[EF11]

Myeloma cells in marrow at harvest for SCT

by EF11 on Sun Mar 08, 2015 3:37 pm

My husband's recent bone marrow biopsy after his induction treatment, which was 4 cycles of Revlimid, Velcade, and dexamethasone (RVD), still showed 4% plasma cells, which are likely myeloma cells based on staining (explained his specialists).

Tomorrow, they will harvest these stem cells which still have traces of myeloma and then infuse them back into him 11 days later, following the melphalan treatment to kill as much remaining cancer as possible.

It seems counterintuitive to give him back the cells when they still contain myeloma plasma cells. How does one achieve a complete response if the cells infused to treat him still have cancer?

He will go on to receive 2-3 more cycles of RVD as consolidation treatment a few months after the SCT. Is this partly to attack those remaining plasma cells?

Thanks.

[Mark11]

Re: Myeloma cells in marrow at harvest for SCT

by Mark11 on Sun Mar 08, 2015 8:58 pm

Hi EF11,

Prior to novel agents, myeloma patients rarely got to as low of a plasma cell percentage as your husband is at now prior to harvest. Years ago, they did some studies where the grafts [harvested stem cells] were purged of myeloma cells. The studies I saw did not show any benefit to purging the grafts. For some reason I thought there may have been a recent study that showed some benefit, but if there is one, I did not save it in my collection of links to studies. This study was published in 2007.

"In 1995, we initiated a European Group for Blood and Marrow Transplantation (EBMT) centre phase III randomized study to assess the safety and efficacy of CD34+ selection compared to unselected PBPC in patients with myeloma under­going autologous trans­plan­tation. A similar study was initiated at around the same time in the United States, the pre­liminary results of which suggested that at a median follow-up of 12 months there was no clinical benefit from CD34+ selection. We now report the long-term results of our study at a median follow up of over 5 years, which confirm the observations of the US study. In addition, this study shows that there is no apparent correlation between relapse risk and reinfused tumor cell load."

"A new finding in the present study was that relapse risk was independent of whether or not there were detectable tumor cells in the reinfused product. This would suggest that reinfused myeloma cells do not contribute significantly to relapse, and that improved disease eradication within the patient may be a more important goal than tumor purging of the grafts."

Source: J-H Bourhis et al, "Relapse Risk After Autologous Transplantation In Patients With Newly Diagnosed Myeloma Is Not Related With Infused Tumor Cell Load And The Outcome Is Not Improved By CD34+ Cell Selection: Long Term Follow-Up Of An EBMT Phase III Randomized Study," Haematologica, August 2007 (link to full text of article)

When I collected for my auto, I was at 10% plasma cells. I got to CR after my auto. If a newer study exists with a better method of purging / testing, hopefully someone else has the link.

Mark

[Melpen]

Re: Myeloma cells in marrow at harvest for SCT

by Melpen on Mon Mar 09, 2015 10:53 am

4% is great! I would not worry about that for a minute. I went to SCT with BMB showing 20 to 30%. After 9 rounds of chemo, many at strongest dose, that is the best I could achieve and the doctors said it was time for SCT. They were worried that more chemo on my bone marrow would be too much and compromise the marrow. In fact, it took weeks for me to engraft after SCT because the marrow did get "beat up" from the cancer and the heavy pre-treatment.

I am not sure yet what my cancer counts are. I will be having SPEP and UPEP this week and bone marrow biospy in another month, so we will see if SCT did any good at bringing cancer down from the 20 to 30%. I had the same concern you did: the transplant would just put the cancer back in. The docs said even though they would have liked my counts to be below 20% before heading to SCT, years ago they sent patients to transplant with even higher counts and patients did achieve remission.

So don't worry. Anything below 5% is considered excellent. You are already off to an excellent start.

[mikeb]

Re: Myeloma cells in marrow at harvest for SCT

by mikeb on Mon Mar 09, 2015 10:57 am

Hi EF11,

Mark gave you some good information. But just to follow up on that a little bit...

Your point that it sounds counterintuitive to transplant stem cells that include myeloma cells is exactly right. It is counterintuitive! I also had a hard time wrapping my head around that concept.

Here's my mental model for it now. Your husband's RVD induction treatment used three different agents to attack myeloma cells in (at least) three different ways. The melphalan that your husband will receive prior to the SCT is a fourth agent, giving a fourth way to attack the myeloma. The other parts of the bone marrow that get killed are collateral damage from the use of the high dose melphalan. The harvested stem cells that are re-infused allow the immune system to grow again.

But even with the use of all four different agents, they aren't able to kill all of the myeloma cells. Some remain in the bone marrow after the melphalan. Apparently, the additional myeloma cells that might be in with the re-infused stem cells are sort of an insignificant factor compared to the ones that remain in the bone marrow after the melphalan, as the study cited by Mark indicates.

The additional RVD consolidation treatment that your husband will receive after the transplant is designed to kill even more myeloma cells at that stage. And the same thing goes for maintenance therapy, if your husband gets that after the consolidation phase. BTW, my doctor mentioned that melphalan works against myeloma cells for a longer period than just the 90-100 days post-transplant when we are typically evaluated to determine the "success" of the transplant.

Even when a patient is in stringent complete response and minimal disease negative, the "working assumption," as my doctor put it to me, is that there are still some myeloma cells present. Too few to be detected by current means, but still some lurking in there nevertheless.

Best wishes to your husband and to you for a smooth SCT.

Mike

[JimNY]

Re: Myeloma cells in marrow at harvest for SCT

by JimNY on Mon Mar 09, 2015 11:05 am

Here's a dumb question that may help clarify things a bit ...

Stem cell transplantation involves the re-infusion of harvested "hematopoietic stem cells." As far as I understand it, hematopoietic stem cells are precursors to all blood cells. They are NOT plasma cells, whether that be myeloma (monoclonal) plasma cells or regular, polyclonal plasma cells.

So, assuming that the stem cells have been harvested correctly and what you're getting is truly only hematopoietic stem cells, why should you be getting any myeloma cells with your re-infusion of the stem cells anyway?

[Multibilly]

Re: Myeloma cells in marrow at harvest for SCT

by Multibilly on Mon Mar 09, 2015 11:29 am

Jim,

Even with various purging techniques, the process of completely removing the cancerous myeloma cells from the graft is imperfect and myeloma cells can and do still exist in the graft....alongside the stem cells. Moreover, the high dose portion of the transplant therapy is also imperfect and that process can also leave myeloma cells intact in the marrow (as Mike points out). At least, that has always been my understanding.

[JimNY]

Re: Myeloma cells in marrow at harvest for SCT

by JimNY on Mon Mar 09, 2015 12:33 pm

Thanks for your reply, Multibilly.

Let's set aside the issue of whether the high-dose melphalan -- or any myeloma therapy -- kills off all myeloma cells in a patient's body. I'm not sure I see how that's really relevant to a discussion of any "dangers" associated with the stem cell graft that's part of stem cell transplantation.

Frankly, I asked my "dumb" question to make a point. People seem to assume that stem cell harvesting equals plasma cell harvesting. It doesn't. The collection process targets hematopoietic stem cells, which are not the same as plasma cells.

Another important point is that, these days, the harvesting process is done using blood, not the bone marrow. We know from minimal residual disease studies that myeloma cells are found much less frequently in the blood than in the bone marrow. In fact, it's hard to find myeloma cells in the blood. That's why conducting minimal residual disease testing with blood samples, rather than marrow samples, is so much more difficult.

So you've got a collection process that isn't even designed to collect the type of cells (plasma cells) that includes myeloma cells. And, it's being done using blood as the source of the target cells, and that source doesn't typically include a lot of myeloma cells anyway.

Could this process pick up some myeloma cells along the way? Sure. The process isn't perfect. But the process is designed to collect a totally different type of cell than myeloma cells, using a source that typically has a much lower percentage of myeloma cells than the bone marrow.

[Multibilly]

Re: Myeloma cells in marrow at harvest for SCT

by Multibilly on Tue Mar 10, 2015 8:33 am

EF11 - First, good luck to you and your husband on this journey. I think Mike provided the answers you were looking for regarding consolidation treatment, etc. Please let the forum know if you have any other questions.

Jim,

Your point is taken and I agree with everything you say, but the fact remains that myeloma cells can and do get into the graft.

There's an interesting discussion on the this point and the potential consequences of the contaminated graft in this paper.

T Nishihori and M Alsina, "Advances in the autologous and allogeneic transplantation strategies for multiple myeloma," Cancer Control, Oct 2011 (link to full-text PDF)

Excerpt:

Despite the favorable therapeutic impact of high-dose therapy followed by autoHCT, disease relapse after autologous transplant remains a continuous risk, and the majority of patients succumb to recurrent disease. Disease recurrence is pre­sum­ably secondary to (1) persistent disease in the bone marrow after transplant due to drug resistance and/or (2) the reinfusion of contaminating malignant plasma cells in the stem cell graft. This view is supported by the lower relapse rates seen after syngeneic transplantation compared to autoHCT. Purging strategies to reduce the contaminating myeloma cells have been evaluated. However, even with a 3 to 4 logs reduction of myeloma cells in the graft, randomized studies showed no im­prove­ment in responses, PFS, or OS. The reasons for the disappointing result may be that only a minute fraction of tumor cells may be required in the graft for relapse or residual myeloma cells in the marrow after transplant may be responsible for the ultimate disease relapse.

In an effort to reduce minimal residual disease after autoHCT, additional therapies have been delivered either with a second autoHCT in a tandem fashion or with a reduced-intensity conditioning (RIC) followed by allogeneic HCT (alloHCT). When compared with single autoHCT, some randomized studies of tandem autoHCT have shown approximately a 10% improvement in OS. The survival benefit was mainly seen in patients who achieved less than very good partial response (VGPR) after first transplant. Caution should be exercised as the finding was noted in an un­planned subgroup analysis and the studies predated the currently available novel anti­myeloma agents. This also suggests that even patients who achieved com­plete response (CR) after autoHCT still harbor highly resistant myeloma cells in the marrow. Additionally, some studies have demonstrated the influence of disease biology on outcomes of autoHCT. Cytogenetic abnormalities detected in the myeloma cells by fluorescence in situ hybridization (FISH), including deletion of chro­mo­some 13, trans­lo­ca­tion of chro­mo­somes 4 and 14, and deletion of chro­mo­some 17, have been associ­ated with sig­nif­i­cantly shorter PFS and OS than those patients without these ab­nor­mal­ities."

[Nancy Shamanna]

Re: Myeloma cells in marrow at harvest for SCT

by Nancy Shamanna on Tue Mar 10, 2015 8:55 am

This is an interesting conversation about how even stem cells collected by aphaeresis may contain some myeloma cells. The reason for the 'induction chemo'' is to bring the number of myeloma cells down a lot and also Cytoxan or other alkylating agent (? for me it was Cytoxan) is used before the stem cell harvest to further debulk the tumor cells. That is an interesting point that usually not many myeloma cells are found to be circulating in the bloodstream.

Before I had my stem cell transplant, people asked me where I was getting the donor cells from. When I replied that I was using my own stem cells, they just were puzzled! Of course, there are donor transplants too (allogeneic), but that wasn't what I was being prepped for!

[EF11]

Re: Myeloma cells in marrow at harvest for SCT

by EF11 on Tue Mar 10, 2015 1:27 pm

Thanks for the informative and interesting responses!

Mark - I love that you pull out a study for all sorts of questions asked on the Beacon - you must be very organized with your collection. Your and Mike's responses to your auto SCTs are very encouraging.

Update on harvest and clinical trial info:

We are at Massachusetts General Hospital (MGH) for day 2 of stem cell collection. My husband collected 2.7 million/kg yesterday. He is participating in a clinical trial for the drug meloxicam (Mobic; similar to Advil). The trial goal is to show that adding meloxicam to the pre-harvest regimen improves the effects of Neupogen in mobilizing stem cells into the blood stream. The double blind trial participants take 5 days of meloxicam or placebo and 5 days Neupogen. The trial protocol is to collect at least 5 million/kg (MGH protocol is minimum of 4 million/kg).

Today, day 6, they did give Neupogen again, and initially we were told he would be collecting for 6 hours instead of 5 hours based on the peripheral blood count of the stem cell marker this morning and the goal of collecting 5 million. Later, the trial nurse said that the trial prohibits the extra hour on the machine, but it is okay if he collects less than 5 million. We were debating coming off the trial to be able to stay the full 6 hours to make sure we at least get 4 million without having to come back another day. The doctors seem confident we will reach at least 4 million in the 5 hours today, so that is likely now our plan. We have 40 more minutes to the 5 hour mark.

As for side effects, my husband's neuropathy in his feet has oddly become worse since he stopped RVD induction, but it has disappeared in his hands. The Neupogen caused mild bone pain, probably not more severe because he is taking Tylenol and oxycodone for the foot pain and potentially also meloxicam for the trial. Otherwise, he's been feeling pretty much his old pre-cancer self since coming off the induction meds.