Expert Reviews New Diagnostic and Staging Criteria in Multiple Myeloma

Jens Hillengass, MD

Due to a dramatic paradigm shift in multiple myeloma, the diagnostic and staging criteria have been updated, which represents the considerable impact the latest developments in the field have made on the management of this disease. In 2014, the International Myeloma Working Group (IMWG) published updates to the 2003 criteria for the diagnosis and staging of myeloma, which now serve as the basis of newer criteria available today.

IMWG initially added 3 new biomarkers, among other modifications, to the previously established criteria, which have become known as CRAB, which features elevated calcium levels (C), renal failure (R), anemia (A), and bone lesions (B). The new criteria, however, which were discussed in a presentation during the 2020 National Comprehensive Cancer Network (NCCN) Virtual Congress: Hematologic Malignancies, feature the addition of 3 new principles to the established CRAB.

The new and current diagnostic and staging criteria, known as SLiM CRAB, now include the following: 60% or more clonal plasma cells (S), light chains (Li), and MRI (M). It has been observed that patients with 60% or more clonal plasma cells in the bone marrow were likely to progress and are considered symptomatic, those with light chain ratios of greater than 100 were likely to progress and required treatment at diagnosis, and those with more than 1 focal lesion on MRI likely required systemic therapy as they have transitioned from smoldering myeloma to symptomatic disease.

In an interview with Targeted Oncology, Jens Hillengass, MD, professor of oncology and internal medicine, chief of myeloma, Roswell Park Comprehensive Cancer Center, and professor of medicine, Division of Hematology and Oncology, Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, shared his insights on the latest edition of the diagnostic and staging criteria for multiple myeloma that have become standard now for the management of these patients.

TARGETED ONCOLOGY: What was the topic of your presentation at this year’s meeting?

Hillengass: I was asked to give a more general overview over the new diagnostic criteria. We're asked, “why do we need new diagnostic criteria in the first place?” The IMWG had published them in 2014, but the idea behind that was that for a long time, myeloma was only treated when a patient developed symptoms because in the old days, with the old treatment that we had, treatment was obviously causing [adverse] effects. The data with the old drugs that we had back in the day was just that patients develop the actual myeloma later. If they had an early stage and were treated, they develop the actual myeloma later, but when they also develop [adverse] effects early on, so the overall survival in all those studies was not better, so the idea was to wait until the disease really caused symptoms and then treat the patient.

Then we had a publication from a Spanish group showing that a newer treatment, lenalidomide (Revlimid) together with dexamethasone, improved the progression-free survival, the treatment [adverse] effects were not too bad, and eventually they showed an overall survival benefit for patients with high-risk smoldering myeloma, which is the early stage of myeloma in patients who had no significant clinical symptoms. That was the reason why the consensus was we need guidelines that give us risk factors that are strong enough to recommend treatment based on them so that the patients have a benefit from the treatment without having unnecessary [adverse] effects to a certain degree.

TARGETED ONCOLOGY: Could you elaborate on the new diagnostic criteria in myeloma?

Hillengass: The new criteria were published in 2014 by the IMWG, and included not only the old so-called CRAB criteria, which stands for: C for hypercalcemia, R for renal damage, A for anemia, and B for bone disease, which are the 4 major symptoms or complexes of symptoms in multiple myeloma. In addition, now in the new guidelines, there are so-called myeloma-defining events that are added to the 4 CRAB criteria, which are a ratio of free light chains that is higher than 100, with the involved light chain being more than 100 milligrams per liter in serum. That has been shown in 2 independent studies to be a prognostic marker for patients who have smoldering myeloma to develop multiple myeloma, so that was defined as 1 factor to define the so-called myeloma defining event.

A second factor was the increase of plasma cells in the bone marrow of more than 60% of plasma cells, so the definition of myeloma is more than 10%, but if a patient with smoldering myeloma, early-stage myeloma, has more than 60%, it has been shown in 2 independent data sets that it is a prognostic significance with a high risk to progress into symptomatic disease. The third was a finding that if we do imaging with MRI, and later on, it was also shown with PET-CT, if the patients have changes in their bone marrow without any changes to the bones, this would have been criteria for bone disease. However, even if they have changes in the bone marrow, and statistically, it was more than 1 focal lesion that we know, more focal lesions without osteolytic lesion are also considered to be a myeloma defining event. These are the new criteria, and someone came up with a nice acronym SLiM CRAB, which is S for 60% plasma cells, Li for light chains, and M for MRI lesions.

TARGETED ONCOLOGY: How does the addition of SLiM criteria add value to the already established CRAB criteria?

Hillengass: The treatment that we now have is much better, much more effective, and, to a certain degree, different or [fewer adverse] effects than the old-school chemotherapy drugs, and the effect there is that if we treat the patients earlier with a rather well-tolerated treatment, they end up having a better prognosis.

Using the SLiM CRAB criteria, we will treat some patients who would not have been treated in the old days, but now we see that they have a better benefit if we treat them earlier, which is the case in other cancers and a lot of people have talked about that in breast cancer, where we would not wait until they have bone metastasis; we would treat a patient earlier, of course. There was a reason, and in myeloma, it has been confirmed that it is beneficial. Now, there are also studies showing that even patients who don't fulfill those SLiM CRAB criteria but have a high-risk smoldering myeloma still might have a benefit from treatment, and this is still in development.

TARGETED ONCOLOGY: Could you elaborate on the prognostic factors in symptomatic myeloma?

Hillengass: There's a new staging system called revised International Staging System (ISS), and it includes 2 rather easily assessed lab markers called Beta-2-microglobulin and albumin. If Beta-2-microglobulin is high and/or albumin is low, that is a marker of worse prognosis, and this revised ISS adds on to this lactate dehydrogenase, which is another marker showing aggressive disease, and fluorescence in situ hybridization cytogenetic techniques for genetic assessment of myeloma cells, and combining those factors together gives us a very good marker for the prognosis of our patients.

TARGETED ONCOLOGY: What are the different treatment options available in myeloma at this time?

Hillengass: It's becoming more and more complex to treat multiple myeloma, which is a good thing because we have so many options to treat patients with a few drug classes that are very commonly used in myeloma. At the moment, the combination of a proteasome inhibitor, immunomodulatory drugs, and a steroid is the standard-of-care induction treatment for patients. In younger patients with fewer comorbidities a stem cell transplant is the standard of care later on, so we still differentiate between so-called transplant-eligible and transplant-ineligible patients. In the old days, again, it was rather based on age, so we said more than 65 years, then it was more than 70 is an exclusion criterion for transplant. Nowadays, most experts agree that it is more considering the biological age than the chronological age of a patient, so those patients are still divided in transplant-eligible and -ineligible, and the induction treatment is rather similar. As I said, it's a combination of a proteasome inhibitor, immunomodulatory drug, and steroid. In some patients, newer publications have shown adding a monoclonal antibody is also beneficial for patients to bring them into deeper remission. This is not approved yet and is not in the guidelines set, but it is something that is investigated in clinical trials. In elderly patients or more frail patients, a combination of an immunomodulatory drug and an antibody alone without a proteasome inhibitor is another option that can be used.

TARGETED ONCOLOGY: What are the remaining challenges in the space right now?

Hillengass: One challenge is that myeloma, still in the vast majority of patients, is incurable, meaning patients nowadays with the new drugs that I mentioned, have a great response most of the time, go into deep remission, and then at 1 point still, after sometimes months or sometimes after many, many years, they relapse, and the disease comes back. We still have a lot of other options. We can do different combinations of different drugs. We have new drugs that are developed and that have completely different mechanisms of action, so that's very exciting. However, still after a while, the disease comes back, then we treat again, the disease comes back again, and at some point, we run out of options, or the patient becomes too sick from the [adverse] effects of the treatment from the cumulative [adverse] effects of treatment, so we still don't really cure a significant number of patients. I think that's the major challenge. Treating patients earlier, I think it's a good first step, because as I said, why wait until they have kind of metastatic disease? We don't call it metastatic in myeloma, but that's something we would not do in another cancer. Treating them earlier might be a good first step to finally cure myeloma, but at the moment, we're not there yet.

TARGETED ONCOLOGY: What are the key takeaways from your presentation?

Hillengass: One major takeaway is that we should not wait too long until we treat myeloma, but we still should be careful not to treat too early because some patients have a smoldering myeloma, an early stage, which develops rapidly into a symptomatic disease, but others have smoldering myeloma that biologically behaves much more like the earliest stage of monoclonal plasma cell disorders, and those patients should not get treatment because they can be without any treatment, sometimes for the rest of their lives. Differentiating those is very important, and the risk factors that I mentioned are helping with that. What I have also talked about is that imaging helps us to differentiate more between the high and the low tumor burden. We can measure response to treatment, and those are factors that are also very important because, obviously, a deeper remission goes along with a better prognosis. We use new techniques for imaging to find the depth of the remission and also molecular and flow cytometry techniques to assess minimal residual disease negativity. These, I think, are the takeaways and also the hot topics at the moment in multiple myeloma.