Monoclonal Antibody-Directed Therapies for the Management of Multiple Myeloma

Noa Biran, MD

Myeloma Division

John Theurer Cancer Center

Hackensack University Medical Center

The overall survival (OS) of patients with multiple myeloma (MM) has improved significantly over the past decade with the development of novel therapies.¹ However, as patients relapse, their disease becomes resistant to existing therapy. Several monoclonal antibodies (mAbs) with MM cell antigen or bone marrow targets have exhibited strong antimyeloma activity and may become potential therapeutic agents.

Structure and Mechanism of Action of Monoclonal Antibodies

Antibodies are made of two or more pairs of heavy and light chains joined by disulphide bonds, comprising a variable and a constant region (Figure). The variable regions differ in structure from one antibody to another and contain the combining site. The constant region is unchanging within a given class and is responsible for effector functions.² It has been proposed that mAbs bind to and cross-link tumor targets, eliciting antibody- dependent cell-mediated cytotoxicity (ADCC), activating complement dependent cytotoxicity (CDC), and/or directly inducing tumor cell apoptosis.³

Monoclonal Antibodies Targeting the Bone Marrow-Stromal Cell Microenvironment

Anti-CS1

Elotuzumab is a humanized monoclonal IgG1 antibody directed against human CS1, a cell surface glycoprotein that is present on plasma cells and may also be expressed in NK and CD8+ T cells, belonging to the immunoglobulin gene superfamily.⁴ The majority of MM cell lines (97%) highly express CS1, which has been shown to mediate tumor cell adhesion, growth and proliferation.⁵ In vitro studies have shown that elotuzumab significantly inhibits myeloma cell binding to bone marrow stromal cells (BM- SCs) and induces ADCC.^6,7

In a phase I dose-finding study of elotuzumab mono- therapy, no objective responses were observed, although 26.5% achieved stable disease (SD).⁸ The most common adverse events (AEs) were cough, headache, back pain, fever, and chills. In the relapsed setting, treatment with elotozumab in combination with lenalidomide and dexamethasone achieved an 80% overall response rate (ORR; partial response or better).⁹ A phase III registration study comparing lenalidomide and dexamethasone with and without elotuzumab in relapsed MM patients has just been completed.

Anti-CD40 and CD40L

CD40 is a transmembrane glycoprotein involved in B-cell activation, differentiation, and the formation of germinal centers.¹⁰ It is normally expressed on B cells, dendritic cells, and is highly expressed in human malignant plasma cells. In the presence of different cytokines (IL-4 and IL-10), the activation through CD40 or CD40-L can initiate B-cell growth and differentiation.^11,12 CD40/CD40-L signaling reduces tumor cell proliferation and survival and may disrupt the protective immune state and stimulate immune-mediated antitumor activity in MM.¹³

Dacetuzumab (SGN-40) is a humanized agonistic IgG1 mAb with murine complementarity-determining regions (CDRs) which targets CD40. Preclinical studies observed that SGN0-40 induces tumor cell death in MM via breaking CD40/CD40-L interactions and activating NK-cell-me- diated ADCC.^14,15 The first phase I study in recurrent or refractory MM patients with high disease burden did not show any objective responses, although SD was observed in 20%. There are ongoing phase I studies of SGN-40 in combination with lenalidomide and bortezomib.

Lucatumumab (HCD122, formerly CHIR-12.12) is a fully human, recombinant IgG1 isotype CD40L antagonist.¹⁶ It inhibits CD40/CD40-L dependent proliferation and survival and stimulates ADCC.¹⁷ In a phase I study of relapsed/ refractory MM patients, 12 of 28 (46%) achieved SD with a median duration of 61 days.¹⁸ Common AEs were infusion reactions, thrombocytopenia, and increased alanine ami- notransferase and lipase.

Monoclonal Antibodies Targeting Tumor Cells

Anti-CD138

The antibody-maytansinoid conjugate BT062 targets CD138, a primary diagnostic marker for MM, and is expressed in a vast majority of cases. Within the hematopoietic compartment, CD138 expression is restricted to normal plasma cells, with no expression on hematopoietic stem cells, while expression of CD138 on MM cells is significantly higher than on normal plasma cells.¹⁹ BT062 is an antibody-drug conjugate, comprising the anti-CD138 chimerized mAB and the cytotoxic maytansinoid DM4. It binds to CD138 on cancer cells, and then releases DM4 after internalization to cause cell death.

Experiments on antibody-maytansinoid conjugates similar to BT062 have been shown to have potent cell killing effects not only on antigen-positive cells, but also on antigen-negative cells that are in close proximity to tumor cells.²⁰ This bystander effect may have impact on BT062 efficacy through eradication of tumor cells that heterogeneously express CD138 or disruption of the tumor micro- environment by elimination of tumor stromal cells.

Data from two studies investigating BT062 as a single agent demonstrated an acceptable tolerability profile and evidence of clinical activity in patients with heavily pretreated relapsed and relapsed/refractory MM.^21,22 In the first-in-man study, 11% responded and SD was noted in 41% of patients.²¹ A phase I/IIa study in MM was initiated to evaluate the safety and efficacy of BT062 in combination with lenalidomide and dexamethasone. In a heavily pretreated population (3 median prior lines), ORR was 80%, including one stringent complete response, two complete responses (CRs), 10 very good partial responses, and 15 partial responses (PRs). The most commonly reported AEs were mucositis, hand/foot syndrome, nausea, hypokalemia, diarrhea, and fatigue.

Table: Summary of Monoclonal Antibodies in Development for Multiple Myeloma

MoAb

Type

Target

Role of the Target

Best ORR in Phase 1/2

Most Advanced Phase

Patient Population

Elotuzumab

Humanized IgG1

CS-1

Surface glycoprotein on plasma cells; mediates tumor cell adhesion, growth and proliferation

80% *

III

Relapsed or Refractory

Lacatumumab

Humanized recombinant IgG1

CD40L

B-cell growth and differentiation; stimulates immune-mediated antitumor activity

4% ^

I

Relapsed or Refractory

Dacetuzumab

Humanized agonistic IgG1

CD40

B-cell growth and differentiation; stimulates immune-mediated antitumor activity

0% ^

I

Recurrent, Relapsed

BT062

Antibody-maytansinoid conjugate

CD-138

Highly expressed on multiple myeloma cells

80% *

II

Relapsed and/or Refractory

Daratumumab

Humanized IgG1-κ

CD38

Transmembrane glycoprotein expressed on MM cells; mediates signaling transduction, regulation of intracellular calcium mobilization

75% *

III

Relapsed or Relapsed/Refractory

SAR650984

Humanized IgG1

CD38

Transmembrane glycoprotein expressed on MM cells; mediates signaling transduction, regulation of intracellular calcium mobilization

64.5% *

II

Relapsed or Refractory

Legend: ORR — overall response rate by International Myeloma Working Group criteria (partial response or better); *in combination with lenalidomide and dexamethasone; ^ as monotherapy

Anti-CD38

Malignant plasma cells express relatively high levels of CD38, a 46-KDa type II transmembrane glycoprotein. The biological function of CD38 includes receptor-mediated adhesion,²³ signaling transduction, and regulation of intracellular mobilization of calcium.²⁴

SAR650984 (SAR) is a humanized IgG1 mAb that binds selectively to a unique epitope on the human CD38 receptor and may induce antitumor effects via ADCC, CDC, and direct apoptosis induction without secondary cross-linking. A phase I study of SAR monotherapy demonstrated an ORR of 24% with two patients achieving a CR and six patients achieving a PR.²⁵ In a phase I study of SAR in combination with lenalidomide and dexamethasone in heavily pretreated (6 median lines of prior therapies) relapsed/refractory (RR) MM patients, ORR was achieved in 64.5% with a median follow-up of 6 months.²⁶ Although no dose-limiting toxicities were observed, the most common AEs were fatigue, nausea, upper respiratory tract infection, and diarrhea.

Daratumumab is a human IgG1-κ CD38 mAb with direct Fc-mediated cell killing activity, mainly via CDC and macrophages ADCC.²⁷ In addition, daratumumab induces apoptosis upon secondary cross-linking and modulates CD38 enzymatic function. In the first phase I study, 42% of heavily pretreated patients with RRMM treated with monotherapy achieved a PR.²⁸ In an ongoing phase I/II multicenter study of heavily pretreated patients with relapsed or RRMM receiving daratumumab in combination with lenalidomide and dexamethasone, preliminary ORR was 75%.²⁹ The most common AEs were diarrhea and neutropenia.

Conclusions

Advances in tumor biology over the past several years have enhanced our understanding of the mechanisms of MM pathogenesis, allowing for the identification of tumor-associated antigens or targets. Antibodies against the BMSC microenvironment, as well as those against the tumor cells, are being investigated clinical studies. Most have shown remarkable antimyeloma activity and are likely to enhance the therapeutic armamentarium for MM, both alone and in combination with other known therapeutic agents.

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