Treatment Regimen Featuring Revlimid-Velcade-Dexamethasone Therapy And Stem Cell Transplantation Yields Deep Responses In Newly Diagnosed Multiple Myeloma
French researchers earlier this week published updated results of a small Phase 2 clinical trial testing the combination of Revlimid, Velcade, and dexamethasone (RVD) in newly diagnosed multiple myeloma patients.
The researchers found that RVD, when given before and after stem cell transplantation – and when followed by maintenance therapy with Revlimid – led to very deep treatment responses and significant survival rates.
The 31 newly diagnosed patients in the French trial initially were treated with three cycles of RVD therapy. Next, the trial participants underwent autologous (own) stem cell transplants, followed by two cycles of RVD consolidation therapy, and concluding with a year of Revlimid maintenance therapy.
All patients in the study achieved at least a partial response to this treatment regimen. Almost 60 percent achieved a complete response or stringent complete response. And a full two thirds of the patients achieved so-called minimal residual disease (MRD)-negative status, meaning that sensitive testing could not find any sign of myeloma in their bodies.
Perhaps the most noteworthy outcome of the trial, however, is how many patients survived a full three years from the time of their diagnosis: 100 percent.
Equally important, however, is the trial’s finding that, among the patients who achieved MRD-negative status, the three-year progression-free survival rate was also 100 percent. In contrast, the three-year progression-free survival rate was just 23 percent for trial participants who did not achieve MRD-negative status.
These results, the authors write, “strongly suggest that MRD negativity must be the goal of treatment for every front-line transplantation-eligible patient with multiple myeloma.”
The French researchers also believe the treatment regimen tested during the trial showed “favorable tolerability.” There were, for example, no cases of severe peripheral neuropathy (pain
Some patients, however, struggled with the Revlimid maintenance regimen. Almost two thirds of the patients dropped their Revlimid dose below the target dose, and a fifth of the patients halted the Revlimid maintenance therapy altogether.
In addition, among the 31 patients who participated in the trial, there were three cases of secondary cancer – two cases in one patient, and one in another. None of the secondary cancers, though, were blood cancers such as leukemia or myelodysplastic syndromes.
The Broader Significance Of The Trial
Overall, the results of the French study are likely to attract attention for reasons that go beyond its noteworthy response and survival rates.
In particular, the outcomes of the current trial may provide a preview of the yet-to-be-announced results of an important U.S.-French clinical trial. The large two-country Phase 3 trial is investigating a key question in myeloma therapy: Is it beneficial to have newly diagnosed myeloma patients undergo a stem cell transplant within a year of their diagnosis, or is it better to wait and carry out a stem cell transplant after a patient experiences their first relapse?
The U.S.-French Phase 3 trial, known as the IFM/DFCI 2009 study, involves two groups of patients: one that is receiving early stem cell transplants, and a second that is not.
The patients in the early stem cell transplant group in the IFM/DFCI trial, it turns out, are receiving a treatment regimen that is almost exactly the same as the one tested in the current (smaller) French Phase 2 study.
Initial results of the IFM/DFCI trial are not expected until later this year, at the earliest. Until then, the results of the current study are the best indication of the outcomes to be expected from the early-transplant arm of the larger trial.
That, in turn, suggests that the bar has been set rather high for the outcomes of the delayed-transplantation arm of the trial.
Study Design
The Phase 2 trial included 31 newly diagnosed myeloma patients under the age of 65 who were eligible for stem cell transplantation. The patients were recruited at ten treatment centers across France between September and December 2009.
The median patient age was 58 years old.
Overall, 27 percent of patients were classified as having high-risk chromosomal abnormalities based on their having either a del(17p) or t(4;14) abnormality, determined by fluorescence in situ hybridization (FISH).
Patients received three 21-day treatment cycles of 25 mg of Revlimid (lenalidomide) per day on days 1 to 14, along with 1.3 mg/m2 of Velcade (bortezomib) administered by infusion (not subcutaneously) on days 1, 4, 8 and 11, and 40 mg of oral dexamethasone (Decadron) on days 1, 8, and 15.
All patients proceeded to transplantation using 200 mg/ m2 of melphalan (Alkeran) as conditioning treatment.
Two months after recovery of blood counts, patients who had not progressed received consolidation therapy consisting of two cycles of RVD at the same schedule as during induction therapy and at the last tolerated dose.
Patients then received maintenance therapy with continuous Revlimid for one year. The starting dose was 10 mg per day, which was escalated to 15 mg per day after three months according to blood cell counts and side effects.
The median follow-time was 39 months.
Study Results
Overall, 93 percent of patients responded to the initial three cycles of RVD therapy, with 10 percent reaching a stringent complete response, 13 percent a complete response, 35 percent a very good partial response, and 35 percent a partial response; 16 percent of patients were MRD-negative after induction therapy.
Responses deepened significantly after transplantation and consolidation therapy, with 40 percent reaching a stringent complete response, 10 percent a complete response, 37 percent a very good partial response, and 10 percent a partial response; 58 percent of patients were MRD-negative after consolidation therapy.
Responses also improved further for some patients during maintenance therapy.
After all treatment sequences, 68 percent of patients had achieved MRD negativity.
The three-year progression-free survival rate was 77 percent. This rate was significantly lower in patients who had never reached MRD negativity (23 percent). In contrast, none of the patients who had reached MRD negativity relapsed within three years of diagnosis.
In addition, all patients were alive at three years after diagnosis.
The researchers note that survival outcomes for patients with high-risk chromosomal abnormalities were similar to those of the entire group. The three-year progression-free survival for high-risk patients, for example, was 86 percent.
The French researchers described the side effects associated with treatment during the trial as predictable and in line with those seen in previous studies.
The most common severe side effects during RVD induction and consolidation therapy were low white blood cell counts (35 percent) and low platelet counts (13 percent).
Approximately half the patients (55 percent) experienced mild to moderate peripheral neuropathy, but there were no severe cases of the condition.
Overall, 39 percent of patients required dose modifications during induction and consolidation therapy.
The most common side effect during Revlimid maintenance therapy was low blood cell counts. In particular, 60 percent of patients experienced severe low white blood cell counts during Revlimid maintenance. Overall, only 37 percent of the patients were able to stay at the planned Revlimid maintenance dose. One fifth of the patients halted maintenance therapy early due to its side effects.
There were three cases of secondary cancer observed among the 31 trial participants: two cases of basal cell carcinoma, a form of skin cancer, in one female patient, and one case of breast cancer in another female patient.
For more information, please see the study by Roussel, M. et al., “Front-Line Transplantation Program With Lenalidomide, Bortezomib, and Dexamethasone Combination As Induction and Consolidation Followed by Lenalidomide Maintenance in Patients With Multiple Myeloma: A Phase II Study by the Intergroupe Francophone du Myélome,” Journal of Clinical Oncology, July 14, 2014 (published online) (abstract).
Related Articles:
- Revlimid, Velcade, and Dexamethasone, Followed By Stem Cell Transplantation, Yields Deep Responses And Considerable Overall Survival In Newly Diagnosed Multiple Myeloma
- Nelfinavir-Velcade Combination Very Active In Advanced, Velcade-Resistant Multiple Myeloma
- Nelfinavir Shows Only Limited Success In Overcoming Revlimid Resistance In Multiple Myeloma Patients
- Adding Clarithromycin To Velcade-Based Myeloma Treatment Regimen Fails To Increase Efficacy While Markedly Increasing Side Effects
- Stem Cell Transplantation May Be Underutilized In Multiple Myeloma Patients In Their 80s
Interesting. As I absorb all of this information over the years (and hope to keep absorbing for many more years), opinions go back and forth between aggressive vs semi passive. This study sounds supportive of what Arkansas has been doing for awhile.
I find it amazing that stem cell transplants are still almost all done with melphalan. And this old drug is still the centerpiece of myeloma treatment. I wonder how much research is devoted to tweaking the chemistry used during the transplant? Since that is the one time when the body can really be "smoked", I'd think they'd use more tricks of the trade at that time.
I don't understand this comment:
" Almost 60 percent achieved a complete response or stringent complete response. And a full two thirds of the patients achieved so-called minimal residual disease (MRD)-negative status, meaning that sensitive testing could not find any sign of myeloma in their bodies."
Don't you have to have CR in order to have MRD negativity? You have more patients that are MRD negative than were in CR.
What am I not getting? Thanks.
Stann, thanks for your comment.
We agree that it's interesting that melphalan is still just about the only drug used during the high-dose chemotherapy ("conditioning") stage of the autologous stem cell transplant process.
As you might expect, though, there have been a number of attempts to come up with alternative conditioning regimens. In our coverage of the recent ASCO meeting, for example, we reported on a study looking at combining the drug busulfan with melphalan as a conditioning regimen (see related Beacon news article).
Also, there is new formulation of melphalan under development that may allow the drug to be administered at higher doses than is currently the case, without additional side effects (see related Beacon news article).
My wife is newly diagnosed with high risk myeloma. She has just started he 4th round of RVD. Her myeloma specialist is at OSHU. She has responded well to the RVD cycles. We will have data tomorrow regrading her remission level, which may be approaching a VGPR.
Given the information in this article, I wonder if there is any chance that we can move to a stem cell transplant ASAP and follow with additional rounds of RVD, like described in this article? Are doctors allowed to vary the protocol in this way? Thank you.
Louis, you ask a great question, because there is a common assumption that you cannot have MRD negative status without also having achieved a complete response.
As it turns out, with the methods that are currently used to determine MRD status, it is possible to be MRD negative, yet not have achieved a complete response.
In particular, what you sometimes see is patients who have achieved a very good partial response, but also have tested as being MRD negative.
How is that possible?
The superficial reason has to do with differences in the way the two outcomes are measured.
MRD status is based on a test of the patient's bone marrow. If the test finds no myeloma cells in the sample, the patient is MRD negative.
A key part of what defines whether a patient has achieved a complete response, on the other hand, is the level of the patient's M-spike. A complete response means the patient has no M-spike. A very good partial response (VGPR) means the patient has an M-spike -- that is, has the monoclonal protein created by myeloma cells in their blood -- but it is at a level that is less than 10 percent what it was when treatment started.
So a patient who has achieved a VGPR, but is MRD negative, has a positive M-spike, but no sign of myeloma in their bone marrow aspirate.
This can happen for two reasons:
1. Bone marrow is "patchy" -- it is not uniformly the same throughout the body
2. Monoclonal protein created by myeloma cells is not immediately removed from the body once it is created.
We asked Dr. Neha Korde of the U.S. National Cancer Institute to explain these issues in more detail. We contacted her because, in a study she presented at last year's ASH meeting, there were cases of patients who achieved a VGPR rather than a CR, but still tested MRD negative.
Dr. Korde elaborated on both of the issues just mentioned, referring specifically to the study that she and her colleagues conducted.
In her study, she noted, "all of our MRD methodologies were performed on random bone marrow sampling from the posterior iliac crest. Thus, due to the patchiness of the disease, we could have just hit an area that was negative for [myeloma] cells, where there could be another area in the body that indeed still harbors disease."
In addition, "Due to the half-life of the paraprotein increasing (especially as responses deepen), we believe that the detection of protein circulating in the blood could be from old protein that has not yet been cleared, rather than new paraprotein being formed from tumor cells. To my knowledge, this phenomenon of re-circulating paraprotein has been mostly linked to IgG [multiple myeloma]. Indeed, among the nCR that were MRD negative, these patients were all IgG patients."
Hi Daryl,
Glad to hear your wife has responded well to her treatment thus far.
You will need to discuss with your wife's doctor whether or not her treatment center (OHSU) strongly insists on its specialists following certain treatment protocols.
Also, even if your wife's physician is willing to alter the plans for your wife's treatment, you still will need to confirm that your insurance will agree to the revised treatment plan.
Finally, bear in mind that your wife's physician is basing treatment decisions regarding your wife on a wide range of factors, including the specifics of your wife's disease and the physician's interpretation of many different potentially relevant research studies, including the one above.
I think that this study may have been done since as far as I know Revlimid is not yet 'approved' in the US for first line treatment. Thus there would not be data about that for the EU to make decisions on, for approval in the EU for Revlimid as a first line treatment (along with Velcade and dex). I also think that the results are very impressive, especially given that there were 27% of high risk patients enrolled. To have 100% survival at three years seems excellent! It was a small study though. Hope that the larger IFM/DMCI 2009 also has such good results.
If I am understanding the article correctly, they were doing MRD testing some time after December 2009 (the quote below states MRD testing was done after induction therapy). It is my understanding testing for MRD is yet to be standarized. But they were doing this back in 2009/2010? Please explain.
Also, thank you Beacon staff for your clarification of Louis's question regarding MRD-negative and m-spikes.
"Overall, 93 percent of patients responded to the initial three cycles of RVD therapy, with 10 percent reaching a stringent complete response, 13 percent a complete response, 35 percent a very good partial response, and 35 percent a partial response; 16 percent of patients were MRD-negative after induction therapy"
Thanks for the comments, Nancy and Doug.
Nancy - The current study probably can't provide any regulatory (approval-related) benefit to either Revlimid or Velcade, since it's too small. The large IFM/DFCI trial, however, could provide the basis for new approved uses for the drugs, but we're not sure that's really the motivation for the trial. Not all Phase 3 trials are carried out for the purpose of generating new regulatory approvals.
Doug - The MRD testing that was done in the current study was done at one central laboratory, and, yes, it most likely was done mainly in 2010. Because the testing was centralized, the MRD testing methodology was uniform across all the patients in the study.
You are correct that efforts currently are underway to standardize MRD testing and reporting in multiple myeloma. However, researchers have been conducting tests to measure minimal residual disease in myeloma patients for quite some time.
There was a paper published in 1993, for example, that discussed whether MRD negative status in myeloma patients who have undergone a donor (allogeneic) stem cell transplant might indicate that the patients have been cured of their disease. A team of Spanish researchers published a paper in 2005 comparing two different methods of measuring MRD status in myeloma patients.
It is true, however, that techniques for detecting MRD have improved over time, and new detection methodologies have been developed. These are some of the reasons why efforts are being made to standardize MRD testing and reporting.
For those who like technical details, the MRD methodology in this study was flow cytometry. Furthermore, the paper notes that "For MRD assessments, assays were performed in a single seven-color tube." The testing appears to have had a sensitivity of 0.0025 percent.
You can find more Beacon news articles about minimal residual disease by going to the topic page for that subject:
http://www.myelomabeacon.com/tag/minimal-residual-disease/
I am a participant in the US-French clinical trial mentioned in this article (IFM/DFCI 2009), and I was randomized into the STC arm of the trial. So I find this article both interesting and encouraging. The French study methodology described is almost exactly what I have gone through in my treatment. One difference is that the protocol in IFM/DFCI 2009 calls for 2 years of Revlimid maintenance, instead of the 1 year in the French-only study here, assuming all goes well.
Today I am starting cycle 11 of the Revlimid maintenance phase. I am in VGPR, but my lab results have been slowly trending in the direction CR or perhaps even sCR.
Louis, I asked exactly your question about CR/sCR and MRD to my oncologist today, before reading this article. His reply was similar to the Beacon staff's reply. And he acknowledged that the terminology is very confusing and that MRD testing has not been standardized yet.
And if I could use this article as an excuse to get up on my soapbox for one second... I'd like to encourage folks to consider participating in clinical trials. I was shocked when I heard several months ago that only 3% of cancer patients who are eligible for clinical trials participate in them. Clinical trials often give you access to cutting edge treatments and they are one of the most important ways in which the science of treating multiple myeloma (and other diseases) is advanced. For those in the US, a searchable directory of clinical trials is available at: https://clinicaltrials.gov. By the way, the US-French clinical trial that I'm in is still recruiting participants. You can find out more about that trial specifically at: https://clinicaltrials.gov/ct2/show/NCT01208662.
Thanks!
Mike
Hi Beacon Staff, I suppose that Velcade may also not be approved for first line therapy in the EU? I gather that from your statement about the study being too small to provide data for regulatory approval. I am sure that there are scientific reasons to run a trial, apart from the possibility of getting a drug approved in a country with state health care, where 'off label' use may not be available. Perhaps this sort of trial with Velcade/Revlimid/Dex has not been run before, but I don't know.
When I clicked up the abstract, there was Dr. Xavier Leleu as one of the authors! I met Dr. Leuleu in Calgary last spring, as he was here to speak to doctors and patients in Alberta. And interesting to see that Mike Burns, posting above, is on the larger version of the clinical trial. Good luck, Mike!
As a follow-up to Dr. Korde's explanation, does anyone know how long the "old proteins" circulate in the blood before they are cleared? I ask since post-transplant my M-spike still is at 0.1 g/dL, as it was pre-transplant. Because my disease is IgG, based on what the doctor is quoted as saying there is some hope for CR once the old proteins are cleared.
To Andrew:
I don't know how long it takes to clear. Though my stem cell transplant improved my bone marrow biopsy numbers, my M-Spike remained at a 0.2 g/dL level. After consolidation therapy, it was down to a "cannot be seen" level and a welcome CR. Was it the consolidation therapy or just a continued response from the transplant? My doctor wasn't sure.
I'm heartened by the results of this study, as it very much mirrors my treatment regimen. Since a June 2011 diagnosis, my CR remains going strong ... !
On insurance: Immediately after diagnosis, I began an RVD regimen, even though I had received no prior treatment. Insurance coverage has never been a problem.
I wonder if the stem cell transplant (ASCT) was of any real benefit. What if the ASCT was skipped and instead of the stem cell transplant, 1 or 2 additional RVD cycles were substituted instead? Thus, the patient receives 6 or 7 cycles of RVD followed by the Revlimid maintenance. I think such a comparison in results would be interesting. I am not convinced the ASCT adds any value. I think the RVD was doing the real work.
Ron
Ron,
I beleive that there is a large trial ongoing now that will answer that question. It has three arms: transplant, tandem transplant and no transplant.
... it just came back to me. For what it's worth: as I mentioned above, post-transplant, my M-spike hadn't budged. My stem cell transplant doctor told me that if I didn't achieve CR by Day 60 (post-transplant), I wasn't going to. That is, without additional treatment.
Hello everyone
Where can this clinical trial be done in France as it is a French-USA study?
I looked into the given link https://clinicaltrials.gov/ct2/show/NCT01208662
But found only clinics and hospitals in the US.
Many thanks
Thanks for the great discussion, everyone. Some quick thoughts and feedback on points that have been raised.
Nancy - Velcade is approved in Europe for use in newly diagnosed myeloma patients. For transplant eligible newly diagnosed patients, it is approved for use in combination with dexamethasone, or with dexamethasone and thalidomide. For transplant-ineligible patients, it is approved for use in combination with melphalan and prednisone. (It also is approved for use in relapsed patients.) In the U.S., its approved use is broad, "for the treatment of patients with multiple myeloma."
Andrew - We'll have to check on the half-life of the monoclonal proteins (paraproteins) that are measured by the M-spike, but we think it's about 3 or 4 weeks.
Ron - The IFM/DFCI trial that we mentioned in the article above is addressing exactly the question that you (indirectly) raise. As Mike Burns mentioned in the comments above, one group of patients is getting a treatment regimen very similar to what was tested in the study discussed in the above article. A second group of patients is not getting an early transplant, but instead they are getting a full 8 cycles of RVD followed by Revlimid maintenance.
Patients in the IFM/DFCI trial are randomly assigned to one group or the other. And the trial is big -- the planned enrollment is 500 patients in each group. So the trial should shed a lot of light on the value of early versus delayed transplantation.
We think that Andrew is right about the three-arm trial that he mentioned, but we don't have the details right now.
Steve L. - It's not so much the issue of the half life of the monoclonal protein that drives why doctors wait 60 or 100 days to see where things stand after a transplant. Instead, as we understand it, the wait is driven by the fact that it takes that amount of time for the body's redeveloping immune system to reestablish itself, and to see how active / aggressive the remaining myeloma cells are in the patient's body.
Maro - We believe this link is for the French arm of the IFM/DFCI trial: https://clinicaltrials.gov/ct2/show/study/NCT01191060 . Note, however, that the trial is no longer recruiting participants.
Hi Ron,
Here is one of those "me" anecdotes.
I went through 2 rounds of VDPACE. The second one didn't touch the MM. This was after a year of Revlimid, Velcade, etc. So I went into my first stem cell transplant [SCT] with a much higher load of MM cells than originally planned. It knocked my M-spike down from 2.5 to 0.8 g/dL (something like that). So I did another SCT and it knocked it down to 0.2, where it's stayed for 2.5 years. No symptoms at all.
Without a doubt, the SCT was by far the most effective treatment I had.
(I did have low dose Revlimid as maintenance for 2 years, but don't know if that was doing anything or not.)
Thanks Myeloma Beacon staff, for the European data. I should of course, have realized that the French system is similar to ours in Canada. It was interesting to hear Dr. Leuleu speak on that topic too. I think that there is more available for relapsed patients than for NDMM. To me, this seems a bit odd, since if only the myeloma could be gotten under control right from the get go, I think that would help. it's the same for 'maintenance', which is different from 'relapse'. The terminology of treating patients is also subdivided into many categories.
Andrew,
The three-arm trial that Andrew mentioned is most likely this one: "Stem Cell Transplant With Lenalidomide Maintenance in Patients With Multiple Myeloma (BMT CTN 0702)"
However, it doesn't really address the early versus delayed transplant question because all patients in the trial will get an early transplant. Instead, it is addressing the value of different post-transplant options, including either another transplant, consolidation therapy, or maintenance therapy.
We believe the other major ongoing trial testing the issue of early versus delayed transplant is a European trial, "Study to Compare VMP With HDM Followed by VRD Consolidation and Lenalidomide Maintenance in Patients With Newly Diagnosed Multiple Myeloma (HO95)"
which is also described a bit more detail (and with a diagram) here. Note, however, that it's a complex trial, with a number of different ways that a patient could end up being treated.
Andrew,
Are they testing against the RVD triplet. In the studies I have seen when ASCT is tested agains novel agents they have been single agents or doublets like RD or TD. I am not aware of a test against the triplet. The triplet combined with a biphosphonate has been very powerful as an intial treatment. An early study with the triplet showed 100% of new patients had at least a partial response with a high percentage of VGPR or better.
Ron
Hi Ron,
If you had read Mike Burns post, he put the link up of the study that is addressing what you are discussing.
Multiple peer reviewed studies are showing 10-15% of patients that use high dose chemotherapy do not relapse.
"This question also is awaiting data from randomized trials. However, careful review of older data sets may help to answer this question. For instance, data from European groups suggest that many centers have a 10% to 15% tail on the OS curve, suggesting that some patients may be cured simply with the use of alkylating agents. An update from the PETHEMA group suggests the presence of a tail on the OS curve,6 as does a series of patients from the Arkansas group, where there are more than 15% of patients from total therapy 1 (induction with vincristine, doxorubicin, dexamethasone , tandem auto-HCT with melphalan 200 mg/m2 and interferon maintenance) who are in continuous CR more than 10 years after completion of therapy.7"
http://www.clinicaloncology.com/ViewArticle.aspx?d=Hematologic%2BMalignancies&d_id=149&i=July+2014&i_id=1082&a_id=27750
"Also, a Mayo Clinic study on younger myeloma patients at 2013 ASH:
OS of patients with MM under 40 years of age in the pre-transplant era (Group A) was significantly shorter than that of patients diagnosed in the era of SCT (Group B) and SCT plus novel agents (Group C). Although improvement of survival outcomes is evident with utilization of novel agents, similar outcomes of Groups B and C indicate lack of incremental benefit over SCT with utilization of novel agents. Maximal survival gain coincides with the introduction of SCT in this unique patient cohort."
http://www.myelomabeacon.com/resources/mtgs/ash2013/abs/2136/
Hard to believe that a therapy that 10-15% of patients never relapse after using it is not convincing evidence that it "adds any value". It does not sound like the doctors at the Mayo Clinic would agree with you. I cannot understand why patients who have never used high dose chemotherapy seem so upset when their fellow patients who use it do well. I am doing well because my doctor combined a novel agent, high dose chemotherapy, and immunotherapy. I never realized they were competing therapies.
Mark
Great discussion everyone! To add my opinion to the presentation of all this complex data, the trend in the US is to use RVD treatment followed by an ASCT in newly diagnosed MM patients, especially with high risk cytogenetic features or higher ISS stage (II or III). Most are then followed by Revlimid maintenance. I understand there is a spectrum of opinions from LA's Dr. Berenson, who rarely recommends ASCT, to aggressive tandem ASCT's and "total therapy" using high dose cytotoxic and novel agent therapy with Dr. Barlogie in Arkansas (thanks to Sam Walton's legacy!).
The ideal approach I suspect needs to be individualized somewhere in the middle of this spectrum. For recurrent disease, combination newer novel agent chemotherapies will likely be most effective for most patients. Traditional multiagent cytotoxic chemo will still have a place in refractory disease. But I believe that various immunotherapies, either based on genomic analysis, or using monoclonal antibodies in innovative ways, will become the most effective. And the possibility of using a salvage allo transplant may be useful for some.
Clinical trials are very useful in expanding our knowledge and experience to properly sequence and dose these options, and explore newer approaches to therapy. Thinking outside the box, and testing agents effective in other cancer therapies, will be the key to further advancement in our goal of making MM a chronic manageable disease, if not lasting CR's and (dare I say it?) cures.
So there you have my gestalt view of MM therapy, present and future. Any comments out there?
Best wishes to all! Jan
Thanks, everyone, for all the additional comments. Lots of great contributions and perspectives.
In regard to the question that Ron is reminding us to consider, we're not aware of any studies that have looked at MRD status in patients who have been treated with an extended number of cycles of RVD / VRD without a subsequent transplant. The standard reference for response rates and other outcomes for extended RVD therapy as initial treatment for newly diagnosed myeloma is the paper from Blood in 2010 by Dr. Richardson and his co-authors,
http://bloodjournal.hematologylibrary.org/content/bloodjournal/116/5/679.full.pdf
but the study did not include MRD testing. (Some of the patients in the Richardson study also went on to do transplants, so you can't really compare survival outcomes from that study with the one above. You really can only look at response rates after the initial RVD therapy.)
We mentioned earlier the presentation by Dr. Korde at ASH. It's worth bringing up again because it looked at response rates and MRD status after initial treatment with Kyprolis, Revlimid, and dexamethasone for newly diagnosed myeloma patients. After eight cycles of treatment, 80 percent of the patients achieved MRD negative status. That's a higher share of patients than was reached in the French study above after initial therapy, transplantation, consolidation, and maintenance.
(And, even if you count only the patients in Dr. Korde's study who achieved both MRD negative status AND a complete response, you get 68 percent of all patients falling into that category ... which happens to be exactly the same share of patients who in the French study achieved MRD status, with or without a complete response, by the end of the maintenance phase of the therapy.)
Here again is the link to the abstract for Dr. Korde's presentation:
http://www.myelomabeacon.com/resources/mtgs/ash2013/abs/538/
So, to Ron's point, it is not out of the question that an extended series of induction cycles alone could lead to a high share of patients achieving MRD negative status. That's why the IFM/DFCI trial results will be very interesting and, even with that trial, the issue won't be settled given the potential new myeloma therapies that are on the horizon.
Ron,
I cannot find the trial that I referred to; perhaps it is the one referred to by the Beacon staff or I just mis-remembered. Sorry for the bad information.
What a wonderful platform for folks to use to discuss such an important topic.
My wife Annie was diagnosed with multiple myeloma on June 19th, 2008. She was in stage 3, over 80% plasma cells, and had aggressive, symptomatic, multiple myeloma. Her prognosis was 3 weeks, maybe a little longer, if she could take chemo. July 7th, 2008 she had her first dose of melphalan and IV Velcade. Her oncologist wanted her on RVD therapy, but Revlimid took time to get back then, so he was doing what he could to maybe slow the rate of disease progression down. The Revlimid arrived on my door step 3 Aug 2008. On 5 Aug 2008, Annie was started on Revlimid, 25 milligrams for 21 days on and 7 days off. And Decadron, 40 milligram tablets on day 1, 8, 15, & 22. Annie could no longer take Velcade as it was devouring her platelets. Prior to Aug 5th, on July 16th, both of Annie's femurs broke, her right hip broke, her spine collapsed, she had 4 broken ribs, lesions peppered over her skull, and a heavy burden of tumors in her spine and hips.
You may be assuming this is a horrible story, but in reality it's very inspirational. As it turned out, even with only the Revlimid and Decadron, Annie was given the all clear, no signs of myeloma, and full remission on Dec 11, 2008. Now that you all know she got her remission, what you don't know is that on Aug 15th, 2008, one month after her broken bones, she went blind, and collapsed into a coma that left the medical professional's saying, "most likely she will not survive the night." But she woke up a couple days later, told us where she had been and what she had seen, then 3 days after that, with only three thousand platelets, she had a brain bleed~stroke. I was told it was very rare for a patient to survive a stroke with three thousand platelets, but she did.
It took her a while to get her speech back to where we could understand her, and although she was never the same, we could clearly understand her. I've taken you 6 months into her journey and it was fought on hope, with much compassion and love for her. The day she got her remission she was in the hospital fighting pneumonia. Four weeks later in Jan she was back in the hospital fighting pneumonia.
Annie was always sick, and what I've just spoken of was the cake walk period. Annie was cancer free until late June 2010. By that time, she had experienced several pneumonia's, shingles, swine flu, double deep lobe pneumonia, sepsis, respiratory failure, surgery for blocked small intestine which caused malnutrition, and her weight dropped to seventy-nine pounds which invoked the word, Hospice.
But I didn't let that happen. All those things I just mentioned except the shingles, happened over a 6 month period, from Sept 7th, 2009, to the 12th of Feb, 2010. By June, 2010, I got her weight back up to one-hundred pounds. If I could do anything different, knowing what I know now, I would not have let her have the autologous (own stem cells) transplant, on April 13th, 2009. Reason being, Annie was cancer free, her platelets which were always critically low, had managed to climb to 126,000 with a beautiful upward trend on the day she received her melphalan 200.
After the transplant, they never recovered to anything near the pre-transplant level. Ultimately, when the cancer came back, her platelets wouldn't even allow for 1/5 of the normal maintenance Velcade. With that small amount of Velcade her platelets dropped below three thousand. At one point near the end, her platelet count was "0." Annie fought an epic 30 month battle, but I knew from the early days that a low platelet count, although rare, would bring her down. Annie had isoantibodies, and although she had many, many bags of platelets over the 30 months, they never worked for her.
I believe when the USA and France release their findings on when to do the transplant, it will be when the oncologist feel the cancer is returning. I think, perhaps if we had held off on the transplant, her remission would have held long enough for her to get her platelet count up so she would be able to fight the myeloma as she did when first diagnosed. But, Annie really wanted the transplant as back then it offered the best chance of a longer remission and survival.
It seems to me the old saying of, "if it's not broke, don't fix it," could well apply to the stem-cell transplant process. Things have really changed since Annie was sick, and I believe we're all full of hope for a brighter future for myeloma patients. Always remember, "If you love someone today, try to love them more tomorrow." "Life Happens."
Since SCT's are easier to tolerate for younger people than older people, I'd think that unless otherwise proven, it makes sense to do it upfront.
If you go through all of the therapies and then opt for the transplant, your body will be older as well as your organs will have been exposed to a lot of chemo already and may be less likely to tolerate the SCT.
I have two older MM friends who exercise and eat healthy (far, far better than myself), but they both had far more problems with their SCT's than I did and said there is no way they'd do a second one. I'm assuming their being 60 vs me being 46 was a big part of the reason.
Do you think it's possible for RVD alone to "cure" or permanently put myeloma into remission or even a very long remission? Or is it still too early to know this?
J the study that the Beacon Staff and Mike Burns have referred to is testing for what you are asking. Dr. Kordes study indicates that the triplet featuring Krypolis, Revlimid and Dexamethasone (KRD) for 8 cycles produce even better results than the French study with the ASCT when measuring for Minimal Residual Disease (MRD) and Complete Response (CR). Krypolis and Velcade are both proteasome inhibiters and thus operate in much the same manner. Thus it will be interesting to see if RVD can produce responses comparable to KRD.
The real question is does a CR plus MRD lead to longer progression free responses and overall survival time. The assumption is yes, but only long term studies can confirm that.
Bob's post underscores the fact that MM is not homogeneous disease. Treatments must be tailored to the individual based upon how they react. RVD or KRD may work for a lot of patients, but for some they will not, or the patient cannot tolerate the drugs, as was the case with Bob's wife's reaction to Velcade. The ASCT has been around for a long time and for years offered the only chance for long remissions. The triplets offer the potential for a similar result without the rigors of the transplant. However, nobody is indicating that either protocol will cure the patient.
Allo transplants for the qualifying young patient offer the potential for true cure but carry a host of risks. Mark is one of the posters that has been very successful with that procedure. However, it is not considered a mainstream front line therapy right now.
Ron
Hi Ron or everyone,
When my mom was diagnosed in the hospital a few months ago our doctor pushed us to consider a clinical trial of upfront treatment KRD vs RVD. He proposed that our insurance wouldn't cover RVD, but it did. Our concern was she needed treatment like now-didn't want to wait for a clinical trial. Do you think at the time he thought KRD would have been a more effective upfront treatment but didn't want to come out and say that? We thought it was odd how hard he pushed for the clinical trial when my mom was so sick and instead of just concentrating on getting her on some sort of treatment. RVD has worked in putting her into remission after one cycle, but because of the severe neuropothy (however you spell it) I almost question if we should have gone for the option to get KRD as a front line treatment. Has anyone else been treated with KRD upfront?
Thanks.
RVD has been available as a front line treatment for several years in the US. I was started on that protocal in Feb 2009. Until the past year, Krypolis was only available in clinical trials. It has been approved for use now in relapsed and refractory patients but technically is not available for initial treatment. (There are ways around that limitation.) Revlimid has also been approved as a front line treatment but the new Pomalyst, which acts in much the same way as Revlimid does, like Krypolis is technically only available for relapsed and refractory patients.
Krypolis is a newer drug and does not cause as much peripheral neuropathy as Velcade. Velcade used to be given only with infusions but now is given with a subcutaneous shot, which has greatly reduced the incidence of peripheral neuropathy. I personally have been on Velcade in both forms for over 5 years without any problems, but each patient is different.
VRD has been around for several years and I was originally started on it back in Feb 2009. KRD up until recently has been only given in clinical trials and as an upfront treatment may not be approved by insurance companies. However, if your wife is having difficulty with Velcade, I think with your doctor's support they can get Krypolis approved by your insurance carrier.
Good luck
Ron
This continues to be a great discussion. Thanks, everyone, for all the comments.
There isn't much that we want to add. However, we did want to note, in response to Ron's last commment, that Revlimid actually is not yet approved by the FDA or any other regulatory authority as first-line therapy for multiple myeloma.
Celgene, the company that developed and markets Revlimid, has applied to have the drug approved for use in newly diagnosed patients (see related Beacon news) in the U.S. and Europe, but a decision on those applications is not expected until next year.
All that having been said, it also is true that Revlimid is widely used in the U.S. in newly diagnosed patients, either alone, in combination with dexamethasone, or in combination with Velcade and dexamethasone.
How is it possible that
" ... 60 percent achieved a complete response or stringent complete response. And a full two thirds of the patients achieved so-called minimal residual disease (MRD)-negative status, meaning that sensitive testing could not find any sign of myeloma in their bodies."
Inasmuch as MRD negative is a superset of CR and SCR, the results as reported are not logically consistent.
That is to say that a patient who is MRD negative must also have achieved a SCR. But there can be patients who have achieved a CR, or even a SCR, and are MRD positive.
Please clarify.
Thanks for your question, Mark.
Please see our response to a similar question from Louis that was asked near the beginning of the comments. (If the link in the previous sentence does not work for you, then cursor up to the comment, which is about the sixth one down from the top.)
There is a common misperception that MRD negative status is seen in only a subset of CR and sCR patients. That's not true. Patients who have achieved a VGPR, for example, can also end up being classified as MRD negative. See our comment for a detailed explanation of how this can happen (and, in fact, does happen).
The above explanation is another great reason why a blood-based MRD test will be welcome in the hopefully near future.
The reply does not consider the newly recommended guidelines for defining MRD negative status. Here is a quote from Brian Durie, Chairman of the IMF.
“We’re saying that to have an MRD response that we think is worthwhile, you need to have both the bone marrow and the blood-negative [status] with our new flow method, and also we’re saying you need to have a negative PET CT scan and a normal heavy/light ratio.” - See more at: http://www.onclive.com/publications/oncology-live/2014/april-2014/new-mrd-assay-helps-move-testing-forward-in-multiple-myeloma-research/1#sthash.04zB2ftr.dpuf
So, MRD negative is NOT determined solely by a negative bone marrow bpx. And the new FC method is superior to a immunofixation electrophoresis detection of a monoclonal antibody.
Perhaps the newly available assay will standardize clinical endpoints for MRD status and place MRD negative as the highest level of response.
Hi Mark,
This is the other Mark. As was mentioned above, flow and PCR testing for MRD negative status has been done for many years in myeloma prior to Black Swan. The explanation above is how MRD negative has been discussed for years. This study did use a 7 color flow method. The doctors from Spain have been the leaders with respect to using the flow method and their studies have typically divided as was discussed above. They typically state being MRD negative as achieving an Immunophenotypic response (IR).
"Achieving an IR translates into superior PFS and TTP compared with conventional CR or stringent CR. These techniques provide complementary information and thus, an effort should be made to refine response criteria in MM."
http://jco.ascopubs.org/content/29/12/1627.full
You cannot change studies with long term follow up just because of what one doctor who was not involved in the early studies says in an interview in 2014.
Mark
Mark,
That one person is Brian Durie, the chair of the IMF, who has been a leading researcher of MM for roughly 40 years. So, I would admonish you not to dismiss his comments so lightly.
The points he made were as follows: (1) The new FC method is superior; it is computer automated and has a 10^-6 resolution! (2) There needs to be a uniformly applied standard for defining MRD negative and that this new standard should be considered the ultimate clinical end point. (3) The new standard needs to included the new FC method applied to both BPX and peripheral blood along with results of a PET-CT scan and the heavy-light chain ratio.
The MB response stated that MRD was determined solely by BPX. This is NOT the suggested guideline anymore. So what did I write that you thought were inaccurate? You didn't refute anything I wrote. You seemed to have inaccurately inferred some things that were absent.
Or perhaps you and I are in violent agreement here.
Hi Mark,
The MB's response was correct and very informative with respect to the question asked. They were not asked what Dr. Durie said in an OncLive interview or what a proposed new guideline may be in the future, they were asked to explain what the authors of a peer reviewed study meant by "MRD negative". The only person discussing the OncLive interview or a proposed new guideline is you. I showed you a 2nd study that also used the same definition. I could show more but there really is no point to doing it. Everything in the OncLive interview is irrelevant to the discussion. I will be happy to discuss it in the forum in an appropriate thread. I have contributed to many threads on MRD testing in the past.
With respect to your first point, I do not see Dr. Durie's name on any peer reviewed study with long term follow up on treated patients with respect to MRD testing. Do you have any links that I have not seen? I do not put much "stock" in interviews on OncLive or Youtube videos.
Mark
Just to make sure there is no misunderstanding on this issue ... there are no "new" MRD guidelines from the IMWG. There is a proposal that is under discussion. It has not yet been approved. Dr. Durie himself alluded to this in the interview mentioned earlier in the comments, saying
"This is something that needs to be, I’m sure, further discussed internally and they’ll come out with recommendations and guidelines. Obviously, these are things that take time. But it’s absolutely up for consideration and discussion, and it’s very much on the radar."
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