Smoldering Asymptomatic Myeloma or active Multiple Myeloma ? Understanding the crucial difference.

BY DANA HOLMES What tests did you have to confirm your smoldering multiple myeloma diagnosis? Did you need to consult with more than one hematologist/oncologist and/or myeloma specialist to get this diagnosis? In a recent Myeloma Beacon forum discussion, a medical advisor myeloma specialist stated that it is very important to make the critical distinction between a monoclonal gammopathy of undetermined significance (MGUS) OR smoldering (asymptomatic) myeloma (SMM) as they are two VERY different disorders. I believe it is even MORE crucial to make this distinction between smoldering multiple myeloma and active multiple myeloma. But how do we go about making certain we have had the right level of evaluation required so we can be comfortable knowing we have an accurate diagnosis? As complex as this disease is, has the evaluation of those with smoldering multiple myeloma been just as detailed? Is there standardization as to which tests we need and which tests we have all had? Does it differ from center to center, from specialist to specialist? How thorough do we really need to be??

Where Do We Start?

We need to know what total % of plasma cells we have in our Bone Marrow Biopsies to meet one of the criteria of the SMM definition. An MGUS (Monoclonal Gammopathy of Undetermined Significance) diagnosis is less than 10% of total plasma cells in the bone marrow. A smoldering myeloma (SMM) diagnosis is equal to or greater than 10% of total plasma cells in the bone marrow WITHOUT CRAB-I  symptoms which are:   C = Elevated Calcium,  R = Renal failure, A = Anemia,  B = Bone lesions,   I= infections. (Here's a helpful link to define CRAB) An active multiple myeloma (MM) diagnosis is equal to or greater than 10% of total  plasma cells in the bone marrow WITH CRAB-I symptoms. If you move a little to the left of this 10% without CRAB-I features (say you are at 9%), then you are considered to have MGUS . Is there a way to teeter on the MGUS fence at 10.2% perhaps? By definition, the answer to that is NO.  Once you have equal to or greater than 10% total plasma cells , you are labeled SMM, no turning back. A bit arbitrary?  Perhaps. We need to know the % in both the core bone marrow biopsy (solid piece of bone marrow) and the aspirate (the liquid marrow).

And Then What? (based on my layperson understanding)

Immunohistochemical samples are sections of biological tissue, where each cell is surrounded by tissue architecture and other cells normally found in the intact tissue. Immunohistochemistry (IHC) is performed on the core sample and can prove monoclonality (many of the same types of plasma cells present) or lack of monoclonality (no monoclonal plasma cells in the bone marrow biopsy, only normal polyclonal - lots of different types of plasma cells present), light chain predominance (kappa or lambda) and provides overall cellularity. This is the section of the bone marrow biopsy report where you will see the presence of a protein called CD138.  CD138 is a classic plasma cell marker and can be found on both normal polyclonal or abnormal monoclonal plasma cells.  Being CD138 positive and knowing the total plasma cell % from the core bone specimin would be the best markers to understand the extent of bone marrow infiltration. The core % is the one used  to tell us if we have equal to or over the 10% of  total plasma cells in the bone marrow, the criteria to meet the smoldering myeloma definition. But, this is still somewhat of a subjective analysis, as the count is manually determined by a pathologist viewing prepared cell slides through a powerful microscope. Immunohistochemistry– A Video about the Procedure

A Video about Tissue Microarray/ IHC The % of plasma cells found in the core often varies from the % of plasma cells found in the aspirate. The aspirate can frequently under-represent the myeloma bone marrow burden and infiltration of plasma cells as the liquid sample contains other blood cells. Additionally,  myeloma cells tend to shed CD138 when stressed and removed out of their microenvironment.  Myeloma cells are closely adherent to the bone matrix and therefore don’t all get released into the aspirate. And the ones that do, can break apart by the mechanical suction during the aspiration. Automated Flow Cytometry studies performed on the aspirate sample provide the information about which proteins are being expressed on the plasma cells. These expressed proteins help to further identify and separate the abnormal myeloma monocolonal plasma cells from the normal polyclonal plasma cells.  The cells are stained and tagged by the proteins they are expressing,  i.e., clusters of differentiation/cluster designations/CD markers:  CD38, CD56,CD45, CD19, etc.   CD markers help to specifically identify which of the cells in this liquid sample are the abnormal myeloma plasma cells.  You will see these CD markers in your bone marrow aspirate biopsy report. The cells are passed through a flow cytometer, a machine which uses colored lasers to highlight the individual, stained CD markers being tested for. Most flow cytometer machines have 4 or 6-colored lasers, and some can have more than 20 colors.  Each laser color highlights a different CD marker. The 8 and 12- color flows cytometers are evolving into a standard and may already be used by some of the dedicated myeloma centers.  A limited number of studies have implicated some CD markers that may have prognostic value. Karyotype, FISH and GEP studies would be performed using the aspirate plasma cells (liquid sample). These tests are performed on the cells which have been identified as the abnormal myeloma plasma cells by the flow cytometry studies which used the colored lasers and the CD markers.  These additional tests identify the biology of the cells.  They are searching for the chromosome abnormalities inherent to the abnormal myeloma plasma cells. But what other criteria do we need to meet to ensure smolderers don't actually have active myeloma? Not having CRAB-I symptoms is crucial. The “C” (Hypercalcemia), “R” (Renal Involvement) and “A” (Anemia) are fairly straightforward. Lab values from the Complete Blood Count (CBC) and Complete Metabolic Panel (CMP) are reviewed and evaluated. Iron stores are also evaluated in the Bone Marrow Biopsy. The “I” is evaluated based on clinical history of current and past “serious” Infections. But the waters get a bit muddied for the “B”, Bone Involvement. What imaging do we need to fully assess this? Full body skeletal surveys remain the gold standard to find focal lytic lesions as well as diffuse, generalized osteopenia/osteoporosis. A bit rusty and outdated if you ask me as you need at least 30% cortical bone destruction before it will show up on a conventional x-ray (not sure how advanced  osteoporosis needs to be before it starts showing upon x-rays). A DEXA scan (bone density scan) is useful to determine diffuse, decreased bone density involvement in the form of osteopenia/osteoporosis. Studies have validated the MM cells express certain signals to increase osteoclastic activity, promoting the bone remodeling imbalances. But they only scan your lumbar spine and your hips.  Can this be representative of your full skeletal bone density? And how do we know this bone density decline is not simply due to hormonal imbalances? Do we need additional advanced imaging? MRI’s, Whole Body MRI’s, CT’s, Whole Body low dose CT’s, PET/CT using flourine/glucose (FDG) trace?  We also need serum and urine tests some of which are considered "semi-quantitative". [M-spike/M-protein levels (Serum and Urine Protein Electrophoresis (SPEP/UPEP); Immunofixation electrophoresis (IFE); Quantitative Immunoglobulins (IgG, IgA, IgM), Free Light Chain Assays (kappa/lambda) and Beta-2 Microglobulin (B2M) ]. Increasing lab trends should warrant additional or repeated testing, perhaps another bone marrow biopsy or additional imaging tests. But what are the standardized guidelines?  Sure we can leave all of this in the hands of our specialists, but wouldn't it be better if we knew and understood?  We are, after all,  a key team player. This is surely not an “easy” diagnosis to acquire. The WHY behind why we should acquire the most accurate diagnosis is another topic altogether! I believe it can give us the information we need to make responsible choices and decisions about participating in early treatment clinical trials versus the standard of care of watch and wait until we develop overt CRAB-I symptoms. I don’t believe we should wait to be thoroughly evaluated through an initial evaluation of a specific early treatment clinical trial to assess or confirm our actual diagnosis. We need to know before, so we can evaluate and compare the early treatment trials that are presently offered, determine which ones we meet the criteria for, decide which one(s) resonate with us, and discuss with our specialists/get their opinions. We need to better understand the rules of testing standardization before we can begin to make  choices and decisions. We need to better understand where we actually stand within the spectrum. In the meantime, we try to keep on smoldering.