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

Jens Hillengass, MD, professor of oncology and internal medicine, chief of myeloma, Roswell Park Comprehensive Cancer Center, professor of medicine, Division of Hematology and Oncology, Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, discusses available imaging modalities in multiple myeloma.

Historically, a skeletal survey using a conventional X-ray was widely used to assess bone disease, says Hillengass. However, whole body low&shy;&shy;&shy;-dose CT scans are used more frequently now due to their increased sensitivity.

Patients who undergo low-dose CT scans are exposed to a slightly higher amount of radiation versus those who undergo X-rays, says Hillengass. However, since low-dose CT scans can identify 25% more patients with bone disease, it is the standard bone-imaging modality in multiple myeloma.

MRI has historically been used to see bone marrow detection before the bone marrow is destroyed. Though MRI can identify osteolytic lesions, it cannot reveal whether lesions are active or not, says Hillengass.

Instead, PET/CT scans, which can show disease metabolism, tumor burden, tumor activity, and bone marrow destruction, should be used. Depending on the sensitivity of the PET/CT scan, focal infiltrations and bone healing may also be seen with this imaging modality, concludes Hillengass.

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Jens Hillengass, MD, discusses available imaging modalities in multiple myeloma.

Dr. Hillengass on Imaging Modalities in Multiple Myeloma

Multiple myeloma is a monoclonal plasma cell disorder characterized by the infiltration and proliferation of malignant cells in the bone marrow. One of the major symptoms of myeloma is the development of osteolytic lesions in the skeleton. This characteristic feature of the disease makes imaging an important tool in the assessment of disease severity.

Until recently, multiple myeloma imaging was performed using conventional skeletal surveys. However, we’ve known for a long time—beginning with data published over 40 years ago&mdash;that 30% to 50% of bone substance has to be destroyed until this degradation shows up on conventional x-ray.

IMWG Research Drives First New Guidelines in 10 Years

In 2017, the International Myeloma Working Group (IMWG) published a retrospective analysis showing that conventional skeletal x-ray survey misses 25% of instances where patients have osteolytic lesions discernible with computed tomography (CT) imaging.

Current CT scanners allow us to perform whole-body low-dose scans with a comparably low radiation dose. Especially in the United States and southern Europe, many centers have been using positron emission tomography (PET)/CT imaging for quite some time to assess tumor burden in myeloma.

The conclusions of that IMWG analysis were clear: If PET/CT is available and in use, the CT part of the scan should be performed with a setting that is equal to a whole-body low-dose CT to get sufficient data on the osteolytic activity.

With a goal of disseminating these compelling findings and filling the void for updated, evidence-based guidance specifically addressing the use of imaging to diagnose, stage, and monitor patients with multiple myeloma, our IMWG imaging panel set about expanding that recommendation into a comprehensive set of guidelines.

The resulting guidance, “International Myeloma Working Group Consensus Recommendations on Imaging in Monoclonal Plasma Cell Disorders,” was published in 

 Imaging approaches and technologies have advanced dramatically since the last such guidance was developed a decade ago, driving earlier and more effective detection and treatment, so it was high time for an update.

Key Changes in Panel's 2019 Recommendations

The most significant departure from previous guidelines on imaging in multiple myeloma, driven largely by considerations over the applicability and economics of implementation—was the recommendation for whole-body low-dose CT as the primary screening method to be replaced by PET/CT where available.

Magnetic resonance imaging (MRI) has been shown to have the highest sensitivity for the detection of focal and diffuse infiltration of the bone marrow by myeloma cells, both of which have been shown to precede the osteolytic process in patients with smoldering myeloma. Therefore, if CT is negative but there is still suspicion of myeloma, whole-body MRI is recommended to rule out focal lesions that have not yet caused bone destruction.

Current treatment regimens lead to far higher complete response (CR) rates and even minimal residual disease (MRD-negative rates than in the past. However, if CR or MRD negativity are confirmed in the bone marrow, this only reliably gives information on the area where the biopsy has been performed.

Since myeloma can grow in a rather patchy fashion, additional imaging is recommended. In this setting, PET/CT has been shown to provide the most reliable results and is therefore recommended— at least within clinical trials&mdash;to confirm that in cases of serological and bone marrow-confirmed deep remission, no residual lesions outside the area of a biopsy can be detected. This is relevant, since those residual lesions in imaging have been shown to be of adverse prognostic significance, most likely representing a source of the disease relapse.

NCCN Clinical Guidelines Also Updated This Year

The National Comprehensive Cancer Network’s (NCCN) Multiple Myeloma Panel also updated the NCCN guidelines for imaging.

 Our panel not only incorporated updated guidance on imaging, adopting the key recommendations of the IMWG, but we also refined many elements related to myeloma diagnosis and treatment.

Among the new, or significantly revised, recommendations within this latest iteration of the NCCN guidelines for multiple myeloma are the following changes:

New options for primary therapy for transplant candidates:	

Bortezomib (Velcade) plus doxorubicin and dexamethasone is now labeled as useful only in certain circumstances. 

Carfilzomib (Kyprolis) plus cyclophosphamide and dexamethasone and ixazomib (Ninlaro) plus cyclophosphamide and dexamethasone are now listed as useful combinations in certain circumstances for patients with renal insufficiency and/ or peripheral neuropathy. 

Two combinations, bortezomib plus dexamethasone and lenalidomide (Revlimid) plus dexamethasone, were removed as recommended primary treatment for these patients.

Updated guidance on primary therapy for nontransplant candidates:	

Daratumumab (Darzalex) plus lenalidomide and dexamethasone was added as a category 1 preferred regimen.

Carfilzomib plus cyclophosphamide and dexamethasone is now labeled as useful in certain circumstances.

Daratumumab plus bortezomib, melphalan, and prednisone is now a recommended regimen (category 1).

Two new regimens for patients on maintenance therapy: 	

Ixazomib is added as a category 1 recommendation after transplant.

Bortezomib plus lenalidomide is added for transplant and nontransplant patients.

Two new regimens for patients with previously treated disease were added:	

Daratumumab plus carfilzomib and dexamethasone

Ixazomib plus cyclophosphamide and dexamethasone

Other new recommendations for patients with previously treated disease:	

Pomalidomide (Pomalyst) plus bortezomib and dexamethasone is now a category 1 recommendation.

Two new regimens are now identified as useful in certain circumstances: carfilzomib plus cyclophosphamide, thalidomide  (Thalomid), and dexamethasone; and selinexor (Xpovio) plus dexamethasone

We also significantly revised our guidance on radiation therapy and supportive care and added a page on management of renal disease in multiple myeloma.

Additional exciting opportunities await. I’m eagerly following research seeking to answer the question of whether incorporating more specific tracers or dyes into our imaging practices can pave the way for further advances in imaging among these patients. I’m also watching for further improvements in imaging technologies and tools.

It’s my sincere hope that broader application of more advanced technologies and techniques will lead to more reliable imaging, more accurate diagnoses, earlier treatments where necessary, and longer remissions for those living with myeloma.

Imaging scans for the same patient show that conventional skeletal x-ray, top, misses osteolytic lesions (shown with arrows) that can be detected with CT, bottom.

Dr Hillengass served as chair of the IMWG Imaging Guidelines Panel and as a member of the NCCN Guidelines Panel for Multiple Myeloma.

Hillengass J, Moulopoulos LA, Delorme S, et al. Whole-body computed tomography versus conventional skeletal survey in patients with multiple myeloma: a study of the International Myeloma Working Group. 

. 2017; 7(8): e599. doi: 10.1038/bcj.2017.78.

Hillengass J, Usmani S, Rajkumar SV, et al. International myeloma working group consensus recommendations on imaging in monoclonal plasma cell disorders. 

. 2019;20(6):e302-e312. doi: 10.1016/S1470-2045(19)30309-2.

NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma, version 2.2020. National Comprehensive Cancer Network website. nccn.org/professionals/physician_gls/pdf/myeloma. pdf. Updated October 9, 2019. Accessed October 28, 2019.

Imaging approaches and technologies have advanced dramatically since the last such guidance was developed a decade ago, driving earlier and more effective detection and treatment.

Jens Hillengass, MD

Articles

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

Dr. Hillengass on Imaging Modalities in Multiple Myeloma

New Myeloma Guidelines Reflect Advances in Imaging, Explosion of Treatment Options