[johanna]

Complete response after ASCT ... or not?

by johanna on Sat Sep 27, 2014 8:37 am

Ian's results since the autologous stem cell transplant (ASCT) in January have been great. Fantastic news, one could not hope for better test results. The serum free light chains (sFLCs) have normalized and are:

kappa free light chains - 14.05 mg/L
lambda free light chains - 10.47 mg/L
k/l ratio - 1.342

But we can't help wonder.

Complete response means you have to obtain these results on top of a normalized sFLC:

1. Negative immunofixation electrophoresis (IFE) in serum & urine
2. Disappearance of any soft tissue plamacytomas
3. < 5% plasma cells in the bone marrow
4. In patients in whom the only measurable disease is by sFLC levels, CR is defined as normal FLC (0.26 - 1.65) in addition to the CR listed above.

Ian never had measurable M-spike in serum OR urine for that matter. That is why they use sFLC to track his disease.

I remember when kappa was over 1000 mg/L the spike was very small, I think just in below 1 and does not correlate, so I don't think they are doing SPEP + IFE anymore. Same with Bence Jones in 24 hour urine. No Bence Jones detected in any of the tests he has done.

To make matters and even more difficult, his myeloma is focal, so it's not spread evenly all over the bone marrow, and therefore, as we understand it , a bone marrow biopsy (BMB) or bone marrow aspirate (BMA) is not very useful, if drilling in a place that has no multiple myeloma cells and results come back normal, though disease is still there ... even if minimal.

So our question is: How do you test for MRD in light chain multiple myeloma (LCMM) when you have no M-spike, no focal involvement, and no Bence Jones, so these tests do not reveal the true nature of the disease, as in Ian's case.

Any advice is welcome as to how we can get a more accurate picture and find out where we stand at this point in time.
Thanking you....

[Multibilly]

Re: Complete response after ASCT ... or not?

by Multibilly on Sat Sep 27, 2014 9:11 am

Johanna,

First congrats on Ian's improvement!

I can see your dilemma regarding how to measure MRD under these circumstances. I'm not a doc and I have no idea if this really makes true medical sense. But has your doctor considered running a PET/CT to see if there are any hot spots? That test by itself could indicate any underlying cancer activity and could be the first step.

I'm also wondering if one could then use the PET/CT results to help choose the specific location for a subsequent BMB to get a sample to then run an MRD analysis on (additional flow immunophenotyping, etc)? At least that way, you would have a somewhat higher confidence that the sample was hitting a general area where one already sees disease on the PET/CT.

Again, I'm not sure if this makes medical sense or not ... just thinking off the top of my head.

Last edited by Multibilly on Sat Sep 27, 2014 3:54 pm, edited 2 times in total.

[JimNY]

Re: Complete response after ASCT ... or not?

by JimNY on Sat Sep 27, 2014 11:37 am

Hi Johanna,

I think you are confusing a number of concepts that are related, but nevertheless different.

First of all, the definition you gave for "complete response" is actually the definition for "stringent complete response." See Table 1 here for a summary of the various response definitions,

SV Rajkumar et al, "Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1," Blood, 5 MAY 2011, 177:18

Second, stringent complete response is not the same as MRD negative status.

A consensus definition of MRD status is still in the works, but the most common definitions used by researchers so far focus only on whether myeloma cells can be detected by various very sensitive methodologies.

Myeloma cells, however, are not the same as paraproteins, which are what you measure with the M-spike level, and free light chains. Paraproteins and free light chains are the result of myeloma cells being in the body, but they are not myeloma cells themselves.

So I guess my question back to you is: Do you want to understand if Ian has achieved a stringent complete response, or whether he is MRD negative?

[johanna]

Re: Complete response after ASCT ... or not?

by johanna on Sun Sep 28, 2014 8:37 am

Hello Multibilly, thank you for your reply.

I was thinking along the same lines -- a PET scan, possibly MRI ? And take it from there. (Just a bit afraid about using them considering these tests seem to attract all bad guys. Together , line them up in a scan, if I'm not wrong.

But didn't cross my mind to use PET, then biopsy the hot spot. That makes perfect sense ))
Thank you.

Thank you JimNY for your reply. CR or nCR I agree are a bit different. Studies on Pubmed and other journals say there is no significant PFS (progression free survival) or OS between them, so I don't tend to distinguish between them much and tend to treat them almost the same.

MRD (-) I agree is where everyone wants to be, and achieve. Unfortunately, it is an almost impossible goal for many of us.

Ian's type of disease is keeping us in the dark a bit, but nevertheless there are people there with non-secretory types, even worse. Like I said, we can't really qualify for all requirements to find out if he is in CR and so I turned to MRD, thinking it will be more revealing and bring some light into things but not sure.

My point is I guess, that even if you do a BMB and you hit a clean "pocket" it's kinda useless,
isn't it ? Can the result be trusted? In CR, you need a true reflection and precise count of cells to say that you are in below 5% and qualify.

In MRD, you still need to hit the spot where the cells are and analyseor possibly do the test with a blood sample? Non focal disease makes it truly risky and more like a gamble? You can never be sure .....

To be honest we would like to take it step by step and know both. CR first, then, MRD .

Since it's so hard to decide what is the way forward in Ian's case, we though we might get some new ideas on this forum that would be worth thinking about and trying.

Ian's oncologist said: With this transplant, you might get another year. And I am not getting complacent !!! Best to try everything you can. These tests, more MRD that anything else, allows you to take a peak at future to see if the disease is planning a surprise come-back, and if so delay as much as possible by all and any means possible.

Thank you both.

[Dr. Ken Shain]

Re: Complete response after ASCT ... or not?

by Dr. Ken Shain on Sun Sep 28, 2014 9:00 am

Congratulations on the excellent response, which, as has been pointed out, is a stringent CR (sCR), as Ian's light chains have normalized, and no clonal light chain restricted plasma cells have been detected in the marrow.

Multibilly is correct in that the use of PET/CT and/or whole body MRIs can be useful in cases like this to establish imaging-negative disease status. This is not typically done, however, and I would not recommend it unless there are imaging studies from the time of diagnosis to use as a comparison. Ian has undergone all the tests that are necessary to define his disease status according to the IMWG (International Myeloma Working Group) response criteria. Serum FLCs (and all blood or urine tests) are measuring systemic disease -- that is, all of the disease -- and I would argue that FLCs are the most sensitive serological test to do so. So, they are an excellent quantitative assessment of Ian's disease burden.

Regarding MRD (minimal residual disease) testing -- This may be an issue of semantics on my part, but MRD testing is not "routinely" carried out outside clinical trials and involves MPF (multiparameter flow cytometry), NGS (next generation sequencing) and, to a lesser degree these days, patient-specific PCR (polymerase chain reaction). These are developing technigues to capture greater levels of response.

You can find numerous publications that demonstrate that the deeper the level of response achieved equates to improved outcomes, whether the response be PR, VGPR, CR, sCR or MRD negative disease. Currently, I consider the level of response to be more like a readout of myeloma disease biology - a measure of your myeloma's sensitivity to drugs. So, although a deeper response is a goal, it is not the only goal.

[Jonah]

Re: Complete response after ASCT ... or not?

by Jonah on Mon Sep 29, 2014 5:07 am

Hi Johanna,

Glad to hear that Ian has responded so well to treatment.

Your statement about achieving a stringent complete response not providing any benefit compared to complete response puzzles me, as there was a study published just recently that says exactly the opposite. It's discussed here,

"Degree Of Complete Response After Transplant May Affect Survival In Myeloma," Myeloma Beacon, Feb 2, 2014.

Results from a recent study conducted at the Mayo Clinic suggest that the de­gree of complete response a multiple myeloma patient achieves fol­low­ing a stem cell transplant may affect their survival.

In particular, the Mayo researchers found that the five-year overall survival rate was nearly twice as high for patients who achieved a stringent com­plete re­sponse (80 percent), compared to those who achieved a com­plete response (53 percent) or near com­plete response (47 percent).

For more details, see here:

S Kumar et al, "Importance of Achieving Stringent Complete Response After Autologous Stem-Cell Transplantation in Multiple Myeloma," Journal of Clinical Oncology, Nov 18, 2013 (abstract)

This is just another example, I think, of the sort of studies Dr. Shain mentions that show that patients who achieve deeper responses to initial therapy tend to have better long-term outcomes.

[johanna]

Re: Complete response after ASCT ... or not?

by johanna on Tue Sep 30, 2014 10:54 am

Dr. Shain, thank you for your detailed reply. I agree that MRD testing is only done in particular settings, and in the context of finding out more about the disease. At this moment in time I must say that any tests for MRD undoubtedly are followed by the question: What do we do with the result? Does it translate in terms of treatment? At least that's what we were told. Doesn't matter what we find out, it won't change the treatment plan.

Nevertheless we are still considering MRD testing for Ian, especially when we were told at the start that he only had 6 months without chemo.

Jonah, thank you for your reply, and to answer your question briefly ..

There are plenty of contradictory trials and results out there, not just conventional treatment (chemo) but alternative treatments as well. Doesn't mean that some are right and some are wrong. With access to so many medical journals today, there are plenty studies to read done all over the world -- the Netherlands, Germany, France, UK, USA ... all over. Results vary greatly because we respond in different ways (age difference / aggressiveness of myeloma / stage of disease etc), and I wound not extrapolate the result of Mayo and use it for all patients with this disease. Other results, like I said, state that there is not much difference in between the 2 CR's.

The truth is somewhere in the middle and we all hope for the best possible result.

Today, with so many treatments on the way, that might just be possible.

Thank you all kindly for your replies any further inputs would be greatly appreciated.

Joanna