three stages: (1) stage I: all the following: serum albumin ≥ 3.5 g/ dL, serum beta 2 microglobulin (B2M) < 3.5 mg/L, normal serum lactic dehydrogenase (LDH) and no high-risk (HR) cytogenetics; (2) stage II: not fitting stages I and III with serum B2M: 3.5–5.5 mg/L; and (3) stage III: all the following: serum B2M > 5.5 mg/L and HR cytogenetics or elevated serum LDH level [1, 2, 3]. According to the RISS, which was developed based on a study of 11 international trials, the 5 years survival rates among the patients with stages I, II, and III RISS are 82%, 62%, and 40%, respectively [3, 12]. The RISS combines elements of tumor burden as well as disease biology and allows the use of (1) specific biomarkers to define the disease in addition to the established CRAB features and (2) modern imaging tools to diagnose MM bone disease and clarify several other diagnostic requirements [2, 3, 13]. The presence of del(17p), t(4;14), t(14;16), t(14;20), gain 1q, or p53 mutation is considered HR-MM. Additionally, the presence of any two HR factors is considered double-hit myeloma; while triple-hit myeloma is defined by the presence of ≥ 3 HR features [1].

3. General treatment outline

In transplant-eligible patients, 3–4 cycles of induction therapy that consist of either bortezomib, lenalidomide, dexamethasone (VRd) or bortezomib, cyclophosphamide, dexamethasone (VCD), or bortezomib, thalidomide, dexamethasone (VTD) are usually given followed by single autologous HSCT [1, 2, 3]. However, for patients with HR-MM, it is recommended to give induction therapy with either daratumumab, bortezomib, lenalidomide, dexamethasone (Dara-VRd), or carfilzomib, lenalidomide, dexamethasone (KRd) as alternatives to VRd followed by single or tandem autologous HSCT [1, 2]. Selected standard risk (SR) patients can receive additional cycles of induction and delay in transplant until the first relapse [1]. Patients who are not eligible for HSCT are typically treated with 8–12 cycles of VRd followed by lenalidomide maintenance. Alternatively, these patients can be treated with daratumumab, lenalidomide, and dexamethasone (DRd) [1, 2, 3]. After autologous HSCT, SR patients need lenalidomide maintenance, while bortezomib-based maintenance is needed for patients with HR-MM [1, 3]. In case of refractory disease, most patients require a triplet regimen at relapse, with the choice of regimen varying with each successive relapse [1, 3]. The old, current, and future therapeutic modalities in MM are shown in Table 1 [14, 15, 16, 17, 18, 19].

(1)	Melphalan
(2)	VAD (vincristine, doxorubicin, dexamethasone) regimen of chemotherapy
(3)	Corticosteroids: prednisolone and dexamethasone
(4)	Immunomodulatory agents: thalidomide, lenalidomide, pomalidomide
(5)	Proteasome inhibitors: bortezomib, carfilzomib, ixazomib
(6)	Monoclonal antibodies: (a) Anti-CD 38 (daratumumab, elotuzumab, isatuximab, and MOR202); (b) Anti-CD138 (indatuximab ravtansine) (c) Anti-interleukin-6 (siltuximab); (d) Anti-RANKL (denosumab)       (e) Anti-KIR2DL1/2/4 (IPH2101)
(7)	Histone deacetylase inhibitors: panobinostat, vorinostat, romidepsin, and ricolinostat
(8)	mTOR inhibitors: everolimus, temsirolimus.
(9)	Checkpoint (programmed cell death protein 1) inhibitors: nivolumab, pembrolizumab
(10)	Bruton’s tyrosine kinase inhibitors: ibrutinib
(11)	BCL2 antagonists (BH3 mimetics): venetoclax, obatoclax, and navitoclax
(12)	Cyclin-dependent kinase inhibitors: dinaciclib
(13)	BRAF and BRAF/MEK inhibitors: selumetinib
(14)	Kinesin spindle protein 1 inhibitors: filanesib, array 520
(15)	Selective inhibitors of nuclear-cytoplasmic transport: selinexor, exportin
(16)	Phosphoinositide 3-kinase-Akt inhibitors: perifosine, afuresertib
(17)	PIM kinase inhibitors: LGH 447
(18)	Kinesin spindle protein inhibitors: the peptide drug conjugate melfuflen
(19)	Vaccines: (A) Multiple myeloma cell/dendritic cell fusion Vaccines; (B) Peptide-based vaccines
(20)	Bispecific antibodies and bispecific T-cell engagers: AMG-4209; AMG-701; CC-93269; Teclistamab; Talquetumab; Cevostamab (BFCR4350A); Blinatumomab
(21)	Antibody-drug conjugates: Belantamab mafodotin directed against B-cell maturation antigen (BCMA).
(22)	Chimeric antigen receptor T cells (CAR T cells) that are directed against: CD-19; CD-38; B-cell maturation antigen; and cell surface glycoprotein

Table 1.

Old, current, and future therapeutic modalities in multiple myeloma.

4. Risk stratification, prognosis, and minimal residual disease

Definition of HR-MM includes the following features: (1) HR cytogenetics and molecular mutations, such as del 17p; t4,14; t14,16; t14,20; 1q21 amplification; and TP53; (2) plasma cell leukemia; (3) extramedullary disease (EMD); (4) 5–20% circulating plasma cells; (5) renal failure; (6) relapsed MM; (7) MM refractory to treatment; (8) advanced disease, stage III; and (9) frailty [16, 20]. In patients with HR-MM (double-hit or triple-hit myeloma), it is recommended to adopt the following line of treatment, induction therapy with 3–4 cycles of VRd followed by autologous HSCT, and then maintenance therapy with bortezomib-based regimen, that is, bortezomib every 2 weeks or low-intensity VRd regimen till disease progression [1, 20, 21, 22, 23]. Alternatively, patients can be treated with either (1) 3–4 cycles of KRd followed by early autologous HSCT, followed by carfilzomib-based or bortezomib-based maintenance therapy, or (2) the combination of daratumumab + VRd [16, 20, 22, 23, 24, 25]. The details of prognostication in MM are shown in Table 2 [25, 26, 27, 28, 29, 30].

(1) Risk stratification

Staging of MM such as the revised international staging system Plasma cell labeling index Cytogenetics; fluorescence in situ hybridization Molecular mutations and single nucleotide polymorphism assay Gene expression profiling Serum biomarkers: β-2 microglobulin and lactic dehydrogenase

(2) Monitoring response to treatment:

Serum-free light chain assay Serum heavy/light chain assay Advanced imaging techniques: magnetic resonance imaging and positron emission tomography

(3) Minimal residual disease (MRD) monitoring:

Circulating plasma cells MRD monitoring techniques: flowcytometry and next-generation sequencing Value of depth of response Proteomic evaluation of MRD

(4) Novel prognostic markers:

Proteomic- and glycomic-based platforms Biomarkers of drug resistance

Table 2.

Prognostication in multiple myeloma (MM).

In patients with MM, the presence of circulating clonal plasma cells is associated with aggressive disease and poor prognosis [31]. Several studies have shown that detection and quantification of circulating plasma cells as well as circulating tumor cell-free DNA by flow cytometry, next-generation sequencing, and whole exome sequencing, which are less invasive than performing BM biopsies can be used as biomarkers of prognosis and risk stratification in patients with either newly diagnosed MM or in patients with MM on treatment to monitor disease response or progression [31, 32, 33, 34, 35, 36, 37, 38, 39]. Two groups of scientists have proposed two separate risk score models, each composed of five genes: EPAS1, ERC2, PRC1, CSGALNACT1, CCND1, and FAM53B, TAPBPL, REPIN1, DDX11, CSGALNCT1, in order to predict prognosis and overall survival (OS) in patients with MM [40, 41]. Another group of scientists has used 15 gene-signature to predict prognosis and OS in MM patients [42].

Minimal residual disease (MRD) detection represents a sensitive tool to appropriately measure the response obtained with therapies, and it can independently predict prognosis during MM treatment [43, 44]. In 2016, the International Myeloma Working Group (IMWG) updated MM response categories defining MRD-negative responses both in the BM and outside the BM. Hence, our ability to induce deep responses has improved and the treatment goal in patients tolerating treatment has moved from delay of disease progression to the induction of the deepest possible response [44]. Intensive treatment regimens administered after establishing the diagnosis of MM can lead to MRD negativity in up to 70% of patients, although the current proportion of curable patients is still unknown [45]. Additionally, using combinations of novel therapies, MRD-negative status can be achieved in a fairly high proportion of patients [44]. In patients who achieve complete response (CR), several high-sensitivity techniques are available for the detection of MRD, including (1) techniques that can detect residual monoclonal plasma cells within the BM, such as next-generation sequencing, and next-generation flow cytometry; and (2) techniques which can detect disease outside the BM by imaging techniques, such as computerized axial tomography scans, positron emission tomography, and MRI or by techniques that detect circulating plasma cells and disease markers in the peripheral blood [45]. Utilization of these advanced techniques allows the determination of the efficacy of antimyeloma treatments and early detection of MRD that can drive clinical relapse [43, 45]. Consequently, high-sensitivity techniques to detect MRD have been developed and validated [44, 46].

The achievement of MRD negativity after therapy, which is considered prognostically important for MM patients, has superseded the conventional CR and has been proposed as a surrogate endpoint for progression-free survival (PFS) and OS as confirmed by data from clinical trials and meta-analyses [43, 45]. So, MRD monitoring can guide treatment intensity, but the efficient application of tools used in monitoring in real-world clinical practice and their potential role to guide treatment-decision making are still open issues [44, 45, 46]. In clinical practice, MRD evaluation is usually performed prior to autologous HSCT, before starting maintenance chemotherapy, and then yearly whilst on maintenance treatment [24].

5. Treatment of relapsed and refractory MM

The choice of treatment regimen at relapse of MM is complicated and is affected by several factors, including the timing of relapse, response to prior therapy, aggressiveness of the relapse, and performance status of the patient [47]. The treatment choices in patients with relapsed MM include (1) salvage with the classical triplet regimens: VRd, VCD, and VTD; (2) daratumumab combinations: daratumumab, bortezomib, dexamethasone; daratumumab, pomalidomide, dexamethasone; DRd; (3) other drug combinations: KRd; ixazomib, lenalidomide, dexamethasone (IRD); elotuzumab, lenalidomide, dexamethasone (ERD); pomalidomide, daratumumab, dexamethasone; and pomalidomide, carfilzomib, dexamethasone; (4) other drugs (panobinostat, bendamustine, venetoclax, pembrolizumab) in various combinations; (5) other single-agent regimens: isatuximab, selinexor, and LGH-447 (pan PIM kinase inhibitor); (6) new immunotherapies, such as chimeric antigen receptor (CAR) T-cells; and (7) salvage or second autologous HSCT in patients relapsing after the first autologous HSCT [1, 47, 48].

Approval of several novel agents in the last decade has substantially changed the landscape of relapsed and refractory (RR-MM) [49]. During the past 2 decades, agents with novel mechanisms of action, such as monoclonal antibodies (MAbs) and histone deacetylase inhibitors (HDACs), have been applied to treat RR-MM [50]. Many clinical trials have assessed the effect and safety of MAbs in combination with proteasome inhibitors (PIs) or immunomodulatory agents (IMiDs) plus dexamethasone/prednisone for the treatment of MM [51]. The choice of therapy for RR-MM requires careful consideration of patient factors including age, frailty, comorbidities, and disease factors, such as symptom burden or biology, as well as treatment-related factors, including drug toxicities and responses to previous therapies. Also, a critical factor in selecting a certain agent is the patient’s sensitivity to lenalidomide and bortezomib at the time of relapse [49].

Combinatory strategies with carfilzomib, plus dexamethasone with or without lenalidomide have shown promising efficacy for patients with RR-MM in pivotal clinical trials [52]. The KRd regimen has been approved for the treatment of RR-MM based on ASPIRE clinical trial as the regimen has been shown to be effective and well tolerated in RR-MM patients [53, 54]. Additionally, a longer PFS was shown in patients achieving a very good partial response (VGPR), in patients who are lenalidomide naïve, and in those relapsing after previous autologous HSCT. Hence, previous autologous HSCT should not hamper the option for KRd therapy [53].

Daratumumab has demonstrated efficacy as monotherapy and combination therapy across several indications, both among newly diagnosed and refractory patients with MM. Daratumumab-based regimens are an effective treatment option across all lines of therapy, with highest response rate in first-line [55]. Daratumumab triplet regimen (DRd) has been shown to be superior to other triplet regimens for the treatment of RR-MM, and daratumumab monotherapy has been shown to be more effective than either single agent in heavily pretreated MM patients, suggesting that daratumumab is effective in the treatment of RR-MM [56]. The EQUULEUS and CANDOR clinical trials have established the efficacy of the DKd regimen (daratumumab, carfilzomib, and dexamethasone) in the landscape of bortezomib and lenalidomide refractory patients. Additionally, the split dosing schedule of the first dose of daratumumab, which was approved by the food and drug administration (FDA) in the USA based on the EQUULEUS trial, has significantly improved patient convenience [57]. Thus, novel and effective regimens are needed in patients with RR-MM who inevitably relapse after treatment containing PIs and IMiDs [57].

Despite the availability of several treatment options, most patients with MM will ultimately become refractory to the three classes of therapy that currently comprise the standard of care for MM: PIs, IMiDs, and MoAbs [58, 59]. Patients who are refractory to the three classes of antimyeloma drugs have poor survival [58, 59]. The current therapeutic approaches of triple-class refractory disease are limited with short-lived efficacy, and they include conventional chemotherapy; salvage autologous HSCT; and recycling of the previous regimens [58, 59]. Salvage high-dose chemotherapy (HDCT) and autologous HSCT are the treatment options for RR-MM [53, 60]. The deep remissions achieved with KRd translate into prolonged PFS, following salvage HDCT and autologous HSCT, and are enhanced by maintenance treatment [53, 60]. It is anticipated that selinexor, CAR T-cell therapy, and next-generation MoAbs will be available for triple-refractory disease in the near future [58, 59].

6. New therapeutic modalities in MM

6.1 CAR T-cell therapy

CAR T-cell therapy is a new cellular immunotherapy that can target and recognize antigens and kill tumor cells, but the efficacy and safety of this therapeutic modality are variable in different studies [61]. Treatment with CAR T-cells has dramatically changed the therapeutic effectiveness in high-grade (HG) B-cell malignancies [62]. However, safety and efficacy of CAR T-cell therapy are affected by the types of costimulatory molecules and CAR T-cell antigens [61].

In recent years, several novel therapeutic agents have improved the prognosis in patients with RR-MM but the prognosis of patients with EMD remains poor [63]. CAR T-cell therapy has demonstrated efficacy and safety in patients with RR-MM with B-cell maturation antigen (BCMA)-targeted and anti-BCMA-contained regimens with superior effectiveness [62, 64]. Despite the HG cytokine release syndrome (CRS) and immune effector cell-associated neurotoxic syndrome encountered, anti-BCMA CAR T-cell therapy allows a remission time for RR-MM patients with EMD, which could be maintained by bridging to HSCT and other therapies [63]. In patients with RR-MM having HR cytogenetics, anti-BCMA CAR T-cell treatment can improve the outcome, particularly if this form of therapy is given early in the course of the disease [64]. Primary resistance and relapse occur with single-target immunotherapy, but humanized bispecific BM38 CAR T-cells (that target both BCMA and CD38) have been shown to be feasible, safe, and significantly effective in patients with RR-MM [65].

6.2 Bispecific antibodies (BsAbs)

One of the hallmarks of MM is immune dysfunction and tumor-permissive immune microenvironment. Hence, ameliorating immune paresis can lead to improved outcomes [66]. However, the OS of triplet-class refractory MM remains poor [67].

BsAbs are novel immunotherapeutic approaches that are designed to bind antigens on malignant plasma cells and cytotoxic effector cells, such as T-cells and natural killer cells [67, 68]. The use of BsAbs early in clinical trials has shown a favorable safety profile and impressive preliminary efficacy in heavily pretreated patients with MM with response rates ranging between 61% and 83% [67, 68, 69]. However, CRS and neurotoxicity have been reported and resistance mechanisms were found to be related to the following: tumor-related features, T-cell characteristics, and impact of components of the immune suppressive tumor microenvironment [66, 69].

Various clinical trials are currently evaluating combining BsAbs with other agents, such as CD38 monoclonal antibodies, and immunomodulatory agents such as pomalidomide to further improve the duration and depth of responses [69]. Together with CAR T-cells, BsAbs represent a new dimension in precision medicine in MM [68].

6.3 Selinexor in the treatment of MM

Selinexor, which is an oral inhibitor of the nuclear export protein exportin-1, has been shown to be safe, tolerable, and effective in the treatment of RR-MM, particularly when combined with either dexamethasone alone or bortezomib and dexamethasone [70, 71, 72, 73, 74].

6.4 Venetoclax in the treatment of MM

B-cell lymphoma-2 (BCL-2) protein is an antiapoptotic protein expressed on clonal plasma cells in patients with MM [75]. Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that can induce apoptosis in MM cells [76]. MM subsets with t11,14 have overexpression of BCL-2 and can benefit from venetoclax when used either alone or in combination with other chemotherapeutic agents with an overall response rate of 40–100% [75]. However, the following side effects have been reported: gastrointestinal disturbances, cytopenias, infectious complications, and death [75, 76]. Venetoclax and dexamethasone combination has demonstrated efficacy and manageable safety in heavily pretreated patients with RR-MM having t11,14 [77]. Additionally, the combination of venetoclax, bortezomib, and dexamethasone has shown encouraging clinical efficacy with acceptable safety and tolerability in a phase-I trial [76].

6.5 Iberdomide in the treatment of MM

Cereblon is the essential binding protein of IMiDs [78, 79]. Almost one-third of MM patients have genetic alterations in cereblon by the time they become refractory to pomalidomide [78]. Three cereblon genetic aberrations that are associated with inferior outcomes to pomalidomide-based regimens have been described in patients who are already refractory to lenalidomide [78]. The biochemical activity of iberbomide, a potent cereblon E3 ligase modulator, translates into greater anti-MM activity than lenalidomide or pomalidomide in IMiD-sensitive and IMiD-resistant MM cell lines [80]. In patients with heavily pretreated RR-MM, the following combinations: iberbomide, daratumumab, dexamethasone; iberbomide, bortezomib, dexamethasone; and iberbomide, carfilzomib, dexamethasone have shown tolerable safety profile and promising efficacy [79, 81].

6.6 Melflufen in the treatment of MM

Melflufen, a peptide-drug conjugate that relies on a novel drug-delivery platform, has 50 times higher cytotoxicity than melphalan and it received accelerated approval by the FDA in the USA after showing potent antimyeloma activity based on the Horizon trial in February 2021, but it was withdrawn from the USA market in October 2021, based on the results of the Ocean trial, which showed inferior survival in patients treated with melflufen [82, 83].

7. Conclusions

The recent advances in therapeutics and diagnostics have revolutionized the management of patients with MM and have significantly improved survival outcomes. The introduction of quadruplet regimens in the treatment of patients with MM has translated into unprecedented therapeutic responses and survival outcomes. The current and future use of new therapeutic modalities such as CAR T-cells, BsAbs, selinexor, venetoclax, and iberdomide represents a new dimension in the era of precision medicine in MM.