By: Nishanth Viswanath, PharmD Candidate c/o 2022

             Multiple myeloma (MM)  is a hematological malignancy characterized by an accumulation and proliferation of monoclonal plasma cells in the bone marrow. ¹ Throughout the course of the disease, malignant plasma cells induce an overproduction of non-functional immunoglobulin (paraproteins), which is evident during urine and blood screenings. ² The production of excess immunoglobulin results in various symptomatic markers during disease progression, most notably being osteolytic lesions, bone pain and fractures resulting from abnormal production of cytokines such as IL-1, IL-16, TNF-a.2 The net effect of this cytokine overproduction is  subsequent activation of osteoclasts, and inhibition of osteoblasts resulting in bone resorption. ² MM patients are also susceptible to renal disease induced by overload from monoclonal protein secretion, and hypercalcemia resulting from increased bone resorption.2 Additionally, patients are frequently anemic due to the infiltration of the MM clone in the bone marrow and poor response to erythropoietin. ² As of today, MM is incurable, as therapy is centered upon disease remission and maintaining quality of life. 

The treatment of MM has advanced greatly in recent years, providing patients with novel immunomodulating and targeted agents as front-line therapy. Current treatment formulas are centered around patients’ eligibility for autologous stem-cell transplantation (ASCL) , and subsequent maintenance therapy. ³ ASCL is a procedure which involves extraction of patients’ stem-cells followed by pharmacological induction-lymphodepletion, and re-infusion of stem cells to allow for hematopoiesis which is free of cancer. ² High dose induction therapy with melphalan (Alkeren) followed by ASCL was the first regimen to provide pronounced clinical efficacy in MM.⁴ Though still incorporated into some regimens, melphalan has been widely replaced by induction therapy with a triple combination of a proteasome inhibitor (PI), an immune-modulatory drug (IMiD), and a corticosteriod. ³ The most common induction regimen used currently involves the PI bortezomib (Velcade®), the IMiD lenalidomide (Revlimid®), and dexamethasone (Decadron®), followed by a further maintenance regimen of lenalidomide and/or bortezomib.³ 

Consequently, in recent years additional small molecule inhibitors, monoclonal antibodies, and other targeted agents have become widely available and possess the potential to redefine current treatment standards and increase survival in patients. Novel agents have widely replaced cytotoxic chemotherapy regimens, and frequently cause clinicians to question the necessity of stem-cell transplantation to induce remission. ³ Today, clinical research continues to elucidate innovative modes of MM remission and afford patients multiple lines of therapy.   

Immunomodulators:

Thalidomide (Thalomid®) was the first IMiD to be introduced to clinical practice in 1999, displaying remarkable anti-angiogenic and anti-proliferative properties along with durable response rates. ⁵ Though notorious for its teratogenic effects through inhibition of cereblon , which is a protein essential for embryonic morphogenesis, thalidomide exhibited unique efficacy in extending overall survival (OS) in MM patients through the same inhibitory mechanism. ⁵ Introduced in 2005, the second generation IMiD lenalidomide displayed more potent anti-MM action through its ability to induce cell-cycle arrest and apoptosis directly in MM cells. ⁵ Additionally, lenalidomide possesses multiple downstream pharmacological pathways which affect the microenvironment of MM cells including inactivation of nuclear factor-kB (NF-kB), down-regulation of C/EBPB and activation of caspase 8. ⁵ Through these mechanisms, lenalidomide has been established as the backbone of the majority of induction and maintenance regimens in MM pharmacotherapy. ³

Despite the pronounced efficacy of lenalidomide in both front-line and maintenance therapy, many patients experience disease progression and seek further management. In this population, pomalidomide (Pomalyst®) is clinically effective, and has been the standard of care in the relapsed/refractory setting in recent years. ⁶ Pomalidomide is a novel IMiD that is constitutionally similar to lenalidomide; certain structural modifications allow pomalidomide to maintain a longer duration of action through dampened renal clearance. ⁶ Further research of IMiDs focuses on the clinical development of iberdomide, a novel cereblon E3 ligase modulator that has displayed antiproliferative effects on B‐lymphocyte‐derived tumor cell lines in vitro. ⁷ Though only introduced in phase 1 studies thus far, iberdomide has displayed significant immunomodulatory effects by reducing CD19+ B‐lymphocyte and CD3+ lymphocyte counts in peripheral blood and reductions in IL‐1B with high potency, causing it to be effective at strengths as low as 0.3mg. ⁷ Through its increased binding affinity for cereblon, iberdomide shows early potential to overcome lenalidomide and pomalidomide resistance, and be efficacious in the heavily pre-treated population. ⁷ Further research will elucidate the potential synergistic effects of iberdomide in combination with other anti-MM agents in the front-line and refractory setting. 

Proteasome inhibitors:

Since the approval of bortezomib in 2003, PIs have become a therapeutic mainstay for both the initial and refractory treatment of MM. ⁸ PIs exert their pharmacological activity by inhibition of the 26s proteasome unit, which intrinsically degrades misfolded/mismatched proteins targeted by ubiquitin. ⁸ Recycling of damaged and unrepaired proteins is essential for the natural function of MM cell lines, and results in their proliferation and survival. ⁸ Inhibition of proteasomes disrupts this cycle, and results in subsequent degradation of the MM cell. ⁸ Early clinical research of PIs revealed that malignant cells require an increased amount of protein recycling and production due to their rapid rate of division, making proteasomes a suitable target to maintain efficacy and diminish adverse reactions. ⁸ Though efficacious, bortezomib resistance frequently occurs and results in treatment failure. Carfilzomib (Kyprolis®) is an epoxyketone PI that has displayed inhibitory properties of bortezomib-resistant MM cell lines, and is reserved for patient populations that are refractory to bortezomib. ⁸ As bortezomib inhibits proteasomes via a reversible mode of substrate binding, carfilzomib acts in an irreversible fashion further increasing efficacy. ⁸ Additional advancements in the clinical research of PIs resulted in ixazomib (Ninlaro®), which was the first orally administered PI to be incorporated into practice. ⁸ Initial confirmatory trials of ixazomib displayed remarkable efficacy in combination with lenalidomide and dexamethasone vs. lenalidomide and placebo, displaying an overall response rate (ORR) of 78.3% and 71.5% respectively (P = 0.03). ⁸

Bortezomib, carfilzomib and ixazomib all act pharmacologically on the B5 subunit of intracellular proteasomes. ⁸ The investigational PI marizomib enhances this degree of action by irreversibly binding to the B5 subunit, along with the B1 and B2, the other major catalytic sites of enzymatic activity. ⁸ In a phase two study, marizomib was administered to 68 patients who were refractory to prior carfilzomib and a partial response (PR) was observed in five patients (7.4%). Additionally, another notable attribute of marizomib is the potential to act on intracranial myeloma lesions and display clinical characteristics in brain metastases, rendering it one of the few agents to have efficacy in metastatic disease. ⁸ Further work will need to be done to evaluate the utilization of marizomib in doublet and triplet-based regimens, as well as the clinical efficacy of other investigational PIs such as oprozomib and delanzomib. ⁸

Monoclonal Antibodies:

The initial use of antibody-based therapies in MM began with the introduction of elotuzumab (Empliciti®). Elotuzumab is an IgG1 monoclonal antibody that targets the signaling lymphocyte activation molecule member family 7 (SLAMF7) protein. ⁹ By binding to SLAMF7, elotuzumab exerts antibody-dependent cellular cytotoxicity by facilitating the interaction between natural killer cells and malignant MM cells. ⁹ Though found to be non-efficacious as a single agent, elotuzumab has demonstrated objective clinical efficacy in combination with lenalidomide, dexamethasone, and/or bortezomib in the refractory setting with minimal increments in toxicity. ¹⁰ Another early antibody-based agent in the treatment of MM is daratumumab (Darzalex®), which is a first in class anti-CD38 modulator with antitumor activity. ¹⁰ CD38 is a transmembrane glycoprotein which facilitates communication with certain cell surface receptors, causes an influx of intracellular calcium, and mediates signal transduction in lymphoid and myeloid cells. ¹⁰ By inhibiting CD38, daratumumab induces cellular toxicity, apoptotic effects caused by inhibition of cellular signaling pathways, and immunotherapeutic effects by generating a greater expansion of clonal T-effector cells. ¹⁰ The clinical efficacy of daratumumab has been well established, causing it to be indicated in front line and refractory settings, and in combination with a variety of IMiDs, PIs, and cytotoxic agents. ¹⁰ 

Isatuximab (Sarclisa®) is a second-generation anti-CD38 antibody that displays similar in-vitro anti-MM activity to daratumumab, with certain pharmacological modifications rendering it more potent. ¹⁰ Having slightly more affinity to the CD38 epitope than daratumumab, isatuximab has stronger activity in inhibiting intracellular calcium influx and cross-cell communication. ¹⁰ Additionally, isatuximab  induces direct apoptosis without cross linking of receptors, leading to more efficient pharmacodynamic activity. ¹⁰ This biological activity translates into clinical efficacy in the refractory population, as isatuximab has demonstrated notable activity in improving progression-free survival (PFS) in MM patients who have relapsed after therapy with lenalidomide and a PI. ¹⁰ In the ICARIA-MM trial, 307 patients who were refractory to at least two therapies including lenalidomide and a PI were randomized in a 1:1 ratio to receive either pomalidomide + dexamethasone (Pd) or isatuximab + pomalidomide + dexamethasone (Isa-Pd). ¹¹ Both groups received therapy in 28 day treatment cycles until progression or unacceptable toxicity. ¹¹ At follow up, the median duration of treatment was 41 weeks for Isa-Pd group  compared to 24 weeks for Pd group, and the average PFS was 11.53 months (95% confidence interval: 8.94 – 13.9) in the Isa-Pd group and 6.47 (95% confidence interval:  4.47 – 8.28) in the Pd group. ¹¹ This improvement in average PFS translated into a 40% reduction in the risk of disease progression in a heavily pre-treated population. ¹¹ Future studies of isatuximab will be needed to elucidate its efficacy in combination with PIs and other chemotherapeutic regimens. ¹⁰ 

In spite of the availability of targeted agents with multiple pharmacological pathways and modes of action, many patients are refractory to all established lines of therapy. Since many patients who progress on all available agents maintain durable performance statuses and present with further treatable malignancies, this population represents a significant unmet need in the treatment of MM. ¹² The capacity of belantamab mafodotin (Blenrep®) to serve such patients indicates an important line of therapy in refractory MM. ¹² Belantamab mafodotin is an anti B-cell maturation agent (BCMA), and is the first antibody-drug conjugate (ADC)  to be used in MM therapy. ¹² ADC-based therapy involves the use of a targeted monoclonal-antibody (mAB), tethered to a cytotoxic agent adjoined by a linking structure. ¹² This mode of pharmacological activity allows for the use of a highly effective cytotoxic molecule, augmented by the targeted effects of a mAB causing the therapy to become more directed and lead to less off-target adverse events. ¹² ADCs have been broadly explored in clinical trials for many years, but have only been implicated in clinical practice recently with agents such as belantamab mafodotin. ¹² BCMA, also known as CD269, is a tumor necrosis factor transmembrane receptor which plays a critical role in B-cell maturation of both malignant, and natural cells. ¹² Additionally, BCMA enhances the survival of plasmablasts and plasma cells but is not critical for the homeostatic mechanisms of B-cell stability. ¹² This makes BCMA an ideal target for the cytotoxic effects of monomethyl-auristatin F (MMAF), which is a small molecule agent that is adjoined to the linker within belantamab mafodotin and becomes internalized and released once BCMA is targeted. MMAF is a microtubule inhibitor that induces apoptosis of B-cells through antibody-dependent cellular toxicity and antibody-dependent cellular phagocytosis.13 In phase III studies, 30% [21%, 43% (97.5% CI)] of patients who received belanatamab mafodotin and received at least 3  prior lines of therapy experienced an objective response to therapy, and 2% of patients were complete responders. ¹³ An interesting toxicity associated with belantamab mafodotin however is frequent corneal and ocular events resulting in microcystic epithelial damage. ¹² The role of belantamab mafodotin in this toxicity profile is unclear, but it is known that other targeted agents that incorporate MMAF host a similar degree of adverse events. ¹² As BCMA is not expressed in the cornea, it is thought that non-specific uptake of MMAF in the cornea contributes to the destruction of actively dividing cells in the basal layer of the cornea. ¹² Certain degrees of this toxicity can result in vision loss, dry eyes, and corneal ulceration as denoted by a black box warning. ¹³ Because of this, it is imperative that patients undergoing therapy with belanatamab mafodotin are monitored by both oncologists and ophthalmologists to assess toxicity levels. ^12,13

Novel nuclear transport regulation:

The intermembrane domains of both hematological and solid tumor cells maintain a mechanism that mediates the transfer of exportin 1 (XPO1) between the nucleus and cytoplasm. ¹⁴ This transport mechanism facilitates the export of tumor suppressor proteins that may potentially induce apoptosis of malignant cells when retained. ¹⁴ Normal homeostatic activity within malignant cells prefers the export of these tumor suppressor proteins out of the cell, where they are rendered unusable. ¹⁴ The discovery of selinexor (Xpovio®) caused this mechanism to be one of particular interest in MM therapy, as selinexor works by inhibiting nuclear export action in cancer cells. ¹⁴ Such agents are considered selective inhibitors of nuclear export (SINE), and play a major role in the treatment of refractory MM due to their favorable toxicity profile, ease of administration, and synergistic effects with other common agents. ¹⁴ Additive administration of selinexor with dexamethasone results in coactive inhibition of MM proliferation through further phosphorylation of glucocorticoid receptors, notably in dexamethasone resistant cell lines. ¹⁴ Additionally, selinexor in combination with PIs reduces Akt and Bcl-2, activates various caspases and their association with autophagy-inducing p62 and LC3II, and increases nuclear retention of inactivating IkB-NFkB complexes, even in MM cells previously resistant to PIs. ¹⁴ Moreover, selinexor also diminishes osteoclast formation via both, inhibition of IL-2, IL-10, VEGF, and MIP1B secretion, and blockade of RANKL-induced NFATc1 induction in osteoclast precursors. ¹⁴ These pharmacological characteristics cause selinexor to be a favorable agent in combination therapy, as it is indicated in combination with bortezomib and dexamethasone for the treatment of MM in patients who have received at least one prior therapy. ¹⁵ 

Therapeutic peptide vaccination:

Therapeutic vaccination of neoplasms and malignancies has remained a concept explored in a variety of tumor types, since the introduction of early agents such as sipuleucel-T (Provenge®) and talimogene laherparepvec (Imlygic®) in prostate cancer and melanoma respectively. ¹⁶ Vaccination efforts in MM have been partially explored, with a primary limitation being discovering an antigen that is widely expressed on malignant cells in MM for an immune response to be mounted. ¹⁶ Mucin 1 (MUC1) is an antigen that is present on 90% of malignant MM cells, and is a re-engineerable glycoprotein that is found on many other cancer cells as well.16 Initial vaccines using MUC1 as an antigen have displayed inconsistent efficacy due to the variability of antibodies produced, which are unable to differentiate between endogenous and synthetic MUC1. ¹⁶ Additionally, previous modulations of MUC1 to create a therapeutic vaccine candidate have failed in causing all relevant major histocompatibility complexes (MHC) to recognize the epitope and generate an adequate immune response to malignant cells. ¹⁷ VXL-100, or ImMucin, is a novel therapeutic vaccine that mimics MUC1 and contains the entire MUC1 signal peptide (SP) domain, and is proposed to mount more efficacious anti-cancer immunotherapy effects. ¹⁷ The clinical efficacy of ImMucin thus far is limited but compelling, as evidenced in  an early phase 1 study seven of nine patients who possessed stable disease maintained their disease status for at least 60 weeks. ¹⁷ Proper dosing regimens and further studies may elucidate the use of ImMucin in induction of minimal residual disease (MRD) and possibly complete disease remission. ¹⁷  

Conclusion:

The treatment paradigm of MM has revolutionized over the past few decades and has significantly improved clinical responses and overall survival in patients. The multitude of possible regimens and lines of therapy has afforded patients many options in front line and refractory disease, causing patients to maintain stable disease and live longer. Lenalidomide and or PI use post ASCL transplant has remarkably furthered disease control and remission, and has set a standard for early pharmacotherapy and management. ⁵ Novel agents in MM therapy may augment this efficacy, and lead to the possibility of minimal residual disease statuses. Further research will reveal that utility of such agents in combination, and the potential for the therapeutic vaccine ImMucin. 

References:

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