Charting a Path for the Integration of Immunotherapy in the Treatment of Multiple Myeloma

Fenghuang Zhan, MD, PhD

Since the inception of the Myeloma Center at the Winthrop P. Rockefeller Cancer Institute at University of Arkansas for Medical Sciences (UAMS) in Little Rock in 1989, investigators have used total therapy to treat patients with multiple myeloma in 7 successive investigator-initiated clinical trials. A total therapy approach combines novel drugs with a backbone of tandem autologous stem cell transplantation in a regimen comprising induction, transplantation, consolidation, and maintenance. This treatment sequence was modeled after the highly successful protocols pioneered by the pediatric acute lymphoblastic leukemia team at St Jude Children’s Research Hospital in Memphis, Tennessee.

Approximately 30% to 40% of eligible patients with standard-risk myeloma and 15% of patients with high-risk myeloma can be operationally cured with intensive therapy. Although intensive therapies such as thalidomide (Thalomid) elicit complete response rates as high as 62% in patients with standard-risk or high-risk myeloma, many patients are not eligible for this approach and do not achieve the long-term benefit of intensive total therapy. In addition, total therapy protocols are associated with toxicities and affect patient quality of life.¹

We believe that it is time for a paradigm shift in the treatment of myeloma. Our 5-year plan is to develop novel targeted therapies that will include immunotherapeutic approaches to reduce the need for intensive cytotoxic chemotherapy and stem cell transplant. The broad vision is to target myeloma using combinations of highly effective immunotherapies and to develop a “total immunotherapy” approach.

Targeting Myeloma Stem Cells with CAR T Cells

One aim is to use dual-specific chimeric antigen receptor (CAR) therapy to target bulk myeloma and myeloma stem cells. Treatment failures in cancers, including multiple myeloma, are most likely because of a persistence of a minor population of cancer stem cells, which are mainly noncycling and therefore resistant to chemotherapies that rely on DNA synthesis.

Commonly used CAR T cells recognize B-cell maturation antigen (BCMA) on myeloma cells but do not target myeloma stem cells. We have confirmed that CD24-positive multiple myeloma cells display stem cell features and that the anti-CD24 antibody SWA11 can efficiently inhibit CD24-positive multiple myeloma cell growth.² We have now generated BCMA/CD24specific dual-specific CAR T cells.³

Our hypothesis is that CAR T cells that specifically recognize myeloma stem cells can be curative. We will use compound CAR T cells that recognize both BCMA, which is widely expressed on myeloma, and CD24 present on myeloma stem cells.3 The objective is to debulk the disease and to also target myeloma stem cells, with an overarching goal to minimize the use of toxic chemotherapy and to avoid stem cell transplant altogether.

Goal: Develop Myeloma Subtype–Specific Antibody Therapies

Our goal is to use our knowledge of the genetic makeup of multiple myeloma to develop antibody treatments that target cell surface proteins specifically expressed at high levels on cancer cells. We were the first to show that multiple myeloma can be divided into 7 distinct molecular subgroups with unique gene expression patterns.⁴ Our hypothesis is that cell surface markers unique to these subgroups represent high-value and very specific targets for new antibody-based therapeutics.

New targets will be discovered and validated by a combination of gene expression profiling, immunohistochemistry, and proteomics. An example is the cell surface molecule that is highly overexpressed on the hyperdiploid subgroup. Using our extensive database of gene expression profiles of primary myeloma cells, we are also developing neutralizing antibodies to secreted proteins that influence tumor cell and/or bone marrow microenvironment.

Existing approved naked antibodies targeting SLAMF7 and CD38 either lack potency or are not sufficiently specific to benefit all patients. In addition, bispecific antibodies targeting BCMA or GPRC5D are marred by a significant incidence of cytokine release syndrome (CRS). Instead, we will test antibody-drug conjugates specific for different molecular subtypes using preclinical cell culture and mouse models. The eventual aim is to test promising antibodies in clinical trials. These antibodies can potentially be used “off the shelf” and are less likely to cause neurologic toxicity and CRS.

Targeting NEK2 to Enable Immune Checkpoint Blackade in High-Risk/Relapsed Myeloma

Although PD-L1 inhibition has been successful in melanoma and certain types of lymphoma, results from clinical studies using the same approach in myeloma have been disappointing. This is partially because of the low expression of PD-L1 in relapsed multiple myeloma.

NEK2, a serine/threonine kinase, is upregulated in patients with high-risk and relapsed myeloma. NEK2 shows a negative correlation with PD-L1 expression in myeloma cells.⁵ Inhibitors of NEK2 increase cell surface PD-L1 expression and sensitize myeloma cells to T-cell cytotoxicity when combined with a PD-L1 blockade.⁶ NEK2 small-molecule inhibitors will be used therapeutically through a novel proteolysis-targeting chimera (PROTAC) technology.

Based on these unique findings, we hypothesize that the hyperdiploid myeloma subtype with high expression of PD-L1 will be sensitive to PD-1/PD-L1 blockade alone and that the high-risk and relapsed myelomas with low expression of PD-L1 are insensitive to such therapy and require pairing of PD-1/PD-L1 blockade with NEK2 inhibitor treatment.

There have been concerns about immunologic adverse effects of PD-1/PD-L1 blockade in the myeloma field. However, in high-risk or relapsed multiple myeloma, the risk-benefit ratio is skewed. Furthermore, this approach avoids the commonly used combination of immunomodulatory drugs, such as lenalidomide (Revlimid), plus PD-1 or PD-L1 monoclonal antibodies, potentially reducing the risk of adverse immune effects.

References

1. Barlogie B, Tricot G, Anaissie E, et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med. 2006;354(10):1021-1030. doi:10.1056/NEJMoa053583
2. Gao M, Bai H, Jethava Y, et al. Identification and characterization of tumor-initiating cells in multiple myeloma. J Natl Cancer Inst. 2020;112(5):507-515. doi:10.1093/jnci/djz159
3. Sun F, Cheng Y, Peng B, et al. Bispecific CAR-T cells targeting both BCMA and CD24: a potentially treatment approach for multiple myeloma. Blood. 2021;138(suppl 1):2802. doi:10.1182/ blood-2021-148543
4. Zhan F, Huang Y, Colla S, et al. The molecular classification of multiple myeloma. Blood. 2006;108(6):2020-2028. doi:10.1182/ blood-2005-11-013458
5. Zhou W, Yang Y, Xia J, et al. NEK2 induces drug resistance mainly through activation of efflux drug pumps and is associated with poor prognosis in myeloma and other cancers. Cancer Cell. 2013;23(1):48-62. doi:10.1016/j.ccr.2012.12.001
6. Franqui-Machin R, Hao M, Bai H, et al. Destabilizing NEK2 overcomes resistance to proteasome inhibition in multiple myeloma. J Clin Invest. 2018;128(7):2877-2893. doi:10.1172/JCI98765