Clinical Management of Triple-Class Refractory Multiple Myeloma: A Review of Current Strategies and Emerging Therapies

Abstract

Major progress has been made in the upfront treatment of multiple myeloma, but the disease ultimately relapses and leads to death in the vast majority of those afflicted. New treatment strategies and modalities are necessary to treat myeloma in relapse, particularly in cases of triple-refractory status defined by disease progression during or shortly after treatment with immunomodulatory agents, proteasome inhibitors, and anti-CD38 monoclonal antibody therapy. In this manuscript, we review recent promising developments in the treatment of triple-class refractory myeloma including bispecific antibodies and T cell engagers, chimeric antigen receptor cellular therapies, as well as chemotherapeutics with novel mechanisms of action.

Selinexor: Targeting a novel pathway in multiple myeloma

“…Furthermore, due to the multiply mutagenic nature of the disease, patients will typically receive at least several lines of therapy over the course of their disease, adding further complexity to treatment selection—thus, a range of distinct treatment options is needed, with optimized sequencing, and with therapies with activity in later‐line settings in patients with RRMM [16]. In particular, given the widespread use of PIs, lenalidomide, pomalidomide and anti‐CD38 mAbs in frontline approaches and/or earlier lines of treatment in the relapse setting, there is a specific need for efficacious treatment options in the triple‐class refractory setting—in which patients have MM that is refractory to a PI, an immunomodulatory drug and an anti‐CD38 mAb [17]—and the penta‐refractory setting (disease that is refractory to two PIs, two immunomodulatory drugs and an anti‐CD38 mAb) [18], which may arise as soon as after only two lines of therapy, in order to provide alternatives following failure of these standards of care.…”

“…In particular, given the widespread use of PIs, lenalidomide, pomalidomide and anti-CD38 mAbs in frontline approaches and/or earlier lines of treatment in the relapse setting, there is a specific need for efficacious treatment options in the triple-class refractory setting-in which patients have MM that is refractory to a PI, an immunomodulatory drug and an anti-CD38 mAb [17]-and the penta-refractory setting (disease that is refractory to two PIs, two immunomodulatory drugs and an anti-CD38 mAb) [18], which may arise as soon as after only two lines of therapy, in order to provide alternatives following failure of these standards of care.…”

Introductory Chapter: Update on Multiple Myeloma

“…Multiple myeloma (MM) is a heterogeneous and an incurable disease that is characterized by periods of remission alternating with relapses or progressions that ultimately lead to refractory disease [1,2]. High-risk (HR) MM is defined by the presence of specific cytogenetic and molecular abnormalities [3,4].…”

“…Over the last two decades, the utilization of various novel therapies such as proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), and monoclonal antibodies (MoAbs) in the treatment of patients with MM has improved the depth and duration of disease response and has eventually translated into improved overall survival (OS) [5,6]. The therapeutic modalities of MM include alkylating agents such as melphalan; corticosteroids including dexamethasone; anthracyclines such as liposomal doxorubicin; IMiDs such as lenalidomide, and pomalidomide; PIs including bortezomib, and carfilzomib; MoAbs such as daratumumab; histone deacetylase inhibitors such as panobinostat; exportin-1 inhibitors such as selinexor; BCL2 inhibitors such as venetoclax; chimeric antigen receptor (CAR) T-cells; and bispecific T-cell engaging (BiTE) therapy [1,4].…”

“…Management of the relapsed disease remains a critical aspect of MM care and an important area of ongoing research [19]. New treatment strategies and therapeutic modalities are needed to treat MM in relapse, particularly in case of triple-refractory disease [1]. Treatment of relapsed MM should depend on: the number of relapses encountered; the previous anti-myeloma treatment; the presence of de novo or acquired drug resistance; aggressiveness of disease relapse particularly in case of extramedullary disease, plasma cell leukemia, or clonal evolution [3,37].Minimal residual disease (MRD) is an important factor that can independently predict the prognosis of MM during treatment as undetectable MRD has been shown to improve PFS and OS regardless: disease status, prior transplant, or cytogenetic risk [38].…”