[JimNY]

Re: Stay in clinical trial or pursue other treatment?

by JimNY on Sat Nov 14, 2015 8:46 pm

Hi Multibilly,

I'm optimistic that we'll eventually agree on this issue as well...

The data for elotuzumab that you mentioned are from an older, smaller trial. The patients in the study had only a limited number of previous therapies (1-3, if I recall), and previous treatment with Revlimid was basically not permitted. Both of those conditions significantly increased both the response rate and PFS results for the trial.

More importantly, a large trial that was similar in design, but with a comparative arm with just Revlimid-dex therapy, showed noticeably less impressive results for the elotuzumab-Revlimid-dex combination. The Beacon had an article about the results this summer,

https://myelomabeacon.org/news/2015/07/30/elotuzumab-eloquent-2-closer-look/

Median PFS in this trial was 19.4 months for the elotuzumab-Revlimid-dex patients, who had a median of only 2 previous therapies. Also, few of the patients were previously treated with Revlimid (maybe 5%), so the Revlimid was probably doing a decent amount of the work in the combination.

I agree that response rates and PFS for single-agent daratumumab are low in comparison to what you see for elotuzumab-Revlimid-dex. But we are talking about SINGLE-AGENT daratumumab, and the trials with single-agent daratumumab also have had more heavily pretreated, harder-to-treat patients (median of 4, or more, previous therapies). The trial that has reported results for SAR650984 involved patients with, I believe, 6 (!) prior lines of therapy.

Given all the treatments Lime's wife has had at this point, I think it is reasonable to focus on an agent that, on its own, could have significant efficacy. Yes, given that Lime's wife was responding to Pomalyst before she had to be taken off of it, there's a reasonable chance she might respond well to elotuzumab, Revlimid, and dex, given that Pomalyst is in the same family of drugs as Revlimid (immunomodulatory agents, or "imids"). But treatment with elotuzumab also would involve a three-drug combination that may be challenging for Lime's wife, given her current condition, than just single-agent daratumumab.

All that having been said, even though I would lean towards daratumumab, I would not protest too strongly against the elotuzumab-Revlimid-dex option.

Here is the info for the elotuzumab (with Revlimid and dex) expanded access program / trial:

https://clinicaltrials.gov/ct2/show/study/NCT02368301

Here is same info for the daratumumab expanded access program / trial:

https://www.clinicaltrials.gov/show/NCT02477891

and here's a Beacon article with more information about the daratumumab program

https://myelomabeacon.org/news/2015/07/07/daratumumab-expanded-access-program/

Sorry, Lime, if this is way more info than you wanted. Hopefully you'll filter out what's not so important to you, and the rest of the information may be helpful to others here in the forum.

Thanks, Multibilly, for the questions you raised and all the other help you give here in the forum.

[Multibilly]

Re: Stay in clinical trial or pursue other treatment?

by Multibilly on Sat Nov 14, 2015 9:21 pm

Hi Jim,

BTW, I didn't want to appear that I was advocating elo over dara.

I'm also not at all qualified to recommend one MAB over another. That's why I was recommending in the other thread https://myelomabeacon.org/forum/post37766.html#p37766 to perhaps get an opinion from a top center that has a lot of familiarity with both MABs. I would personally love to hear what a multiple myeloma specialist with a fair amount of MAB familiarity would have to say on the subject, given the patient's history and current condition.

Also, point taken on the results of the early elo trial vis-a-vis the ELOQUENT trials. The original 33 month PFS data is one of those pieces of data that will be forever stuck in my head given how exciting that data was at the time.

Take care.

P.S. Lime: None us are trying to turn this thread into a debate. First and foremost, folks on this forum would love to see your wife find a solution to the poor situation that she finds herself in.

[JPC]

Re: Stay in clinical trial or pursue other treatment?

by JPC on Sat Nov 14, 2015 11:10 pm

Hello, all.

The discussion is getting interesting, but as both Multibilly and Jim have said, Thelime has asked a question of concern. A couple of observations of the MAB's.

1. Both are under an accelerated review. Today you need to get them on a clinical trial, however, the FDA has approved expanded access for both, while its under review, because the results for both do seem to be positive.

2. I have heard reported that their is a good chance an approval decision will be before the end of the year; and that elo will be approved for administration after one line of treatment (after first relapse), but Dara will probably be approved for 3rd or higher line of treatment.

3. Dara is being pushed through based on a much lesser degree of clinical studies because the single agent activity is looked on very positively. As an aside, because of this some people speculate that Dara might be better, but there has certainly not been any head to head comparison.

4. I am not very experienced in the biology, but I understand that there are different "targets". Elo works against "SlamF7" (whatever that is) and Dara works against CD 38. What this means is that if your multiple myeloma has more SlamF7, elo will work better; and if your multiple myeloma has more CD 38, Dara will work better. Also, these targets are on the surface of the multiple myeloma cells. Bad cytogenetics are on the inside of cells. Some doctors are speculating the MAB's will overcome bad cytogenetics.

5. Lastly, for MAB's so far, they do have side effects, but much less than IMID's and PI's. In fact, when you compare RVD to elo-RVD, the side effects are not different, so MAB's do not "pile on" with the side effects, and from what I understand, they seem to go away after a number of days and are not accumulative or permanent (this is the early read, and hopefully does not change for the worse).

OK, getting back to Thelime. I do not think that any doctor in America would administer both of them together at this time, however, I have heard some doctors speculate that is exactly what might happen down the road when we have more experience with them. I think that based on what you said, your wife will be potentially eligible for treatment with both. So I would be thinking as follows: Take the first one as soon as you can get it, and then follow it up with the other one as soon after as you could when that gets available. Don't worry about which is better (its probably impossible to figure that out at this time, anyway), do the first one that you can get, as soon as you can.

Good luck, Thelime and your wife; and thanks to all for the interesting input.

[rumnting]

Re: Stay in clinical trial or pursue other treatment?

by rumnting on Sun Nov 15, 2015 11:35 am

One other issue that we have learned this fall: trials will not accept you when you are "not doing well".

To be accepted, your disease needs to have progressed on your most recent treatment, but you also have to have decent (100,000?) platelets (not transfusion dependent) and many other factors. Trials do not want their numbers skewed by patients who likely will do poorly.

[Lev]

Re: Stay in clinical trial or pursue other treatment?

by Lev on Sun Nov 15, 2015 12:56 pm

One other issue that we have learned this fall: trials will not accept you when you are "not doing well". To be accepted, your disease needs to have progressed on your most recent treatment, but you also have to have decent (100,000?) platelets (not transfusion dependant) and many other factors. Trials do not want their numbers skewed by patients that likely will do poorly.

Hi Rumnting,

I think you are at least somewhat right here. Some trials are designed with the purpose of keeping those who respond well to induction, ASCT or other treatments and are in general good health conditions.
But other are directed towards groups who are specifically in another situation: Patients who's Myeloma is agressive and who have not succeeded with the primary recommended treatment.
Another problem is of course the general strength of the patient, other cancers etc. Those can be contraindicated in the programme.
The latest years a lot of new treatments for elderly patients who did not respond very well at the initial treatment(s) are emerging.

Try asking your Myeloma specialist about this.

[Dr. Ken Shain]

Re: Stay in clinical trial or pursue other treatment?

by Dr. Ken Shain on Sun Nov 15, 2015 3:05 pm

It always a difficult situation when our myeloma is becoming refractory to an increasing number of therapies and/or our bodies are struggling to be able to tolerate the available therapies. Obviously, I cannot speak to all of the therapies/combinations of drugs that you have received beyond what has been listed, or to your wife's performance status (general health). Your doctors know you/your wife and her multiple myeloma the best.

I hope that the folks at MD Anderson would have additional potential clinical trials, if your wife meets the inclusion criteria. Or hopefully things can remain in control long enough until the approval of daratumumab – an antibody that recognizes the protein "CD38" on the surface of myeloma cells. This should be approved for relapsed and refractory multiple myeloma (RRMM) as monotherapy, as it can actively kill multiple myeloma cells alone and in combi­na­tion with the immune system.

Another antibody therapeutic that is just on the horizon (hopefully like daratumumab, it will be FDA-approved before December 2015) is elotuzumab + Revlimid and dex. Elotuzumab recognizes SLAMF7 on the surface of multiple myeloma cells and part of the immune system. Unlike daratumumab, there is a requirement for combination with Revlimid and dexamethasone, as it has no single-agent activity. However, this will be a "specific group of patients" with 1-3 prior lines of therapy with some restrictions on prior Revlimid exposure.

These are both very well tolerated options; however, as you can see, they are being "approved (hopefully)" for different patient populations. But in the "gray areas" should be potential options for your wife.

Furthermore, panobinostat (Farydak) in combination with Velcade (approved: PANORAMA1) or with Kyprolis appear to be reasonable options. Based on the platelets being low, this may be a bit difficult.

Always try to put these new therapeutics in perspective. These new options are very promising; however, they are buying us time, and hopefully time with quality of life. To this end, you and your wife with assistance of doctors, family, and friends need to decide the most appropriate path for you. I try to state it this way: "There are things that we can do, but this does not always mean that we should do them."

[JPC]

Re: Stay in clinical trial or pursue other treatment?

by JPC on Sun Nov 15, 2015 3:16 pm

Hello Runmting and Lev:

Actually, reading both your posts, you are both entirely correct from a certain point of view. The "bureaucracy" of clinical trials, from a patient perspective, are very hard to deal with. In the ideal, they are there to protect the public by ensuring a minimal level of proof of safety and efficacy. Drug companies, can use and do use the rules to maximize their chance of success, there is no doubt of that. In this case, if platelet suppression is one of the safety concerns of elotuzumab, they may have a reason for that particular exclusion.

However, Runmting: Please concentrate on the following. If your doctor was looking to be put you on the clinical trial for elotuzumab, then you should be able to apply for the expanded access program. That you should do. I have not idea how long the approval process will take, but elotuzumab and daratumumab are scheduled to get an answer on the application in the near future. If they get approved, and you have not been accepted on the expanded application, that your doctor should be able to prescribe elotuzumab or daratumumab.

So forget about your systematic problem and focus on the best way you can bring in one of the two new MAB's. Good luck.

[rumnting]

Re: Stay in clinical trial or pursue other treatment?

by rumnting on Sun Nov 15, 2015 4:07 pm

I am afraid I have come across as anti-trial. I am not at all! I do not harbor any ill thoughts towards the drug companies and only appreciate that their research brings promising new treatments. I was only saying that just because a trial exists, a patient doesn't always qualify for it.

My husband doesn't qualify for the daratumumab, elotuzumab, or some other yet unnamed drug. His myeloma specialist has been completely helpful in assisting us in trying to find a trial he does qualify for. The unnamed drug (letters & numbers that I don't remember) turned him down because he had a brain bleed this summer (caused by vomiting while platelets were super low from chemo). He was at his myeloma treatment center, all ready to start, when he was turned down because they would not take anyone who was a bleeding risk. His myeloma doctor tried to get them to understand he was no longer a bleeding risk because his platelets had recovered. He will qualify for this trial again 6 months after the bleed.

Elotuzumab wouldn't take him because he responded to D-PACE (D-PACE cannot be used for maintenance).

Web sites say that daratumumab expanded access is available at 2 different centers in Michigan. Neither center have the drug yet, and they don't know when they will. Trials are a great thing - it's just not a sure bet that you can get in one.

The D-PACE has knocked his M-spike down enough that they are hoping he can be on no treatment until daratumumab is approved soon.

[Thelimeusa]

Re: Stay in clinical trial or pursue other treatment?

by Thelimeusa on Mon Nov 16, 2015 4:45 am

My wife's platelet count and white blood cells are normal at the moment. Her red blood cell count is a little low.

She is in good shape for trial approval as she got approved for the BBI608 study.

[Mark11]

Re: Stay in clinical trial or pursue other treatment?

by Mark11 on Mon Nov 16, 2015 10:40 am

Good discussion. I agree with Dr. Shain on his point that we need to keep in perspective what the soon to be approved therapies appear to be:

Always try to put these new therapeutics in perspective. These new options are very promising; however, they are buying us time, and hopefully time with quality of life.

I agree with JimNY with respect to elotuzumab. I understand that everyone is excited to have an antibody for therapy, but elotuzumab appears to just be an "assistor" drug for Revlimid. The CD38 antibodies have single-agent activity so that MAY end up putting them in the category of pro­teasome inhibitors, IMids, and high-dose melphalan in the future.

Thank you to Rumnting for her posts. Patients need to understand that you just do not get into clinical trials for new drugs whenever they need it. Her posts are reality and did not sound anti-clinical trial to me.