Cellular Therapy Strategies Offer the Prospect of Deep Remissions for Multiple Myeloma

Philip McCarthy, MD

For more than a decade, we’ve been able to approach multiple myeloma, in most cases, as a chronic disease treatable through long-term maintenance therapy. However, this disease has long been an outlier among cancer types.

Multiple myeloma is a primarily incurable disease but new treatment options—particularly newly approved cellular therapies—have opened the possibility for extending disease control for patients who would otherwise not have treatment options. As a result of these advances, we now have reason to move our eyes toward heightened goals of treatment.

Despite the availability of multiple treatment options, the majority of patients with multiple myeloma will have recurrent or progressive disease. Patients with newly diagnosed multiple myeloma who require therapy typically receive induction therapy with a combination of drugs to decrease tumor burden.

Multiple myeloma is a spectrum of disease. Monoclonal gammopathy of undetermined significance is an early plasma cell disorder that can progress to multiple myeloma or remain stable for years. Smoldering multiple myeloma is a more advanced form of early disease and may require therapy based on disease burden. Multiple myeloma requires induction therapy for patients who present with bone lesions, high serum calcium levels, renal insufficiency/ failure and anemia.¹

Standard treatment for newly diagnosed multiple myeloma typically involves a combination of glucocorticoids, immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs) and monoclonal antibodies (mAbs).

To deepen remission, induction therapy can be followed by high-dose therapy—usually with a melphalan-based treatment with autologous hematopoietic cell rescue, also known as autologous stem cell transplant. After transplant, patients typically receive maintenance therapy to prolong response to induction and high-dose therapy. An important consideration for patients who are eligible for transplant and elect to delay transplant is to have hematopoietic cells collected for future use.

Newly diagnosed patients with multiple myeloma who are transplant-ineligible patients—those who are frail or have significant comorbidities—should receive induction therapy and once response is achieved continue treatment with dose-reduced therapy to maintain that favorable response.

CAR T Joins Options for Relapsed/Refractory Multiple Myeloma

For patients whose disease continues to progress after multiple lines of treatment, it becomes progressively difficult to control multiple myeloma that is resistant or refractory to approved therapies. The FDA approval of the first chimeric antigen receptor (CAR) T-cell therapy in March 2021 for the treatment of relapsed/ refractory multiple myeloma represented a significant advance^2,3 (Snapshot²).

Snapshot. Idecabtagene Vicleucel for Multiple Myeloma2

Idecabtagene vicleucel (ide-cel; Abecma), targets BCMA, which is expressed by malignant as well as normal plasma cells. It is approved for patients with relapsed/ refractory multiple myeloma after 4 or more prior lines of therapy, including treatment with an IMiD, a PI, and an anti-CD38 mAb.³

CAR T-cell therapy involves the insertion of a CAR into the T cell, targeting a cell surface molecule that is expressed by the myeloma cells. This form of gene therapy utilizes the T cell cytolytic capacity to target and eradicate the cancer cells.

The process involves using a patient’s own T cells for CAR insertion, which is achieved using a viral vector. The cells are obtained through leukapheresis, altered through insertion of the CAR and then expanded in the laboratory. The patient then undergoes lymphodepletion followed by infusion of these CAR-enhanced T cells. The lymphodepletion is thought to temporarily favor the expansion of the CAR T cells over the patient’s own T cells. The CAR T cells target myeloma cells, reducing tumor cell burden.

The toxicities associated with CAR T-cell products for multiple myeloma are similar to those of the CAR T products for lymphoma and include tumor lysis syndrome, cytokine release syndrome, and immune effector cell associated neurotoxicity syndrome. Other adverse effects include cytopenias as well as B cell aplasia, resulting in hypogammaglobulinemia because of the targeting of B cells. These toxicities can be managed but require early identification and treatment by the clinical team.

Investigations Underway in Roswell Park's Labs and Clinics

Other CAR T-cell products are being evaluated in clinical trials, including 2 at Roswell Park. The products our teams are investigating both target BCMA with different approaches to vector design and expansion in the laboratory. It remains to be deter-mined how successful these CAR T-cell products will be for long-term control of relapsed/refractory multiple myeloma; however, this is an exciting new therapy that can be offered to patients for whom who may not have many options left for control of the disease.

Our research team is devoted to understanding the biology of multi-ple myeloma as well as improving therapeutic outcomes. Maximilian Merz, MD, initiated a project using single-cell RNA sequencing on isolated malignant plasma cells as a postdoctoral research fellow at Roswell Park. The team behind that work observed that biopsies from standard bone marrow samples contained multiple myeloma cells that had important differences in molecular behavior when compared with multiple myeloma cells from osteolytic lesions—knowledge that will allow us to better understand the mechanisms of drug resistance that develop during multiple myeloma treatment. This research was presented during the 2020 American Society for Clinical Oncology Virtual Scientific Program and has been submitted for publication.⁴

Hemn Mohammadpour, DVM, PhD, a Roswell Park postdoctoral fellow in the laboratory of Elizabeth Repasky, PhD, is leading a proj-ect to characterize the immune cells in bone marrow and osteolytic lesions. This study is ongoing and will allow us to characterize the mechanisms by which local immune suppression occurs during the development and treatment of multiple myeloma.

Investigators at Roswell Park aim to also develop strategies to reverse immune dysfunction to prevent infections as well as control the endogenous immune response to multiple myeloma. Mohammadpour is investigating how myeloma tumors prevent the immune system from recognizing and eradicating the cancer. He has an interest in both allogeneic and endogenous tumor killing—the former during allogeneic hematopoietic cell therapy and the latter during tumor immunotherapy.

Mohammadpour is also pursuing novel strategies for allogeneic CAR T-cell therapy. This approach, which is under investigation, uses an allogeneic T cell, modified to express a CAR, to prevent rejection and to prevent alloreactivity by the T cell against the host.

We’re proud to highlight these clinical, translational, and basic research projects because they all represent exciting opportunities to improve patient outcomes and provide novel therapies for our patients. Cellular therapies, along with promising new agents, will continue to allow us to develop strategies that will lead to long-term disease control and possibly cure.

References

1. Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol. 2020;95(5):548-567. doi:10.1002/ajh.25791
2. Abecma. Prescribing information. Celgene Corporation; 2021. Accessed August 18, 2021. https://www.fda.gov/media/147055/download
3. FDA approves idecabtagene vicleucel for multiple myeloma. FDA. Updated March 29, 2021. Accessed August 18, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-ap-proves-idecabtagene-vicleucel-multiple-myeloma
4. Merz M, Merz AMA, Wang J, et al. Prospective evaluation of spatial heterogeneity at single cell resolu-tion in multiple myeloma. J Clin Oncol. 2020;38(suppl 15):8524. doi:10.1200/JCO.2020.38.15_sup-pl.8524