Novel therapies in monoclonal gammopathies

Abstract

Multiple myeloma (MM) is a plasma cell malignancy with an incidence of approximately 20 000 cases per year. Over the past decade, the advent of novel therapies has resulted in a positive shift in survival for patients with advanced MM. Over the last decade progress has been made in the understanding of the mechanisms involved in myeloma cell proliferation, trafficking and survival. Through this understanding, molecular therapeutic targets have been identified and treatment programs which incorporate these concepts are beginning to appear. The current review does not intend to be a comprehensive compendium of available treatments rather to highlight the most exciting avenues of research in myeloma therapeutics. Novel immunomodulating drugs, proteasome inhibitors and monoclonal antibodies will be highlighted.

Keywords:

• Multiple myeloma
• Novel immunomodulating therapies
• Proteasome inhibitors
• Monoclonal antibodies

Multiple myeloma (MM) is a clinically defined collection of plasma cell neoplasms, in which malignant plasma cells are arrested at various stages of differentiation.

It affects over 20 000 people annually in the USA, and is the cause of over 10 600 deaths.1 The pathogenesis of MM is complex and involves the interplay of intrinsic chromosomal and molecular abnormalities.2

Outcomes of MM have been historically poor. The introduction of novel agents, including thalidomide in the late 1990s, marked an improvement in survival outcomes. The subsequent introduction of second-generation immunomodulatory therapies, such as lenalidomide, as well as the proteasome inhibitor, bortezomib, increased treatment options and further improved outcomes in MM. Bortezomib, thalidomide, and lenalidomide have been incorporated at various steps in the treatment algorithm for MM based on the data supporting their clinical benefits.3,4 The introduction of these agents has helped shift the goals of MM therapy to achieve durable responses with acceptable toxicity. However, the management of MM remains challenging, particularly in some patient populations. For example, in patients with relapsed/refractory multiple myeloma (RRMM) who have been previously treated with lenalidomide- and bortezomib-containing regimens, there is an unmet need for an antimyeloma therapy that is both effective and tolerable.5

Herewith we will review the role of newer therapies in the treatment of MM. We will explore the unmet need for more effective treatments for patients with RRMM who are refractory to lenalidomide- and bortezomib-containing regimens, and the potential role for pomalidomide, carfilzomib, and elotuzimab in the treatment of this population.

Pomalidomide

Pomalidomide (CC 4047) is a second-generation immunomodulatory agent and potent IMiD.6,7 In vitro studies have shown that pomalidomide is 10-fold more potent than lenalidomide and up to 15 000 times more potent than thalidomide at inhibiting tumor necrosis factor alpha.8 Pomalidomide has a distinct mechanism of action compared with lenalidomide including direct anti-proliferative, pro-apoptotic, and anti-angiogenic effects as well as modulatory effects on bone resorption and the immune system.9 Pomalidomide has shown significant clinical activity in phases 1 and 2 trials of patients with RRMM, and is well tolerated in doses ranging from 1 to 5 mg/day.10^–12 In the first phase 2 study, 60 patients with RRMM (median age 66 years) who had received 1–3 prior lines of treatment were treated with pomalidomide, 2 mg/day daily for a 28-day cycle, plus dexamethasone, 40 mg/week.12 The overall response rate (ORR) was 63% including 3 complete responses (CRs, 5%), 17 very good partial responses (VGPRs, 28%), and 18 partial responses (PRs, 30%). Importantly, responses were seen in 40% of patients refractory to lenalidomide, 37% of those refractory to thalidomide, and 60% of those refractory to bortezomib, indicating a lack of cross-resistance between pomalidomide and the other novel agents. Furthermore, 14 of the 19 patients (74%) who had high-risk cytogenetic profiles responded to pom/dex (one CR and five VGPRs). The median progression-free survival (PFS) in patients who responded to pom/dex was 11·6 months, and did not differ significantly between the patients with high-risk and those with standard-risk disease. Six-month survival rate was 94%. Long-term follow-up of this study has recently been reported: after a median follow-up of 27·2 months, the ORR was 65%, with a median duration of response of 21·3 months and a 2-year overall survival rate of 76%.13 A recent report from the Mayo clinic shows that pom/dex can be given at 2 or 4 mg/day continuously. In this study, patients were refractory to both lenalidomide and bortezomib with a median age of 62 years.14 Pom/dex was associated with a higher ORR (⩾PR) in the 4 mg group (29% versus 25%) and a shorter median PFS (6·4 versus 3·3 months, respectively) as compared with the 2 mg group. No overall advantage was associated with the 4 mg pomalidomide dose.14 Another independent, randomized phase 2 study from the Intergroupe Francaise due Myelome (IFM) (IFM 2009-02) has studied the efficacy of pom/dex treatment in patients with relapsed disease previously treated with at least two cycles of lenalidomide and bortezomib, either sequentially or in combination.15 In the IFM 2009-02 study, patients received 4 mg pomalidomide either for 21 of 28 days (group A) or continuously for 28 days (group B) plus dexamethasone, 40 mg weekly. Thromboprophylaxis was given to all patients in the study. A total of 84 patients with progressive disease were enrolled (43 in group A and 41 in group B), a high proportion of whom had high-risk cytogenetic profiles [e.g. del (17p) and t(4:14)]. The most recently reported data from this study indicate that the ORR was 42% in group A (including seven patients with ⩾VGPR) and 39% in group B (including five patients with ⩾VGPR). The median times to progression in groups A and B were 7 and 9·7 months, respectively, and the 6-month overall survival rates were 88 and 85%.15 Pomalidomide, in combination with dexamethasone, has a manageable toxicity profile in patients who have relapsed from multiple lines of therapy.12,14 The most common grade 3 or 4 toxicities reported in the phase 2 trials were hematological, primarily neutropenia, which occurred within the first three treatment cycles. Other important non-hematological grade 3 or 4 adverse events included fatigue and pneumonia. Peripheral neuropathy (PN) has only been reported in one of the phase 2 studies of pom/dex12 and the incidence was low (3%), with only one case of grade 3 PN. All patients in the phase 2 studies received thromboprophylaxis during pom/dex treatment and the incidence of thromboembolic complications was low (<5%).12,14 Pomalidomide is now being tested in combination with clarithromycin and dexamethasone. Pomalidomide is given at 4 mg/day for days 1–21 of a 28-day cycle, while dexamethasone is given at 40 mg once weekly and clarithromycin 500 mg twice a day.16 The results thus far have almost doubled the response rate (60%) and the PFS of double refractory patients (8·13 months) when compared with other pomalidomide trials. Similarly the combination of pomalidomide, cyclophosphamide, and prednisone appears promising.17 Pomalidomide is also suitable for use in combination with proteosome inhibitors (bortezomib or carfilzomib) and a phase 1/2 clinical study of pom/dex in combination with bortezomib is planned (NCT01212952).

Carfilzomib

Carfilzomib is a tetrapeptide epoxyketone-based inhibitor of the chymotrypsin-like activity of the 20S proteasome. Carfilzomib, which is structurally and mechanistically different from the dipeptide boronic acid proteasome inhibitor bortezomib, showed less off-target activity when measured against a broad panel of proteases including metallo, aspartyl, and serine proteases compared to bortezomib; the latter showed off-target inhibitory activity in the nanomolar range against several serine proteases.18 In addition, carfilzomib is more selective for the chymotrypsin-like protease activity of the proteasome than bortezomib. This selectivity may be responsible for the reductions in myelosuppression and neuropathy observed in preclinical studies comparing carfilzomib with bortezomib. Based upon in vitro and in vivo studies, it is anticipated that a more intense and sustained proteasome inhibition can be achieved with carfilzomib relative to bortezomib, resulting in enhanced antitumor activity. Several phases 1 and 2 studies have shown substantial activity and a favorable safety signal. A single-arm, phase 2 trial of carfilzomib in patients with RRMM showed that single-agent carfilzomib had durable responses in 36% of the 257 patients evaluated.19 In phase 1 studies, a starting carfilzomib dose of 27 mg/m² was associated with a ‘first-dose effect’ in some subjects that included a constellation of symptoms that may represent rapid tumor lysis and/or cytokine release, such as fever, chills, and/or rigors following the first day of infusion. This was often followed on day 2 by a transient increase in creatinine. Two studies have utilized carfilzomib monotherapy in a stepped-up dose fashion in an attempt to avoid or ameliorate the symptoms associated with the first-dose effect: Study PX-171-002 in hematological malignancies and Study PX-171-003 in RRMM. In both studies, subjects initiated treatment in cycle 1 at a carfilzomib dose of 20 mg/m²; after completion of either the first week or the first cycle of dosing, individual subjects were escalated to carfilzomib 27 mg/m². To date, over 250 subjects have received this stepped-up dosing paradigm which, along with PO and IV hydration and concomitant dexamethasone (4 mg predose), has appeared to reduce the incidence of this first-dose effect. Preliminary results of subjects receiving the stepped-up dosing schedule indicate that this dosing approach is feasible and well-tolerated, with no significant incidence of cardiac toxicity, tumor lysis syndrome, renal dysfunction, or creatinine elevation. Additionally, long-term tolerability has been demonstrated by the fact that approximately 10% of subjects have received carfilzomib at full dose for over 12 cycles. The new schedule will allow further escalation as in the 007 study in which the maximum tolerated dose (MTD) is now 56 mg/m². The 20/56 mg/m² dose for carfilzomib administered as a 30-minute IV infusion was associated with 60% ORR, noteworthy for a late-line, heavily pretreated patient population. The dose group additionally reported an acceptable safety profile (with one patient reporting G1 neuropathy), supporting the pre-clinical finding that longer infusion time enables higher dose and achieves greater levels of proteasome inhibition.20 In another phase 2 trial of patients with RRMM, carfilzomib in combination with lenalidomide and dexamethasone demonstrated an overall response rate of 78%. Researchers found that carfilzomib could be administered over a period of 14–23 months with no new or overlapping toxicities.21

In a phase 2 trial, carfilzomib had a 53% ORR among patients with RRMM who had not previously received bortezomib. This study also showed that prolonged carfilzomib treatment is well-tolerated with approximately 22% of patients continuing treatment beyond 1 year. Carfilzomib can be given in renal failure patients with no untoward further toxicity or deterioration of kidney function.22

In phase 2 trials of carfilzomib, the most common grade 3 or higher treatment-emergent adverse events were thrombocytopenia, anemia, lymphopenia, neutropenia, pneumonia, fatigue, and hyponatremia.

A phase 3 trial comparing carfilzomib, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed multiple myeloma is ongoing.

Elotuzimab

Elotuzimab is an anti-CS1 monoclonal antibody (mAb) in development for MM which exerts anti-MM effects via NK cell-mediated ADCC.23 The expression of the elotuzumab target, CS1, is restricted to malignant myeloma cells and subsets of normal leukocytes in humans (NK, NK-like T cells [NKT], activated monocytes, a subset of CD8⁺ T cells, and tissue plasma cells). Elotuzumab (100 and 200 mcg/ml) in vitro had no effect on lymphocytes, CD3⁺, CD4⁺, CD8⁺, and B cell counts in blood samples from healthy donors. Natural killer cell counts were decreased on average by 20% at both doses of elotuzumab. The observed decline was variable between donors and ranged between 0 and 45%. Elotuzumab at concentrations up to 500 mcg/ml did not adversely affect the ability of bone marrow-derived hematopoietic stem cells to differentiate down the erythroid and myeloid pathways.

The initial development in clinic started with a phase 1 study, in which escalating doses (0·5–20 mg/kg) of elotuzumab monotherapy were administered intravenously (IV) every 2 weeks for a total of four doses in subjects with advanced MM. Subjects with stable disease or better had the option to receive additional doses of elotuzumab. A total of 35 subjects were enrolled: 3 in the 0·5 mg/kg cohort, 4 in the 1·0 mg/kg cohort, 6 in the 2·5 mg/kg cohort, 4 in the 5·0 mg/kg cohort, 4 in the 10 mg/kg cohort, and 14 in the 20 mg/kg cohort. Although the MTD was not reached, SAE found included grade 4 acute renal failure, grade 2 chills, grade 2 pyrexia, grade 3 hypersensitivity, grade 2 bradycardia, and grade 2 chest discomfort.

In a phase 1/2 study of elotuzumab in combination with bortezomib (plus dexamethasone if applicable) in subjects with MM who have had 1–3 prior therapies,24 no DLT was observed and MTD was not established up to the planned highest dose of 20 mg/kg. The best clinical response (⩾MR) and the best response rate (⩾PR) by the combined European Group for Blood and Marrow Transplantation and uniform criteria 15 in 27 response evaluable subjects was PR+CR, 48%.

Similarly elotuzumab has been combined with lenalidomide and low dose dexamethasone (Ld) in subjects with MM who have had one or more prior therapies. No DLT was observed during dose-escalation and an MTD was not established. Infusion reactions, one grade 4 SAE of anaphylaxis (related to elotuzumab) and one grade 3 SAE of stridor (related to elotuzumab/dexamethasone). Subsequent to these events, a new premedication regimen for the whole program has been instituted to minimize infusion reactions. The median number of prior therapies was 3. The ORR (⩾PR) was 82% in all evaluable subjects who received elotuzumab/Ld.25