The prospects for mAbs to change the treatment paradigm for multiple myeloma have grown considerably brighter as early-phase clinical trial results suggest that emerging agents with novel mechanisms of action are capable of delivering significant efficacy.
The FDA has approved nearly two dozen monoclonal antibodies (mAbs) that have revolutionized the treatment of a variety of different cancers. Until recently, however, mAbs seemed to have limited capacity to improve survival in multiple myeloma, a common hematologic cancer that remains incurable despite substantial improvements in treatment options.
Now, the prospects for mAbs to change the treatment paradigm for the malignancy have grown considerably brighter as early-phase clinical trial results suggest that emerging agents with novel mechanisms of action are capable of delivering significant efficacy. Two of these agents, elotuzumab and daratumumab, have garnered the FDA’s coveted breakthrough therapy status as part of combination regimens. And, the success of immune checkpoint blockade strategies in other malignances has spurred researchers to consider agents targeting the programmed cell death 1 (PD-1) pathway in multiple myeloma therapy.
Indeed, the field is brimming with discovery efforts (Table). Of these novel agents, elotuzumab is the most advanced mAb in terms of clinical development and results from phase III trials are eagerly anticipated.
Rationale for Pursuing mAbs
Multiple myeloma, the second most common hematologic malignancy, is characterized by aberrant clonal expansion of malignant plasma cells in the bone marrow. In the past decade, an evolving understanding of the pathophysiology underlying multiple myeloma has fueled successful development of several novel agents, including immunomodulatory drugs (IMiDs) such as lenalidomide (Revlimid) and thalidomide (Thalomid) and the proteasome inhibitors bortezomib (Velcade) and carfilzomib (Kyprolis), which have significantly improved survival.
Despite these advances, multiple myeloma remains mostly incurable; the majority of patients eventually relapse or become refractory to therapy and then face an average survival of less than a year. Researchers, however, believe that multiple myeloma is a fundamentally curable disease, if this therapeutic challenge can be met. This has driven the development of new therapies, including histone deacetylase inhibitors, next-generation proteasome inhibitors, and a number of immunotherapies.
mAbs function as anticancer agents via a number of different mechanisms that are not mutually exclusive. These include:
In 1997, rituximab (Rituxan), which targets the CD20 antigen, became the first mAb to receive regulatory approval for the treatment of B-cell lymphomas but is not specifically indicated for patients with multiple myeloma. Although CD20 is expressed in 15%-20% of multiple myelomas, rituximab has shown limited efficacy in the clinical setting in this malignancy. Similarly, other mAbs spanning a diverse range of targets, including epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), CD40, CD56, and CD74 have not advanced in development despite significant promise in preclinical studies.
Novel mAbs Gain Spotlight
The lack of success with mAbs can be attributed, at least in part, to the complex and heterogeneous nature of multiple myeloma. Now, technological advancements and a greater understanding of the disease’s pathophysiology have permitted the identification of target antigens that are more specific and broadly expressed, spawning the development of a number of novel mAbs that are demonstrating clinically meaningful efficacy. The ongoing success of these agents was highlighted in numerous reports at the 2014 American Society of Hematology (ASH) Annual Meeting in San Francisco in December.
Two principal targets for mAb therapy are showing particular promise. CD2 subset 1 (CS1), also known as signaling lymphocytic activation molecule 7 (SLAMF7), and CD38 are both glycoproteins expressed highly and nearly uniformly on the surface of multiple myeloma cells. Importantly, they are also expressed only at low levels on other lymphoid and myeloid cells; CS1 in particular is undetectable on the majority of normal tissues or hematopoietic stem cells, making it an ideal therapeutic target.
This illustration depicts some of the many interactions in the microenvironment that help promote the growth of multiple myeloma cells. Notable targets for anticancer therapy include CS1, IL-6, BAFF, CXCR4, and VEGF.
BAFF indicates B-cell activating factor; BMEC, bone marrow endothelial cell; BMSC, bone marrow stromal cell; CS1, CD2 subset 1; CXC, chemokine receptor; ERK, extracellular signal-regulated kinase; FGF, fibroblast growth factor; HGF, hepatocyte growth factor; IGF, insulin-like growth factor; IDO, indoleamine 2,3-dioxygenase 1; IL-6, interleukin-6; MET, mesenchymal epithelial transition factor; NF-Ä¸B, nuclear factor kappa-light-chain-enhancer of activated B cells; tol-DC, tolerogenic dendritic cell; VEGF, vascular endothelial growth factor.
Adapted from Rutella S, Locatelli F. Targeting multiple-myeloma-induced immune dysfunction to improve immunotherapy outcomes. Clin and Developmental Immunol. 2012; article ID 196063. http://dx.doi.org/10.1155/2012/196063.
The precise biological function of CS1 is unknown. Of note, CS1 is expressed on natural killer (NK) cells and is thought to play a role in their activation. Consequently, the potential of the CS1 pathway to regulate NK cell cytotoxicity is an area of intense interest since this could give CS1-targeted agents powerful immunotherapeutic potential.
Elotuzumab is a first-in-class humanized immunoglobulin (IgG1) mAb targeting CS1. Preclinical studies demonstrated substantial single-agent antitumor activity in multiple myeloma, primarily via ADCC mediated by NK cells. Several studies have shown that elotuzumab likely has other mechanisms of action but these are currently less well defined. These promising findings pushed elotuzumab forward into clinical development, but monotherapy did not prove effective; although more than a quarter of patients achieved stable disease (SD), there were no responses.
In preclinical studies, elotuzumab also demonstrated synergistic activity with lenalidomide and bortezomib and it is in the combinatorial setting that this mAb has proved most promising. The hypothesis about this synergy is that the upregulation of the immune system mediated by IMIDs is focused by the mAb, selectively augmenting the antitumor immune response against a specific antigen, rather than just generally boosting the immune system.
In combination with lenalidomide, elotuzumab has been well tolerated in phase I and II studies, with durable responses in a significant proportion of patients. Clinical efficacy of the combination of elotuzumab, lenalidomide, and low-dose dexamethasone in patients with relapsed/ refractory disease was established in a phase Ib/II study (NCT00742560). Preliminary results from the 28 patients enrolled in the phase I dose- escalation portion of the trial demonstrated an objective response rate (ORR) of 82%, with no dose- limiting toxicity (DLT) to the maximum dose of 20 mg/kg and a median time to progression (TTP) of 33 months for all treatment groups.
In the phase II part of the trial, a further 73 patients were treated at 10 mg/kg and 20 mg/kg doses of elotuzumab. The overall ORR remained consistent with that previously reported at 84% (92% and 76% in the 10 mg/kg and 20 mg/kg groups, respectively), including stringent complete response (CR) or CR of 14%, very good partial response (VGPR) of 43%, and partial response of 27%. The median duration of response was 20.8 months and the median progression-free survival (PFS) was 29 months; follow-up on overall survival (OS) continues. The most common treatment-related adverse events (AEs) were diarrhea, muscle spasms, fatigue, constipation, nausea, and upper respiratory tract infection, while grade 3/4 AEs included neutropenia, thrombocytopenia, lymphopenia, and anemia. Based on these data, the FDA awarded elotuzumab breakthrough therapy status in May 2014.
The results of a phase Ib study of this combination in patients with various levels of kidney function (normal, severe renal impairment, and end-stage renal disease) were also presented at ASH. The combination was well tolerated regardless of kidney function and responses were observed in all three groups. Renal impairment is common in patients with relapsed/refractory disease and adversely affects treatment outcomes— thus, elotuzumab could represent an important treatment option for these patients.
Two large phase III trials of elotuzumab in combination with lenalidomide and dexamethasone are currently under way in newly diagnosed (ELOQUENT-1) and relapsed/refractory (ELOQUENT-2) settings. Patient recruitment is complete and the results are eagerly awaited.
Additionally, elotuzumab in combination with bortezomib led to PRs in 48% of patients, two-thirds of whom were refractory to bortezomib, with 63% obtaining at least minor repsonse (MR), in a phase I trial. This combination was also well tolerated, with no DLTs and maximum tolerated dose (MTD) reached. Phase II trials are ongoing. Preliminary results of a phase I/II study of elotuzumab with lenalidomide, bortezomib, and dexamethasone (SWOG 1211) in newly diagnosed patients with high-risk disease also suggest this four-drug combination is well tolerated.
The functions of CD38 span cell adhesion, signal transduction, and calcium signaling, among others, making this tumor-associated antigen an attractive target. Currently, there are three mAbs targeting CD38 in active clinical development: daratumumab, SAR650984, and MOR202. Each binds to a different part of the CD38 receptor, though the clinical significance of this has not been determined. Daratumumab is the most advanced in terms of development and has also gained the FDA’s breakthrough therapy designation. As with elotuzumab, significant antitumor activity and synergy with lenalidomide and bortezomib were observed in preclinical studies.
Daratumumab has better single-agent activity than elotuzumab in clinical trials, with doses ≥4 mg/kg generating 42% PR and 25% MR in phase I/II trials. However, it still holds most promise in combination with IMiDs and proteasome inhibitors. The first reports of a phase I/II study of daratumumab in combination with lenalidomide and low-dose dexamethasone were seen at the 2014 American Society of Clinical Oncology Annual Meeting. Enrollment in this study is now complete and updated results were presented at ASH for 43 heavily pretreated relapsed/refractory patients (13 phase I dose-escalation, 30 phase II expansion cohort at 16 mg/kg dose). ORR was 100% in phase I (including CR, 31%; VGPR, 46%), and 86.7% in phase II (including CR, 6.7%; VGPR, 43%), and the VGPR rate was 75% in patients treated for at least 6 months. The combination was well tolerated, with manageable toxicity.
Preliminary results of an ongoing phase I study of SAR650984 in combination with lenalidomide and dexamethasone were also reported at ASH. Among 31 heavily pretreated patients, many of whom were double refractory to IMiDs and proteasome inhibitors, the median PFS was 6.2 months, the ORR was 64.5%, the clinical benefit rate (CBR) was 71%, and median DOR was 23.1 weeks at 6 months’ follow-up. The combination also was well tolerated, with no DLTs and no unexpected toxicities.
aIndividual trials may have additional industry or academic collaborators.
bTrial is ongoing but not recruiting participants.
cLirilumab targets KIR.
BAFF indicates B-cell activating factor; CS1, CD2 subset 1; CTLA-4, cytotoxic T-cell lymphocyte antigen-4; CXCR4, chemokine receptor type 4; ICAM-1/CD54, intracellular adhesion molecule 1; IL-6, Interleukim-6; KIR, killer cell immunoglobulin-like receptor; MM, multiple myeloma; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1; SLAM7, signaling lymphocytic activation molecule F7; VEGF-A, vascular endothelial growth factor-A.
Other Promising Targets
Indatuximab ravtansine (BT-062) is another promising mAb with a different mechanism of action. It is an antibody—drug conjugate, using the CD138 (syndecan-1) antigen, expressed on the surface of the majority of multiple myeloma cells, as a means of specifically directing the cytotoxic activity of a conjugated drug, the maytansinoid DM4, to multiple myeloma cells. Numerous clinical trials are ongoing and preliminary data from the phase I dose-escalation portion of a phase I/IIa study of BT-062 in combination with lenalidomide and dexamethasone were reported at ASH. Among 36 patients evaluable for response, the ORR was 78%, including 3% stringent CR, 5% CR, 28% VGPR, and 42% PR. There was also a 5% MR and a 17% SD rate, translating into a clinical benefit rate of 100% when add to the ORR rate.
Targeting the Bone Marrow Environment
With improved understanding of the molecular mechanisms of multiple myeloma has come an increasing appreciation of the importance of the bone marrow microenvironment, which is intricately linked to multiple myeloma cells and plays a critical role in regulating their growth and survival and in promoting resistance to conventional therapies.
Researchers have begun to mine the components of the bone marrow microenvironment and mediators of its interaction with multiple myeloma cells as targets for more effective mAb therapy. Indeed, both CS1 and CD38 may play a role in mediating adhesion of multiple myeloma cells to the bone marrow stroma cells, which may also partly explain the success of targeting those antigens.
Siltuximab (Sylvant) is a chimeric mAb targeting interleukin-6 (IL-6), a cytokine produced predominantly by the bone marrow stromal cells that plays a role in the proliferation and survival of multiple myeloma. It has been studied as both monotherapy and in combination with lenalidomide/dexamethasone and bortezomib/ melphalan/prednisone in phase II trials, demonstrating promising efficacy in heavily pretreated populations.
Ulocuplumab (BMS-936564) is a first-in-class fully human IgG4 mAb targeting the chemokine receptor CXCR4. Chemokines, such as CXCL12, are produced by the bone marrow stromal cells and play an integral role in multiple myeloma cell growth and progression and their recruitment to the bone marrow microenvironment.
CXCR4 is widely expressed on hematopoietic cells, including multiple myeloma cells, and is the receptor for CXCL12. Thus, disrupting binding of CXCR4 to CXCL12 is a potentially promising therapeutic target. A phase Ib study presented at ASH evaluated ulocuplumab alone or in combination with lenalidomide and low-dose dexamethasone or bortezomib and dexamethasone in 44 patients with relapsed/refractory disease. It proved safe and demonstrated high response rates, with no MTD up to a 10 mg/kg dose, only 1 DLT (delayed platelet recovery) in the bortezomib arm, and no grade 4 toxicity. The ORR was 50%, including 2% CR, 14% VGPR, and 34% PR.
Jane de Lartigue, PhD, is a freelance medical writer and editor based in New Haven, Connecticut.