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.

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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

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