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Malignant plasma cells

NEW YORK—As the number of therapeutic options for multiple myeloma (MM) increases, so too does the need to reassess prognostic markers for the disease, according to a speaker at Lymphoma & Myeloma 2016.

“A good prognosticator for one patient may have little meaning for another patient,” said Scott Ely, MD, of Weill Cornell Medicine in New York, New York.

“It’s really important before doing any testing to ask, ‘Will the result of this test affect patient care?’”

To answer this question, Dr Ely reviewed the different testing methods used in MM patients and explained the advantages of each.

“[I]t’s really important to understand that a lot of methods are really great for research but don’t work or are not feasible for real-life diagnostic purposes,” he added.

Dr Ely also said it’s important to consider who wants the data, how much the test costs, and who will pay for it, keeping in mind that, these days, the patient’s share of the bill is increasing.

Dr Ely stressed that, until more precise targets or a better understanding of drug mechanisms exist, clinical features—patient age, performance status or frailty, renal function, and disease stage—remain the most important prognosticators.

“But still, 2 patients in the same box based on clinical features will often have very different outcomes,”  he said. “So in addition to clinical factors, we need prognosticators for tumor cell behavior. We need to know how fast they are growing and how they will respond to treatment.”

Methods to assess myeloma cell proliferation

Cytogenetics (FISH), gene array technology, and genomics using next-generation sequencing can provide some information, but they are not necessarily good methods to assess proliferation, Dr Ely explained.

To determine the proliferation rate of a patient’s cancer, you can look at tens of thousands of genes by gene array, he said, “or you can just look at one thing, which is Ki67.”

If the cell has Ki67, it’s proliferating, and if it doesn’t have Ki67, it’s not.

“Often, looking at all the other upstream molecules can be confusing and even misleading,” he noted. “So Ki67 is the best way to look for proliferation when it comes to myeloma.”

Other methods include the plasma cell labeling index (PCLI), gene expression profiling, flow cytometry, and multiplex immunohistochemistry (mIHC).

Dr Ely, as a hematopathologist, has found IHC to be the best method to determine proliferation, most likely because the other methods use bone marrow aspirate and IHC uses core biopsy of histologic sections.

It’s the gold standard, he said, for determining the percentage of plasma cells because core biopsy takes a “complete, intact piece of marrow that’s truly representative of what’s going on in the patient.”

In a study of more than 350 bone marrow samples comparing core biopsy with aspirate smears, plasma cells were under-represented in approximately half the aspirate specimens by about 20%.

In addition, Dr Ely noted that myeloma cells die very quickly once they are removed from the stroma.

“So if you take myeloma cells out as an aspirate,” he said, “myeloma cells die and others survive.”

And if the aspirate is sent overnight to the lab, the number of plasma cells in the specimen will already be reduced when the lab gets it.

Aspirates are best for leukemia and myelodysplastic syndromes, Dr Ely said, while core biopsies are best for lymphoma and myeloma.

Plasma cell proliferation indices

Proliferation is a myeloma-defining criterion, Dr Ely said. It predicts an 80% probability of progression in 2 years.

And PCLI has shown conclusively that plasma cell proliferation is a good prognosticator in all types of myeloma patients. However, it is not really feasible to use or easy to perform.

On the other hand, core biopsy combined with IHC is a feasible way of measuring plasma cell proliferation for routine clinical use.

Using standard IHC, it’s difficult to distinguish proliferating from non-proliferating cells, Dr Ely said.

“The solution to this problem is multiplex IHC,” he said, using 3 stains—red for CD138 (the plasma cell marker), brown for Ki67 (the proliferation marker), and blue as a negative nuclear counter stain.

A red membrane around the stained cell indicates a myeloma cell. Non-proliferating MM cells have blue nuclei, and proliferating MM cells have brown nuclei.

This assay is called the plasma cell proliferation index (PCPI).

“[A]ny lab that can do standard IHC can do multiplex IHC,” Dr Ely added.

It uses the same machines, the same reagents, the same expertise, and it’s easy to set up.

Validation studies

Dr Ely and his colleagues performed extensive laboratory validation to make sure the new PCPI correlated with the old PCLI.

They also performed 3 clinical validation studies, the first in bone marrow transplant patients. The investigators followed the patients for 12 years and found the PCPI correlated with survival.

The investigators performed a second clinical validation in 151 newly diagnosed patients. On multivariate analysis, the team found PCPI to be an independent prognostic indicator.

Each 1% increase in PCPI was associated with a 3% increased risk of disease progression (hazard ratio=1.03, 95% CI, 1.01-1.05, P=0.02).

The third clinical validation the investigators conducted was a retrospective cohort study in which they evaluated the effect of rising PCPI at relapse in 37 patients. The team defined rising PCPI as a 5% or greater increase in plasma cells.

Nineteen patients had a rising PCPI, and 17 patients had stable or decreased PCPI.

Patients with a rising PCPI at relapse had a shorter median overall survival than patients with stable or decreased PCPI—72 months and not reached, respectively (P=0.0069).

Patients with a rising PCPI also had a shorter median progression-free survival on first post-relapse treatment compared to patients with stable or decreased PCPI—25 months and 47 months, respectively (P=0.036).

“It’s also important to note that if you’re getting high-risk by PCPI plus β2-microglobulin albumin, I’d advise that, for all high-risk patients, getting the cytogenetics doesn’t really help,” Dr Ely said

Three patients considered high-risk by cytogenetics were standard-risk by PCPI plus β2 microglobulin.

“So we found that cytogenetics isn’t really adding anything except the cost,” Dr Ely asserted.

Other labs are now using PCPI for prognostication, he noted, adding, “We hope PCPI will be incorporated into the International Myeloma Working Group diagnosis of MM.” end hematology article


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