[DanaH]

High Risk SMM, MGBS or MGUS ???

by DanaH on Sun Feb 17, 2013 9:47 pm

Initial MGUS IgG kappa diagnosis in December 2010
Reclassified as High Risk SMM in January, 2012 due to plasma cell % and aberrant plasma cell % coupled with IgA immunoparesis per PETHEMA (Spanish risk progression study).
M-spike has remained constant
FLC kappa and ratio slow upward trend
IgA remains low
Polyclonal IgG is greatly diminished per lab reports.
Calcium in 10 – 11 range, but since Zometa IV 9.7
HgB apprears to be trending downward ?
Lymphopenia
Foamy Urine/proteinuria, but no Bence Jones M-spike, TP 72 mg/24 hours @100% Albumin @ 3/2011; TP 126 mg/24 hours @ 27% Albumin, 20% Alpha 1, 14% Alpha 2, 30% Beta, 8.7% Gamma 10/2012
2 Bone Marrow Biopsies (each @ different onc/hem, not multiple myeloma specialists)
Neuropathy constant & continues.

DEXA scan of 9/24/2012 revealed beginning stage of severe osteopenia due to interim demineralization of Left femoral neck (T score -1.9) and lumbar spine (-1.8) Left Hip (-0.5) within normal range.
DEXA scan of 9/24/2010 revealed beginning stages of Lumbar Spine Osteopenia (T score -1.1), Left Femoral neck (-0.9) & Left hip (-0.3) within normal range. Zometa IV commenced 10/2012, every 3 months protocol.

No evidence of FDG avid lesions to suggest active myeloma per October 2012 PET w/FDG, low dose CT and Full spine and bilateral knee non-contrast MRI’s of 1/29/2013.

55 year old, Caucasian female, post menopausal since June, 2005. C-section 4/1989, High Cholesterol since 1998 , viral pneumonia 10/1990. Low blood pressure. Open angle glaucoma 2/2011 (both mother & father had), Hashimoto’s 9/2011 based upon elevated TPO (thyroid still functioning normally), frequent sinus infections w/ antibiotic therapy. Due to undertreated (7 days of Amoxicillin) strep throat infection, left tonsil abscess 9/2012 resolved with 20 days of Levofloxacin. Annual flu vaccines and pneumonia vaccine 10/2011. No medications, only supplements.

In June, 2009, developed constant tingling in toes and fingertips. Gradually radiated to knees and elbows by September, 2010 coupled with morning stiffness of hand, knee and ankle joints, fatigue, urinary frequency, pain in left thigh, mild night sweats and shortness of breadth.

PCP ordered blood tests revealed nothing abnormal (CBC, CMP, GFR, A1C, ANA, RA, CCP IGG, TSH). Xray of Hands normal, Cervial Spine revealed moderate disc space narrowing& small spurs @ C5-C6 with degenerative changes.
DEXA scan of 9/24/2010 revealed beginning stages of Lumbar Spine Osteopenia (T score -1.1), Left Femoral neck(-0.9) & Left hip (-0.3) within normal range.

Referred to Neurologist in October, 2010. Autoimmune testing normal (LYME, HU ANTIBODY, ANA, CRP, ESR, GM1AB–IGG & IGM, MAG-SGPG AB IGM ), but discovery of M-spike @ .87 g/dL. IgG 1242 mg/dL, IgA 71, IgM 105.
December, 2010 EMG/NCS normal - ruling out large fiber neuropathy and carpal tunnel.
December, 2010 Stress ECHO normal.

Referred to hem/onc in December, 2010. M-spike @ 0.81 g/dL, FLCk @ 36.4 mg/L , FLCl @ 8.9, FLCr @. 4.09, IgG 1236 mg/dL, IgA 73, IgM 101.

12/30/2010 BONE MARROW BIOPSY.
FINAL DIAGNOSIS: bone marrow aspirate, aspirate clot section and biopsy:
- Kappa light chain restricted plasmacytosis: consistent with a plasma cell neoplasm.
- MGUS diagnosis IgG Kappa.
Comment: Immunophenotypic studies by flow cytometry are non – contributory, plasma cells appear positive for BCL-1. Special stains for Amyloid (Crystal Violet and Congo Red) are negative.

BONE MARROW ASPIRATE:
Particles are cellular with scattered plasma cells. No large aggregates or sheets of plasmas cells. Megakaryocytes are present.
200-cell differential:
Blasts, less than 1%
Granulocytic precursors showing normal maturation, 49%
Monocytes, less than 1%
Erythroid precursors showing normal maturation , 34%
Small lymphocytes without significant atypia, 9%
Plasma cells with some plasmacytoid forms, 8%

BONE MARROW BIOPSY:
Mildly hypocellular (30-40%) with scattered interstitial plasma cells. No sheets or large aggregates of plasma cells. The aspirate clot section is mildly hypocellular (30%) with scattered interstitial plasma cells. Megakaryocytes are present. Maturing myeloid and erythroid precursors are present. Stainable iron is present (1-2+). Multiple levels are examined.

Studies Performed: CD3, CD20, CD56, CD138, BCL-1, MUM-1, PAX-5, & p53. CD138 AND MUM-1 demonstrated scattered interstitial plasma cells. There are no sheets or large aggregates of plasma cells. The plasma cells also appear positive for BCL-1. The T-cell antigen, CD3, and the B-cell antigens, CD20 and PAX-5 demonstrate scattered interstitial cells. There is no significant expression for CD56 or p53.

GATED FLOW CYTOMETRIC ANALYSIS:
Population Gated: Lymphocytes/Blasts/Plasma cells.
IMPRESSION: NO MONOCLONAL PLASMA CELL POPULATION IDENTIFIED.
Studies Performed: CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD11c, CD13, CD14, CD16, CD19, CD20, CD23, CD33, CD34, CD45, CD56, CD64, CD117, FMC-7, surface and cytoplasmic kappa and lambda.
Flow cytometric studies performed by four-color analysis identify no significant population of cells with low right angle light scatter and intermediate CD45 (LCA) expression characteristic of blasts. Further immunophenotypic analysis shows no atypical expression for the myelomonocytic antigens, CD13, CD33, and CD64, or the monocytic antigen CD14. There is no significant expression for the early myeloid antigen, CD117 (c-kit ligand), or the progenitor stem cell antigen CD34. The lymphocytes consist of predominantly T-cells, without obvious phenotypic abnormality. Both CD4 positive and CD8 positive T-cell subsets are present. The B-cells present consists of a mixture of kappa and lamda light chain bearing cells without evidence of light chain restriction. Cytoplasmic kappa and lambda light chains are non-contributory. There is no atypical expression for the NK-cell antigens, CD16 and CD56. In summary, the immunophenotypic findings are non-contributory.

1/5/2011 Abdominal Fat Pad Aspiration Biopsy for Amyloid negative.

1/12/2012 BONE MARROW BIOPSY.
DIAGNOSIS: bone marrow biopsy, aspirate and peripheral smear:
- Variably cellular bone marrow with increased atypical Cyclin-D1 positive plasma cells with Kappa light chain predominance
- Maturing trilineage hematopoiesis
- High Risk SMM DIAGNOSIS due to 97% aberrant cells of the 10% “averaged” plasma cells upon flow cytometry coupled with IgA immunoparesis per PETHEMA (Spanish risk progression study)
Comment: The percentage of plasma cells varies within the biopsy: some area have 5-10% plasma cells while other areas have 10-15% plasma cells.

MARROW BIOPSY Sections:
Cellularity is variable ranging from 20-40%, overall 30% cellular.
Megakaryocytes: present, non-dysplastic
M:E ratio 2:1
Immunohistochemical stains:
CD138 immunostain highlights increased plasma cells which vary in concentration within the biopsy; some areas contain 10-15% plasma cells while other areas contain 5-10% plasma cells. The plasma cells are positive for Cyclin D1 and negative for CD 56, CD117 and CD20. Kappa an Lambda immunostains as well as Kappa and Lambda in0situ hybridization demonstrated kappa light chain predominance. CD3 demonstrates scattered T-cells. Reticulin demonstrated mild grade 1-2* out of 4 fibrosis. CD34 positive cells are less than 5%.

MARROW ASPIRATE Smears:
200 cell differential:

Blasts, 2%
Myeloid precursors, 52%
Erythroid precursors, 24%
Lymphocytes, 10%
Eosinophils, 5%
Plasma cells, 6%
Mast cells, 1%

Myeloid maturation: progressive
Erythroid maturation: progressive
Megakaryocytes: present, rare monolobated forms seen
Stainable Iron: Present, no ringed sideroblasts

Marrow Aspirate Sections: Consistent with marrow biopsy.
Marrow Biopsy Touch Prep: Consistent with marrow biopsy

PERIPHERAL BLOOD Smear:
Lymphopenia in an otherwise morphologically unremarkable specimen.


FLOW CYTOMETRY
DIAGNOSIS: Bone Marrow Aspirate: Clonal abnormal plasma cell population.

NOTE: The patient has a history of MGUS and the specimen is submitted for evaluaton of disease. The bone marrow aspirate may contain significant blood contamination and morphology should be used for the bone marrow differentia.
97% of the plasma cells (European Myeloma Network gating criteria) are abnormal monoclonal plasma cells ecpressing dim CD27, bright CD38, CD138 partial CD56, dim CD45, moderate to negative CD20, dim CD81, dim CD126, dim CD200 and intracellular kappa but negative for intracellular lambda, CD19 and CD28. The abnormal plasma cells do not express surface light chains. The B-Cells are polyclonal. The immunophenotypic data correlates with morphology.

% Abnormal Plasma Cells (of total plasma cells): 97%
Plasma cells - % of all nucleated cells: 0.3%
Plasma cells - % of mononuclear nucleated cells: 1.4%

GROSS DESCRIPTION: Viability 93%

LAB RESULTS (so sorry, did not know how to post as a easy to read table)
1/5/2011 3/28/2011 7/7/2011 9/27/2011 4/4/2012 10/2/2012 2/4/2013
M-spike G/dL 0.76 0.66 0.75 0.78 0.77 0.74 0.75
Kappa mg/L 33.46 35.6 40.77 43.39 50.14 42.57 54.34
Lambda mg/L 6.34 6.71 7.33 7.59 7.02 5.35 5.9
Ratio 5.278 5.306 5.562 5.717 7.142 7.957 9.210
IGG mg/L 1235 1365 1326 1268 1249 1185 1321
IGA mg/L 51 57 50 51 49 46 50
IGM Mg/L 111 124 117 118 102 98 95
Protein G/dL 7.8 7.6 7.3 7.5 7.7 7.5 7.3
Albumin G/dL 4.9 4.3 4.8 4.6 4.7 4.8 4.5
Calcium mg/dL 10.8 10.7 10.2 11.0 10.3 10.0 9.7
Creatiti mg/dL 0.8 0.79 0.88 0.81 0.74 0.74 0.81
HgB G/dL 14.1 14.5 15.2 15.0 14.8 13.4 13.1
WBC 7.1 5.5 4.1 6.5 3.9 4.6 5.9
Lymph 0.9 1.0 0.8 1.1 0.8 0.9 1.0
Platlet 245 216 247 225 238 195 324
LDH U/L 177 191 - 222 183 142 172
CRP mg/L 0.6 0.7 0.7 0.7 0.5. 0.6 0.5
B2M mg/L 1.64 1.58 1.52 1.30 1.78 1.37 1.35


Additional Blood tests w/ normal results: Cryoglobulins, CCP AB IGG, EIA, PTH, ACE, HEAVY METALS, SCHLERODERMA, GD1b ANTIBODY, DNA (DS) ABS, SJOGRENS AB (SS-A), SJOGRENS AB (SS-B), VASCULAR ENDO VEGF, C3 COMPLEMENT, C4 COMPLEMENT, CALCITONIN, MYELOPEROXIDASE AB, PROTEINASE-3 AB, EBV, CORTISOL, ACTH, ATA TRANSGLUTAMINESE ANTIBODY, ATA ENDOMYSIAL ANTIBODY, TROPONIN, BNP, PROTHROMBIN TIME, PTT, ANTIPHOSPHOLIPID AB PANEL, 5’ NUCLEOTIDASE, ALDOLASE

Since M-spike has remained constant, but FLC shows slow upward trend, are my “multiple myeloma” markers really reflective of what’s going in my bone marrow environment? I am concerned I have oligosecretory disease.
Would you concur with my “label” High risk SMM? Would the term MGBS (monoclonal gammopathy of borderline significance) apply to my situation?
Should I consider early intervention clinical trials? Thank you to anyone who took the time to read my novel !

[DanaH]

Re: High Risk SMM, MGBS or MGUS ???

by DanaH on Tue Feb 19, 2013 11:21 pm

I know I posted a lot of information, but can anyone help me interpret these results?

[Nancy Shamanna]

Re: High Risk SMM, MGBS or MGUS ???

by Nancy Shamanna on Wed Feb 20, 2013 10:18 am

Hi Dana, I can see why you are concerned about your health and also why you are a bit confused too. With so much information at your fingertips, it is not a simple task to interpret it all.
I am not a doctor, but I see that you have been monitored since Jan. of 2011, so that is more than two years now. Is it the rising kappa/lambda ratio that you are most concerned about?

I think that if you are not sure of your diagnosis after two years, you should probably get a second opinion from another myeloma specialist. I take it that you have not started any treatment so far, except for Zometa. If you can find the right specialist(s) to confer with, you could at least start to think about what course of treatment to take if necessary.

There are people on the forum from many geographical regions. If you could share with us where you live, probably someone could recommend a treatment centre or specialist for you. Also, the Beacon has a list of treatment centres. Hope this helps...good luck with sorting it out!

[Multibilly]

Re: High Risk SMM, MGBS or MGUS ???

by Multibilly on Wed Feb 20, 2013 12:15 pm

Hi Dana,

If you are worried about being diagnosed as high risk SMM, you would certainly want to know what your cytongenetics are and if you have any negatives related to multiple myeloma. Not sure that I see any chromosome testing and/or FISH results in all the above data.

A second opinion is always good to get with this disease, especially if you are considering treatment options.

Regarding risk classification, this was an informative thread that helped me out.
https://myelomabeacon.org/forum/formal-risk-of-progression-classification-for-smoldering-multiple-myeloma-t1542.html?hilit=risk%20of%20progression As you will see, there is not consensus in the medical community regarding risk classifications for multiple myeloma and SMM.

Best of luck.

[DanaH]

Re: High Risk SMM, MGBS or MGUS ???

by DanaH on Wed Feb 20, 2013 2:13 pm

Thanks to both of you.

Nancy, i think my greatest concern is with the stable M-spike vs the increasing FLC's and the PC% in my BMB. I am concerned my blood markers are not truly indicative of what is going on in my marrow. I am trying to understand if my FLC results are the markers to focus on for possible progression, especially since my M-spike has remained stable. Secondary concern is if the bone demineralization process detected by subsequent DEXA scans is related to a myeloma process.

Multibilly, thanks for the link. This is one of my reasons for my confusion as to my "label" due to the different study parameters. I am high risk per the Spanish study (97% aberrant plasma cells and IgA immunoparesis) and low to intermediate risk per the Mayo study (greater than 10% BMB PC and abnormal FLC ratio greater than 8 - which is more recent, and my m-spike is a non-risk factor in this study). I found this link re the discordance between these 2 studies : http://www.ncbi.nlm.nih.gov/pubmed/23311294
This is of concern since as you noted in your other postings, some research supports early intervention in the High Risk SMM. I feel I need to identify my SMM label ( High risk or low to Intermediate) so I can figure out my options, and the options are very different: possibly early intervention for High risk vs. "watch & monitor" for low to intermediate.

I did have FISH studies in December, 2010....no abnormalities, (not sure if that changes though throughout the course of this disease - can it be normal at one stage and then become abnormal?)

I know I need to find an multiple myeloma specialist who can help me sort out my confusion. I am in the NYC area.

[Dr. Ken Shain]

Re: High Risk SMM, MGBS or MGUS ???

by Dr. Ken Shain on Wed Feb 20, 2013 7:18 pm

You are correct that there are different ways to classify risk in smoldering myeloma (Mayo and PETHEMA). Defining risk is important in the face of "evolving" data on early intervention in high risk smoldering patients as well as your expectancy for rates of progression. Critically, before we can change our overall management strategies we first need to come to a consensus about risk stratification. A recent article in Leukemia and Lymphoma (Cherry et al) demonstrated that the Mayo and PETHEMA risk stratification systems have little concordance (28.6%- meaning they do not agree 71.4%). This was only 77 patients, but makes the point quite well.
-As an example from the study- of the 38 High Risk SMM patients defined by PETHEMA (immunoparesis and abnormal FCM plasma cells) only 4 (11%) were high risk by Mayo, 22 (58%) were intermediate and 12 (32%) were low risk. This does not mean that either is incorrect, just that there is more work to be carried out to confirm one, both, or new criteria.

That being said, smoldering myeloma remains a disease where the prevailing managment strategy remains observation- close monitoring- with labs (myeloma, CBC. CMP...) and visit q 3 months and other testing on an annual basis (or if changes are observed). With new well tolerated therapies, we are moving to a point where the treatment of HR SMM may become a standard of care. However, we are not there today. More work needs to be done to 1) define who will benefit (e.g. who really is high risk) 2) what is the most appropriate therapy (Rev/dex vs other), and 3) do we really see reproducible disease modification with these strategies. We are working on it.

So unless on clinical trial or demonstrating signs of myeloma related organ involvement active surveillance remains the management strategy of choice.

[Multibilly]

Re: High Risk SMM, MGBS or MGUS ???

by Multibilly on Wed Feb 20, 2013 8:02 pm

There is a trial ongoing right now for doing chemo (I believe its RVD or a subset therefof). They are at the stage where they are doing double blind studies to see just what the long term benefit might be to treating SMM with chemo early on. While I can technically qualifiy for the trial, I opted not to participate. I decided to instead try to hold things at bay with curcumin and various antioxidants (I won't know till my next round of tests if this is having an effect on my markers...I just started the supplement regime this weekend after getting my latest lab results last week. I will use that data point and earlier data as reference points). If I develop CRAB or if my if my markers really turn south, I will then consider chemo. Playing the SCT card will be my last resort. Anyway, for what it's worth, that's my current philosophy...who knows what circumstances might cause me to change my philosophy?

[terryl1]

Re: High Risk SMM, MGBS or MGUS ???

by terryl1 on Wed Feb 20, 2013 8:11 pm

There is a high risk for progression SMM trial at the NIH in Bethesda, MD with CRD (carfilzomib/Revlimid and dex). I am in the same trial but for newly diagnosed. So far, so good.

[DanaH]

Re: High Risk SMM, MGBS or MGUS ???

by DanaH on Wed Feb 20, 2013 8:25 pm

Dr. Shain, thank you, I so very much appreciate your reply.

I especially agree with your comment "define who will benefit (e.g. who really is high risk) as this seems to be the real challenge in my particular case. I truly don't have a handle on if I am high risk or not.

One thing I am trying to determine is whether the declining bone demineralization per my DEXA scans (1st in 9/2010 and 2nd in 9/2012) is a direct result of this disease. If it is, then the question is whether I'm clinically experiencing the "bone involvement" related to myeloma activity. But perhaps lytic lesions are required to have "bone involvement".

Best to you
Dana

[DanaH]

Re: High Risk SMM, MGBS or MGUS ???

by DanaH on Wed Feb 20, 2013 8:33 pm

Thanks again for your comments Multibilly and also to you terryl1 for your information. I have actually looked at the NIH study, but again, I don't have a clue if I truly qualify for it since I can't seem to claify if I am High risk SMM, hence , my continued dilema !

I do appreciate this forum and the supportive nature.

Best,
Dana