Dr McCarthy on Neutrophil Activity in Multiple Myeloma

Philip McCarthy, MD, director emeritus, Transplant & Cellular Therapy Program, member, Tumor Immunology and Immunotherapy Program, Roswell Park Comprehensive Cancer Center, discusses findings from a study investigating neutrophil gene signatures within focal lesions that are linked to progression-free survival in patients with multiple myeloma.

Multiple myeloma can present diffusely in bone marrow or focally through osteolytic and extramedullary lesions, and neutrophils can comprise over half of normal bone marrow cells. Neutrophils can be altered by cancer but are understudied in multiple myeloma. However, understanding neutrophil populations in the multiple myeloma tumor microenvironment may aid the development of novel therapies for patients with this disease.

In this study, investigators observed the expression of CXCL2 and CXCL1 on neutrophils, alongside elevated levels of interleukin 8 (IL-8), all of which are integral to neutrophil chemotaxis and development, McCarthy begins. Additionally, several other cytokines and surface markers that are typically absent in healthy donor bone marrow were identified, he says. Among the inflammatory markers, IL-6 was notably upregulated, which was expected; however, investigators also found an increase in IL-10, which is known for its anti-inflammatory properties, according to McCarthy.

These findings indicate a complex interplay between malignant plasma cells within osteolytic lesions and the neutrophils that are likely drawn to these areas by chemotaxis, McCarthy explains. Although the exact role of these interactions in the development of osteolytic lesions remains unclear, it is evident that they contribute to the immunosuppressive environment that is characteristic of multiple myeloma, he notes. This immunosuppression is reflected in the hypogammaglobulinemia that is observed in many patients with multiple myeloma, which results from the suppression of normal plasma cells, McCarthy reports. Moreover, T-cell dysfunction is evident in myeloma cells, which increases the susceptibility of patients with this disease to infections that are typically controlled by T cells, such as shingles, he concludes.

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Philip McCarthy, MD, discusses a study of neutrophil gene signatures within focal lesions that are linked to progression-free survival in multiple myeloma.

Dr McCarthy on Neutrophil-Mediated Immunosuppression in Multiple Myeloma

Philip McCarthy, MD, director, the Blood and Marrow Transplant Program, Roswell Park Comprehensive Cancer Center, discusses findings from an investigation into neutrophils in the tumor microenvironment (TME) of multiple myeloma and their impact on progression-free survival (PFS).

The study evaluated the role of neutrophils in multiple myeloma, which McCarthy notes presents in 3 distinct ways: diffuse bone marrow infiltration, osteolytic lesions, and plasmacytomas, the latter of which are often extramedullary. The goal of the study was to determine if the TME of each area was different, McCarthy says, explaining that osteolytic lesions and plasmacytomas were grouped together and referred to as focal lesions.

 McCarthy and colleagues presented data from this analysis, which included comparisons between healthy donor bone marrow, as well as marrow and focal lesions from patients with multiple myeloma. Using a novel biopsy system developed by Hemn Mohammadpour, DVM, PhD, and Jens Hillengass, MD, PhD, both of Roswell Park Comprehensive Cancer Center, investigators identified significant differences in neutrophil populations between the bone marrow and focal lesions.

Key findings revealed that neutrophils, natural killer (NK) cells, and T cells in focal lesions exhibited distinct phenotypes. McCarthy notes that the evaluation of NK and T cells is ongoing. Regarding the current analysis, abhorrent neutrophils were found in the TME of focal lesions that were not present in the bone marrow of patients with multiple myeloma or in that of healthy donors. Two populations of neutrophils that were unique to focal lesions were associated with inflammatory and immunosuppressive cytokines, contributing to the overall immunosuppressive environment in multiple myeloma due to the suppression of T-cell activation.

McCarthy and colleagues concluded that these unique neutrophils in the TME of focal lesions could affect PFS. Additionally, analyzing these neutrophils could lead to the identification of novel targets and agents for multiple myeloma to improve responses to immune therapy.

Philip McCarthy, MD, discusses findings from an investigation, assessing the impact of neutrophils within the tumor microenvironment of multiple myeloma. 

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.

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

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.

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.

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.

Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. 

. 2020;95(5):548-567. doi:10.1002/ajh.25791

Abecma. Prescribing information. Celgene Corporation; 2021. Accessed August 18, 2021. https://www.fda.gov/media/147055/download 

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

Merz M, Merz AMA, Wang J, et al. Prospective evaluation of spatial heterogeneity at single cell resolu-tion in multiple myeloma. 

. 2020;38(suppl 15):8524. doi:10.1200/JCO.2020.38.15_sup-pl.8524

Articles

The FDA approval of the first chimeric antigen receptor T-cell therapy in March 2021 for the treatment of relapsed/refractory multiple myeloma represents a significant advance.

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

Although graft-versus-host disease (GVHD) remains a significant clinical challenge for transplant medicine specialists, recent research suggests new strategies for better predicting, addressing, and perhaps preventing this very serious adverse effect of treatment.

Investigators at Roswell Park Comprehensive Cancer Center in Buffalo, New York, are working on a variety of novel approaches, including developing prophylactic drug regimens, studying methods of rejuvenating the recipient’s immune system, and analyzing genetic characteristics to improve donor selection.

GVHD is among the most common and significant toxicities that can occur after allogeneic hematopoietic cell therapy (allo-HCT), also known as allogeneic bone marrow transplant. Patients can develop GVHD shortly after transplant or long afterward, with symptoms ranging from mild to severe and life-threatening.

In allo-HCT, the transplantation of a suitable donor’s hematopoietic stem cells into a recipient results in the engraftment, or take, of the donor hematopoietic system. GVHD occurs for some transplant recipients after the donor cells recognize the recipient tissue as foreign, resulting in the activation of the donor’s immune system against the recipient and, in some cases, damage to normal tissue.

GVHD can occur in 30% to 60% of allo-HCT recipients; the likelihood that a patient will develop GVHD depends on several factors, including the type of donor, degree of tissue (human leukocyte antigen [HLA]) matching, and whether or not the patient is in remission. Acute GVHD usually arises within the first 100 days after transplant and typically affects the skin, gastrointestinal (GI) tract and/or liver. Chronic GVHD, meanwhile, usually occurs after day 100 post transplant.

About 10% of allo-HCT recipients will experience severe GVHD.

 A mild case can be a good sign that the transplant will be more successful over the long term, because patients with mild acute GVHD—especially milder chronic GVHD&mdash;are less likely to experience a cancer relapse.

Several current treatment approaches aim to decrease the incidence and severity of GVHD. Corticosteroids and other immune-suppressing drugs help control the excessive immune response that can, in particular, attack the skin and GI tract during acute GVHD.

For chronic GVHD, steroids can be administered in topical creams for skin rashes, drops for eye symptoms, and mouth rinses for oral symptoms. However, high-dose corticosteroids may lead to additional adverse effects, such as muscle weakness, bone loss, and fractures, as well as increased risk of infection. Many patients with acute GVHD will receive medicines to prevent infections, and intravenous feeding can help those with severe GI GVHD regain strength. Patients using steroids long term may receive bone-strengthening medications.

Another treatment especially for chronic GVHD is photopheresis, a process in which a patient’s white blood cells are collected, exposed to a light-sensitizing drug, and treated with light therapy before being reinfused. This specialized treatment is part of standard therapy for patients with chronic GVHD at academic centers.

Table. Comparison of Conditioning Regimens for Chronic GVHD Prophylaxis

To prevent acute GVHD during the early transplant process, investigators at Roswell Park have tested several regimens to determine whether they could improve the efficacy while reducing the toxicity of the standard approach of tacrolimus (TAC) and methotrexate (MTX) to prevent severe GVHD for patients who had received reduced-intensity conditioning before allo-HCT. They found that a regimen containing TAX, micro-dose MTX, and mycophenolate mofetil (MMF) was as effective as TAX/MTX and superior to TAC/MMF (

Allo-HCT can also generate a graft-versus-tumor (GVT) effect against hematologic malignancies, whereby the donor’s immune system is activated to recognize and destroy the recipient’s cancer, primarily leukemias and lymphomas, and create a graft-versus-leukemia (GVL) effect.

 Donor T lymphocytes can cause GVHD and GVL. Removing all T lymphocytes will result in no GVHD but also no GVL—and, thus, a higher relapse rate. Decreasing the morbidity and mortality of GVHD while preserving the GVT/GVL effect is the holy grail of allo-HCT.

During the allo-HCT process, the recipient undergoes conditioning to encourage donor cell engraftment and prevent donor cell rejection by the recipient. Conditioning consists of immunosuppressive therapy to facilitate engraftment of the donor cells and some form of myeloablative or myelosuppressive therapy to eradicate or suppress recipient hematopoiesis (production of bone marrow and blood cells).

In the past, the donor and recipient needed very closely matched HLA within the major histocompatibility complex on chromosome 6, meaning that donors were usually suitably HLA-matched siblings or unrelated donors from the national Be The Match registry (bethematch.org).

However, the development of an in vivo approach to deplete allo-reactive donor T lymphocytes using post—allo-HCT cyclophosphamide obviated the need for in vitro T-cell depletion and facilitated the widespread adoption of haploidentical, or half-matched, transplants.

 Thus, most patients can now find a suitable matched or half-matched donor among family members or through the Be The Match, dramatically expanding the field of potential suitable donors.

Many Roswell Park investigators are assessing new treatment strategies and risk prediction models through current clinical trials.

In 2 separate clinical trials, Sophia Balderman,MD, and Christine Ho, MD, are examining the use of mobilized peripheral blood cells and tocilizumab (Actemra) with posttransplant cyclophosphamide for GVHD prophylaxis in haploidentical transplant recipients and the use of posttransplant cyclophosphamide for GVHD prophylaxis following sibling and unrelated-donor allo-HCT (NCT03333486, NCT03192397).

Our team also has developed a systematic approach to studying preclinical and clinical GVHD during allo-HCT. George Chen, MD, has a particular interest in the understanding and control of acute and chronic GVHD.

 His current work includes developing both preclinical models of GVHD and strategies to enhance immune reconstitution after allo-HCT.

Our collaborator, Elizabeth Repasky, PhD, studies the role of ß-adrenergic signaling in the development and control of GVHD.

 Our goals with this work are translational clinical research protocol development to investigate addressing GVHD during allo-HCT and enhancing the GVL effect.

Theresa Hahn, PhD, coleads a genome&#8209;wide association study (GWAS) in more than 3500 patients who received an HLA-matched unrelated donor allo-HCT. Several publications have been generated from this GWAS that may lead to better donor selection, which may result in less morbidity and mortality for the recipient and improved outcomes.

 This data set has also been used to validate previous genetic associations with chronic GVHD.12 Further analyses are ongoing.

Four major clinical priorities that need to be addressed after allo-HCT: infection, overall toxicity, GVHD infection, and relapse. If we can minimize immunosuppression, decrease the severity of GVHD, and preserve GVT/GVL, we will decrease the complications of allo-HCT and improve the cure rate.

We are very excited to embrace these challenges with the tools and strategies that have emerged in the past several years. Although we’ve been highly encouraged to see survival following allo-HCT improving, our work is not done until we can cure every case of GVHD.

Arora M, Cutler CS, Jagasia MH, et al. Late acute and chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation.

 2016;22(3):449-455. doi: 10.1016/j.bbmt.2015.10.018.

Chen GL, Zhang Y, Hahn T, et al. Acute GVHD prophylaxis with standard-dose, micro-dose or no MTX after fludarabine/melphalan conditioning. 

. 2014;49(2):248-253. doi: 10.1038/bmt.2013.167.

Chen GL, Liu H, Zhang Y, et al. Early versus late preemptive allogeneic hematopoietic cell transplantation for relapsed or refractory acute myeloid leukemia.

. 2014;20(9):1369-74. doi: 10.1016/j. bbmt.2014.05.013.

Luznik L, O’Donnell PV, Symons HJ, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. 

 2008;14(6):641-50. doi: 10.1016/j.bbmt.2008.03.005.

Aurora M, Hemmer MT, Ahn KW, et al. Center for International Blood and Marrow Transplant Research chronic graft-versus-host disease risk score predicts mortality in an independent validation cohort. 

2015;21(4):640-645. doi: 10.1016/j.bbmt.2014.10.022.

Chen GL, Carpenter PA, Broady R, et al. Anti-platelet-derived growth factor receptor alpha chain antibodies predict for response to nilotinib in steroid-refractory or -dependent chronic graft-versus-host disease. 

2018;24(2):373-380. doi: 10.1016/j.bbmt.2017.10.021.

Leigh ND, Kokolus, KM, O’Neill RE, et al. Housing temperature-induced stress is suppressing murine graft-versus-host disease through ß2-adrenergic receptor signaling.

 2015;195(10):5045-5054. doi: 10.4049/jimmunol.1500700.

Mohammadpour H, O’Neil R, Qiu J, McCarthy PL, Repasky EA, Cao X. Blockade of host ß2-adrenergic receptor enhances graft-versus-tumor effect through modulating APCs. 

2018;200(7):2479-2488. doi: 10.4049/jimmunol.1701752.

Hahn T, Sucheston-Campbell LE, Preus L, et al. Establishment of definitions and review process for consistent adjudication of cause-specific mortality after allogeneic unrelated-donor hematopoietic cell transplantation. 

2015;21(9):1679-1686. doi: 10.1016/j.bbmt.2015.05.019.

Karaesmen E, Rizvi AA, Preus LM, et al. Replication and validation of genetic polymorphisms associated with survival after allogeneic blood or marrow transplant. 

2017;130(13):1585-1596. doi: 10.1182/blood-2017-05-784637.

Zhu Q, Yan L, Liu Q, et al. Exomechip analyses identify genes affecting mortality after HLAmatched unrelated donor blood and marrow transplantation. 

2018; 131(22):2490- 2499; doi: 10.1182/blood-2017-11-817973.

Martin PJ, Fan W, Storer BE, et al. Replication of associations between genetic polymorphisms and chronic graft-versus-host disease. 

 2016;128(20):2450-2456. doi: 10.1182/blood-2016-07-728063.

Roswell Park Transplant Specialists Explore New Strategies for Tackling GVHD

Philip McCarthy, BA, MD, professor of oncology and internal medicine director, blood and marrow transplant program, Roswell Park Cancer Institute discusses maintenance therapy for multiple myeloma patients that are eligible for transplant.

Bortezomib has been looked at as a maintenance therapy for transplant eligible multiple myeloma patients in several studies, said McCarthy. Previous studies have shown that up to three years of bortezomib with thalidomide will improve progression-free survival (PFS).

More recent studies have shown that two years of bortezomib after bortezomib induction improves PFS and causes a survival benefit, although it is modest.

Lenalidomide has also been studied as a maintenance therapy for transplant eligible multiple myeloma patients in three large studies, presented in a meta analysis at the EHA and ASCO meetings this year. The studies included a total of 1,200 patients. There was a PFS benefit in all three studies and a 72% 7-year survival benefit with lenalidomide compared to 50% with placebo. The median overall survival has not been met in the lenalidomide maintenance group.

Philip McCarthy, MD

Articles

Dr McCarthy on Neutrophil Activity in Multiple Myeloma

Dr McCarthy on Neutrophil-Mediated Immunosuppression in Multiple Myeloma

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

Roswell Park Transplant Specialists Explore New Strategies for Tackling GVHD

Dr. Philip L. McCarthy on Maintenance therapy for Multiple Myeloma