Noa Biran

Current approaches to the management of multiple myeloma (MM), in particular the introduction of proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs), have improved the survival of patients. However, nearly all patients ultimately relapse as drug-resistant subclones of the disease emerge. In general, treatment principles for relapsed and refractory (RR) MM depend on host factors as well as the genetics and biology of the disease. Both PI- and IMiD-based therapies are especially active in RRMM, and multidrug combinations are particularly useful in overcoming resistance in this setting. The addition of both commercially available and investigational agents to the treatment backbone of PI- and IMiD-based regimens have shown significant activity in the RR setting and are areas of current study. In particular, immune-based therapy, epigenetic modulators, and transcriptional regulators are in various stages of drug development and have shown promising activity in patients with RRMM. This review will discuss the mechanisms, clinical application, and common toxicities of both commercially available and investigational agents used in RRMM and provide a generalized and rational approach to management.

Multiple myeloma (MM) is a neoplasm of plasma cells and accounts for 10% to 15% of hematologic malignancies. Current approaches to the management of newly diagnosed MM, in particular the introduction of proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs), have significantly increased survival from a median of 3 to 5 years to a 5-year survival of >70% in transplant-eligible patients.

However, nearly all patients, even with the achievement of a high-quality and prolonged duration of response with initial therapy, ultimately relapse and require further therapy. In recent years, significant progress has been achieved in the characterization of MM pathophysiology in terms of gene mutations, structural chromosomal lesions, and transcription profiles.

There is no standard sequence of therapy in relapsed (ie, previously treated myeloma that progresses and requires the initiation of salvage therapy) or relapsed/ refractory MM (RRMM), defined as those who, having achieved a minor response or better, relapse/progress while on salvage therapy or experience progression within 60 days of their last therapy. RRMM constitutes a specific and unmet medical need, as median overall survival (OS) ranges from 6 months to 9 months, and responses to treatment are characteristically short.

Each line of therapy results in progressively shorter durations of response, reflecting the emergence of drug resistance and development of new tumor clones.

The initiation and progression of MM is influenced by mutations, translocations, and epigenetic changes, many of which have been characterized through conventional cytogenetics and fluorescent in situ hybridization (FISH). These mutations occur in different pathways and genes, which deregulate the intrinsic biology of the plasma cell or the preplasmacytic compartment (ie, clonal, preplasmacytic B cells that are not recognized by CD38/CD45 flow cytometry). Sequential acquisitions of multiple genetic events over time and through a branching, nonlinear pathway, lead to disease progression and, ultimately, treatment-resistant disease.

This results in a complex pathophysiology and heterogeneous genetic lesions of the tumor cells in the setting of genomic instability and molecular evolution of the disease over time and poses challenges to the efforts of improving treatment using targeted therapy. Tumor heterogeneity can be present at diagnosis, and certain tumor clones can dominate over others, which may shift over time, and influence specific classes of agents used during the course of treatment.

Subclonal heterogeneity exists in MM, as demonstrated by whole genome sequencing and next-generation sequencing approaches.

Risk Stratification Determines Prognosis but Not Therapy

Although some of the genes and pathways involved in progression of disease have been elucidated, there are limitations to their applicability. In fact, recent sequencing data have demonstrated there is no single genetic change underlying this process that can be targeted therapeutically. Additionally, there is no uniform consensus on what causes these genetic events to occur. Preclinical models do not always translate in vivo, especially for MM, making it difficult to translate even the most promising investigational therapy from preclinical to clinical trials and to individualize the use of targeted agents for patients with specific molecularly defined subsets.

Risk stratification in MM determines prognosis and can influence treatment strategies, although there is a lack of guidelines regarding management strategies for standard- versus high-risk patients. It is essential to define risk in patients with MM, because high-risk patients will have a median OS of 2 years or less, while standard-risk patients survive more than 10 years.

Consensus guidelines from the International Myeloma Working Group support a comprehensive cytogenetic and FISH evaluation in all patients with MM at the time of diagnosis and also at relapse.

In addition, a patient is considered to have high-risk disease if the high-risk genetic features are found at diagnosis, at relapse, or at progression. However, it is important to note that at this time, with the exception of use of bortezomib for t(4;14), there is no different treatment recommended for patients in the high-risk group compared with those with standard risk.

summarizes risk classification and frequency of each genetic abnormality at diagnosis as it pertains to cytogenetics, FISH, and gene expression profiling.

Table 1. Genetic Risk Stratification in Multiple Myeloma and Frequency of the Genetic Abnormality at Diagnosis

*Poor-risk abnormality can be overcome with novel therapy.

Therapeutic decisions are often dictated by practitioner- specific as well as patient-specific factors. In general, host factors, biology of disease, and genetic factors are all taken into consideration. For example, a patient with high-risk disease with adequate performance status may be treated with highly active 3- or 4-drug combinations to achieve a maximal response in the relapsed or refractory setting, although current prospective evidence does not entirely support a multidrug approach. Conversely, patients with favorable cytogenetics, indolent clinical features, and prolonged response to prior therapy may require less intensive therapy, perhaps an IMiD- or PI-based doublet. Participation in clinical trials is an important aspect of therapy in this patient population.

Approved Agents in the Treatment of Relapsed and Refractory Multiple Myeloma

Although cytogenetics and FISH allow us to begin to understand the genetics of MM, these studies are limited to a number of mutations, while MM is characterized by a wide array of molecular heterogeneity. Newer technologies such as global gene and micro-RNA expression, genome-wide DNA profiling, and next-generation sequencing technology will ultimately allow us to better investigate the genomic alterations underlying the biological and clinical heterogeneity of MM.

High-throughput technologies have allowed a better comprehension of the molecular basis of disease and early identification of high-risk patients. With time, we expect that these will provide more sensitive, accurate, timely, and cost-efficient methods of risk stratification.

Multiple new therapeutic agents have been developed over the past decade, and the repertoire of treatment options for RRMM has expanded noticeably. The PIs bortezomib and carfilzomib, as well as the IMiDs thalidomide, lenalidomide, and pomalidomide, are now the cornerstones of almost all regimens in the RR settings. Combinations incorporating a PI and/or an IMiD in conjunction with corticosteroids and alkylating agents are often utilized.

Proteasome inhibitors exert their mechanism of action through the ubiquitin-proteasome signaling pathway, which regulates both cellular homeostasis and survival and represents the predominant nonlysosomal route for degradation of misfolded, oxidized, or otherwise damaged protein.

The proteasome is a multiprotein enzyme complex, made up of two 19S caps flanking the 20S proteasome catalytic core, and degrades proteins by a conjugation of multiple ubiquitin molecules that target the substrate.

The ubiquitin-proteasome pathway activates the transcriptional factor nuclear factor-&kappa;B (NF-&kappa;B), which induces expression of growth and angiogenic factors, and promotes myelomagenesis. However, PIs have also been found to act by NF-&kappa;Bindependent mechanisms: PIs induce degradation of cellcycle regulatory proteins, leading to cell apoptosis; they increase the levels of cell-cycle inhibitors, resulting in G1/S cell-cycle arrest and apoptosis and activate the JNK-signaling pathway, promoting activation of caspase-3- and caspase-8-dependent cell death; and they interfere with tumor cell&ndash;stroma cell interaction by elevation of I-&kappa;B levels, resulting in the inhibition of angiogenic cytokines and adhesion-molecule synthesis.

Bortezomib, a dipeptide with a boronic acid moiety, which binds to the 26S catalytic site of the proteasome, was the first PI to be introduced to clinical practice. It has been approved for the upfront and relapsed setting, and most recently for patients with a suboptimal response to bortezomib monotherapy in conjunction with dexamethasone.

A subgroup analysis demonstrated that bortezomib is superior to dexamethasone in patients aged 65 or older and with high-risk characteristics including >1 prior therapy, International Staging System stage 2 or 3, and refractory to last prior therapy.

Furthermore, the poor prognosis associated with chromosome 13q deletion and t(4;14) is overcome with the use of bortezomib.

The most common toxicities associated with bortezomib are peripheral neuropathy, gastrointestinal symptoms, fatigue, thrombocytopenia, and reactivation of herpes zoster. As such, it is essential to use concurrent antiviral prophylaxis. In the VISTA study of patients treated with melphalan and prednisone with or without intravenous (IV) bortezomib, 13% of patients in the bortezomib group experienced grade 3 peripheral neuropathy, with less than 1% having grade 4.

A pooled analysis of 2 large phase II trials (SUMMIT and CREST) was conducted to assess the frequency, characteristics, and reversibility of bortezomib- induced peripheral neuropathy. Bortezomib was held, dose-reduced, or discontinued depending on peripheral neuropathy severity. Overall, 37% of those treated with 1.3 mg/m2 and 21% of those treated with 1.1 mg/m2 had treatment-emergent peripheral neuropathy, including 9% with grade 3 or higher. Neuropathic pain and other symptoms resolved to baseline levels or improved in 71% of patients. Resolution or improvement occurred during treatment in 37% of patients and after treatment in 31% of patients. The median duration from the last dose to resolution or improvement of peripheral neuropathy was 47 days (range 1 to 529 days). Efficacy was not related to dose modifications for grade 2 or higher neuropathy.

Subcutaneous (SC) bortezomib was shown to be noninferior in efficacy to the IV route, with a significantly improved safety profile, in particular, decreased peripheral neuropathy of any grade (38% vs 53%, P = .044) and grade 3 or worse (6% vs 16%, P = .026), and it should be considered standard of care.

A retrospective analysis of 3 different prospective studies compared 3 dosing schedules of bortezomib, melphalan, and dexamethasone (VMP). Efficacy of VMP and cumulative dose of bortezomib were similar with weekly versus twice-weekly bortezomib.

The rates of peripheral neuropathy and associated discontinuations and dose reductions were lower with VMP regimens using primarily weekly bortezomib dosing compared with twice weekly (13% grade 3 or higher peripheral neuropathy in VISTA biweekly, 14% in GIMEMA biweekly, and 7% in GIMEMA once-weekly dosing). However, the results of this study should be interpreted with caution, because the proportion of planned bortezomib dose actually delivered was significantly lower in the twiceweekly schedules compared with the once-weekly schedules, due to protocol-specified dose reductions (57% and 62.3% vs 86.1% and 90.4%, respectively). Additionally, it is difficult to interpret a betweenstudy comparison, as potential confounding factors can exist across studies. No prospective randomized study of once-weekly versus twice-weekly bortezomib dosing has been done to date.

A significant number of patients treated with bortezomib, even with once-weekly subcutaneous dosing, continue to have chronic, sometimes debilitating irreversible neuropathy.

Carfilzomib, a novel and irreversible epoxyketone PI that is selective for the chymotrypsin-like protease and binds to the &beta;-5 subunit of the 26S proteasome, was shown in preclinical studies to induce cell apoptosis in myeloma cell lines and in primary myeloma cells from patients whose disease was resistant to therapies including bortezomib.

In the pivotal single-arm phase II PX-171-003-A1 study, patients with a median of 5 prior lines of therapy receiving carfilzomib alone, 80% of whom were refractory to or intolerant of bortezomib and lenalidomide, achieved a 23% overall response rate (ORR)defined as partial response (PR) or better.

Median duration of response (DOR) and OS were 7.8 and 15.6 months, respectively. Carfilzomib was given as 20 mg/m2 IV twice weekly for 3 of 4 weeks in cycle 1 and 27 mg/m2 for up to 12 cycles thereafter with low-dose dexamethasone as premedication for the first 2 cycles. As a single agent, carfilzomib was not able to overcome the impact of high-risk cytogenetics.

Common adverse events (AEs) associated with carfilzomib included anemia, fatigue, nausea, and thrombocytopenia. The incidence of peripheral neuropathy was much less than that observed with bortezomib, present in 12% any grade and only 1% grade 3 or greater. Dyspnea was seen in 34% of patients but thought to be related to carfilzomib in 17% and grade 3 or greater in 3.4%.26 The safety profile has been confirmed by data from 4 phase II studies including 526 RRMM patients treated with carfilzomib.

Carfilzomib is safe in patients with varying degrees of renal impairment, including those on chronic hemodialysis, which does not influence pharmacokinetics of carfilzomib. In addition, renal impairment did not affect response or AEs associated with carfilzomib.30 In the phase III ASPIRE trial of lenalidomide and dexamethasone with or without carfilzomib, dyspnea of any grade was seen in 19.4% versus 14.9% of the carfilzomib and control group, and grade 3 or higher in 2.8% versus 1.8%, respectively.

Cardiac failure of any grade was seen in 6.4% of the carfilzomib group versus 4.1% of the control group. Recent studies have shown that doses of carfilzomib that are twice the amount of those approved (up to 70 mg/m2 once weekly) are generally well tolerated when infused over 30 minutes.

Several PIs, including ixazomib, marizomib, and oprozomib, are under investigation in phase I/II clinical studies. The investigational PI with which there is the most experience is ixazomib (MLN9708), a second-generation boronate PI, the first oral PI to be evaluated in MM clinical trials. Unlike bortezomib, at higher concentrations, it can inhibit the caspaselike proteolytic &beta;-5 site of the 20S proteasome and trypsin-like &beta;-2 proteolytic sites.

A phase II study evaluated ixazomib administered as a single agent in patients with RRMM who were bortezomib na&iuml;ve. With a median follow-up of 7 months, OS at 6 months was 96%. Common grade 3 or 4 AEs included diarrhea, thrombocytopenia, nausea, and fatigue and occurred in 56% of patients.

In a preliminary analysis from a phase Ib/II study of oprozomib and dexamethasone in 29 patients with RRMM and a median of 3 prior lines of therapy, best ORR was 41.7%, and most common toxicities included diarrhea (83%), nausea (79%), and vomiting (62%), in addition to anemia and pneumonia.

The mechanism of IMiDs has not been completely elucidated. Following more than a decade of research on the mechanism of thalidomide, the first IMiD to be introduced into the MM armamentarium, preclinical studies identified E3 ligase protein cereblon as a direct molecular target for the teratogenicity of thalidomide, binding directly to thalidomide analog affinity beads. Cereblon, of which its auto-ubiquitination was inhibited by thalidomide, is highly conserved from plants to mammals, and the mRNA for human, rat, and mouse cereblon is ubiquitously expressed.

Cereblon has recently been proposed as a mediator of the anti-MM activity of lenalidomide and pomalidomide as well

and is a substrate receptor of Cul4- E3 ubiquitin ligase complex, and thus recognizes proteins destined for degradation. Binding of cereblon and IMiDs inhibits or modifies the specificity of the entire ubiquitin proteasome complex, which partly explains their antitumor effects. In addition, a correlation between cereblon gene expression and effectiveness of treatment in MM patients treated with IMiDs was confirmed.

Follow-up studies have suggested that IMiDs are not simply cereblon antagonists but, instead, alter the substrate specificity of cereblon to include proteins important in myeloma. Numerous novel cereblon-binding proteins altered in MM cells after IMiD treatment have been implicated, particularly the Ikaros transcription factor zinc-finger proteins 1 and 3, IKZF1 and IKZF3, which were previously demonstrated to regulate B-cell activation and differentiation. Recently, 2 landmark studies both independently established that IKZF1 and IKZF3 are substrates of cereblon ubiquitin ligase.

Analysis of myeloma cell lines have linked lenalidomide&rsquo;s antimyeloma activity to down-regulation of IKZF1 and IKZF3, and conversely, expression of the stabilized versions of IKZF1 or IKZF3 conferred lenalidomide resistance to myeloma cells.

Another study found that low IKZF1 expression levels were associated with a poor response to IMiDs and shorter OS.

This observation may be explained by the fact that myeloma cells surviving with low IKZF1 are less dependent on IKZF1-associated signaling for proliferation and survival and are therefore resistant to IMiDs. Thus, novel cereblon-binding proteins altered in MM cells after IMiD treatment such as IKZF1 and IKZF3 may serve as biomarkers for clinical outcomes.

In the initial phase II study of single-agent thalidomide, 84 individuals with RRMM received thalidomide at doses ranging from 200 to 800 mg daily. The ORR was 32%, with an OS rate of 48%.

Importantly, in RRMM, thalidomide plus dexamethasone has not been compared prospectively with high-dose dexamethasone alone. However, in a study comparing thalidomide and dexamethasone to dexamethasone alone in 470 patients with newly diagnosed MM, common AEs included constipation (49.6% vs 21.1%), peripheral edema (34.2% vs 24.6%), tremor (26.5% vs 12.5%), fatigue (21.4% vs 15.5%), and deep vein thrombosis (11.5% vs 1.7%).

Unlike the peripheral neuropathy seen with bortezomib, the peripheral neuropathy associated with thalidomide is caused by loss of large-diameter myelinated nerve fibers and axonal injury and is directly related to cumulative exposure.

Lenalidomide is a structural analog of thalidomide and was developed in the search for a drug with more potency and less toxicity. Two large multicenter phase III studies including a total of 704 RRMM patients, MM-009 and MM-010, demonstrated the activity of lenalidomide plus dexamethasone (Ld).

Compared with placebo/dexamethasone, Ld induced a significantly higher ORR (60% vs 24%; P <.001), complete response (CR) (16% vs 3.4%; P <.001), and OS (HR 0.66; P = .03). A subset analysis, however, demonstrated a significantly greater median OS (not reached vs 30.8 months; P = .028) and progression-free survival (PFS) (14 vs 9.5 months; P = .047) in patients who were in their first relapse compared with patients who had >1 line of prior therapy.

This may confirm the notion that MM becomes more heterogeneous with each line of therapy and that due to various subclones and resistant disease, more intense therapy is required as the disease progresses.

Significant toxicities associated with Ld include myelosuppression and venous thromboembolic events. Thromboprophylaxis is required when using an IMiD and a corticosteroid.

Pomalidomide is also a structural analog of thalidomide and was developed before lenalidomide. In the pivotal randomized phase II study of pomalidomide with or without dexamethasone, MM-002, patients with RRMM who were resistant to both IMiDs and PIs (including both bortezomib and carfilzomib) received either Pd (pomalidomide 4 mg daily days 1-21 in a 28-day cycle with dexamethasone) or pomalidomide alone.

ORR was 34% in those who received pomalidomide and dexamethasone, and median PFS was significantly longer for the combination (4.2 vs 2.7 months, P = .003). Median DOR was 8.3 versus 10.7 months in patients who received pomalidomide with or without dexamethasone, respectively. More importantly, activity was shown in patients with high-risk features including del 17p, t(4;14) and in those with extramedullary disease.

Table 2. Selected Multi-Drug Combination Regimens in the Relapsed/Refractory Setting

Abbreviations: NR = not reached; ORR = overall response rate (partial response or better); OS = overall survival; PFS = progression-free survival.

Pomalidomide plus low-dose dexamethasone was compared with high-dose dexamethasone in a 2:1 randomized phase III study involving 302 patients with RRMM and demonstrated the superiority of the combination in terms of both PFS (4 vs 1.9 months, P <.0001) and OS (12.7 vs 8.1 months, P = .028), including in patients with moderate- to high-risk cytogenetics.

Favorable tolerability was observed. Common AEs included myelosuppression, with minimal peripheral neuropathy (1%) and venous thromboembolic events (1%). Discontinuation due to AEs occurred in 9% of patients; the main reasons for therapy discontinuation were infections (34%), pneumonia (14%), thrombocytopenia (22%), and febrile neutropenia (48%).

Selected Investigational Agents Currently in Clinical Trials

highlights selected multidrug combination regimens that have shown significant activity in RRMM.

Translating promising investigational therapies from the bench to the bedside has presented a challenge in the treatment of RRMM. Several recent advances in the understanding of the pathogenesis of MM have led to promising therapeutic agents and combinations.

Epigenetic changes have been shown to play a role in MM pathogenesis, as several genes for histonemodifying enzymes (such as MMSET, MLL, and MLL2) have been found to be recurrently mutated in MM cells.

Through increased acetylation of intracellular protein, alterations occur in transcription and activity of tumor suppressor genes. Deacetylase inhibition has demonstrated preclinical synergy with bortezomib in MM cells.

As such, pan-histone deacetylase inhibitors such as vorinostat, panobinostat, and romidepsin, as well as the HDAC6-specific inhibitor ACY-1215, have demonstrated significant anti-MM activity in preclinical studies and have been evaluated in the relapsed and refractory setting in various combinations.

In the phase I multicenter, open-label, doseescalating study of vorinostat in combination with lenalidomide and dexamethasone in patients with relapsed MM or RRMM, a confirmed PR or better was reported in 14 of 30 (47%) patients, including 31% of patients previously treated with lenalidomide and 32% of patients previously treated with PIs.

This suggests that vorinostat in combination with lenalidomide and dexamethasone has the potential to recapture response in patients who are lenalidomide- and bortezomib-refractory. The most common AEs were anemia (58%), thrombocytopenia (58%), diarrhea (55%), fatigue (55%), and cough (45%). Side effects were generally manageable with dose reduction and supportive care. Vorinostat, although not approved for treatment of MM, is included in the National Comprehensive Cancer Network (NCCN) guidelines.

In the phase II study PANORAMA 2, of panobinostat 20 mg orally 3 times weekly, bortezomib 1.3 mg/m2 twice weekly, and dexamethasone 20 mg on days of and after bortezomib, 34.5% of heavily pretreated patients who were bortezomib-refractory achieved a PR or better.

The phase III trial PANORAMA 1 found panobinostat, bortezomib, and dexamethasone to significantly improve PFS compared with placebo, bortezomib, and dexamethasone, with a median of 12 versus 8.1 months (P <.0001) in 387 patients who received 1 to 3 prior therapies and were not bortezomib-refractory.

Common grade 3 or greater toxicities included thrombocytopenia (67% vs 31%), neutropenia (35% vs 11%), and diarrhea (26% vs 8%). On-treatment deaths occurred in 8% and 5%, respectively.

Immune-based therapies have shown both preclinical and clinical activity in patients with RRMM. Use of monoclonal antibodies against specific surface molecules in MM cells have shown promising activity.

Elotuzumab, which is directed against CS-1, a glycoprotein that is highly specific to plasma cells (also expressed in natural killer cells and CD8+ T cells), is the best evaluated agent of the monoclonal antibodies. Enrollment for a phase III trial comparing lenalidomide and dexamethasone with and without elotuzumab has been completed. The combination of elotuzumab with lenalidomide and dexamethasone has shown an ORR >80% in relapsed patients who had a median of 3 prior lines of therapy and a prolonged PFS of 33 months in the most recent update.

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Current approaches to the management of multiple myeloma (MM), in particular the introduction of proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs), have improved the survival of patients.

Noa Biran | Authors

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