[Cheryl G]

Controversies in the treatment of multiple myeloma

by Cheryl G on Mon Feb 22, 2016 1:21 pm

The U.S. National Cancer Institute has updated its "PDQ" (Physician Data Query) summary of information about plasma cell neoplasms, of which multiple myeloma is one.

The PDQ guides are useful because they are peer-reviewed and intended to be "evidence-based", rather than being reflections of the latest fads or hype.

In the current version of the summary is a useful description of "Unresolved questions in multiple myeloma", which I thought it would be useful to quote and discuss.

There are 4 controversies in the list, but they really reduce to three, which I would describe as:

1. Is stem cell transplantation necessary? (Points 1 and 3 in the PDQ list)
2. Is there a benefit to intensive therapy with 3 or 4 drugs at one time, versus less intensive therapy? (Point 2 in the PDQ list)
3. Is there an overall survival benefit to maintenance therapy? (Point 4 in the PDQ list)

Here is a full quote of the summary's list of "unresolved questions":

1. Does a high-dose alkylator-induced immune "reset" after induction therapy (i.e., autologous stem cell transplant [ASCT] consolidation) result in long-term benefits that outweigh potential toxicities such as the emergence of resistant clones or second malignancies? Some clinicians in the United States and many in Europe consider ASCT to be the backbone after induction therapy or after trials introducing new agents into induction therapy. Other clinicians think that combinations of new agents and the availability of other agents provide the ability to avoid ASCT.
    
2. In choosing initial induction therapy, should new triple-drug regimens (e.g., lenalidomide [Revlimid], bortezomib [Velcade], dexamethasone) be employed to achieve the best response and most durable remission? Or should active agents be used in singlets and doublets in a sequential fashion, using the same approach as for an indolent lymphoma? Should this decision be made in a risk-adaptive way, with favorable-prognosis patients employing the sequential approach? Or should all new patients receive triple-drug regimens?
    
3. As newer agents, such as carfilzomib [Kyprolis] and pomalidomide [Pomalyst, Imnovid], and newer inno­va­tions (e.g., the anti-CD38 monoclonal antibodies under investigation) are used, will the stringent complete remissions equal or surpass ASCT with less long-term toxicities?
    
4. Maintenance therapies are under active clinical evaluation; the prolonged remissions and improved progression-free survival (PFS) have not translated into established overall survival (OS) benefits in most trials. (Refer to the Maintenance Therapy section of this summary for more information.) How will this approach augment induction and consolidation therapies?

The full text of the PDQ summaries are available at several different locations on the Internet, and there is a patient-friendly version and a version intended more for healthcare professionals.

Healthcare professional version:

http://www.ncbi.nlm.nih.gov/books/NBK65924/#CDR0000062866__107 , or
http://www.cancer.gov/types/myeloma/hp/myeloma-treatment-pdq

Patient-friendly version:

http://www.cancer.gov/types/myeloma/patient/myeloma-treatment-pdq

Last edited by Cheryl G on Mon Feb 22, 2016 5:36 pm, edited 1 time in total.

[Multibilly]

Re: Controversies in the treatment of multiple myeloma

by Multibilly on Mon Feb 22, 2016 3:31 pm

As usual, really a nice post, Cheryl. For those reading through this, I think it's worth the time to scan the healthcare version of the PDQ.

[KarenaD]

Re: Controversies in the treatment of multiple myeloma

by KarenaD on Mon Feb 22, 2016 5:37 pm

Hi Cheryl,

Thanks so much for posting this … a very interesting read.

The International Staging System for multiple myeloma indicates that if one is diagnosed at Stage 3, the median survival is only 29 months. However, if one is in the “Good Risk” group for cytogenetics, the median survival is 8-10 years. I’m assuming this means that cytogenetic factors trump diagnosis stage with respect to median survival times. (My doctor has confirmed as much to me, i.e., that stage at diagnosis is less important that cytogenetic factors and responsiveness to therapy, but I would like to be certain that this is indeed the case.)

Since I will be undergoing an ASCT in April, I found the following comment of concern:

While some prospective randomized trials showed improved survival for patients who received autologous peripheral stem cell or bone marrow transplantation after induction chemotherapy versus chemotherapy alone, other trials have not shown any survival advantage.

Two meta-analyses of almost 3,000 patients showed no survival advantage

Even the trials suggesting improved survival showed no signs of a slowing in the relapse rate or a plateau to suggest that any of these patients had been cured. The role of ASCT has also been questioned with the advent of novel induction therapies with high complete-remission rates.

However, it is also indicated that regarding high dose chemotherapy and ASCT:

Upon review of eight updated trials encompassing more than 3,100 patients, at 10 years' follow-up, there was a 10% to 35% event-free survival (EFS) rate and a 20% to 50% OS rate.

I’m very newly diagnosed and still trying to understand both the basics and intricacies of this disease, but, to me, 10-35% event free survival and 20-50% overall survival at 10 year’s follow up would seem to be indicative of a reasonably successful treatment strategy given the afore­mentioned median survival times.

Karen

[Cheryl G]

Re: Controversies in the treatment of multiple myeloma

by Cheryl G on Mon Feb 22, 2016 5:51 pm

Thanks, Multibilly and Karen.

I know a lot of people will focus on the first controversy (stem cell transplants). But it's not really my intention to stir that pot further.

For me, I think the more interesting thing about the list is that it includes maintenance therapy and, especially, the issue of treatment intensity.

As far as maintenance therapy goes, I have begun to put more emphasis in my own mind on a point that Mark11 has made many times about the value of treatment-free intervals. I think there can be value to doing maintenance therapy for a defined period of time -- for example, to give time for a treatment to reach its full effect. But I worry about the impact on the body, and particularly on the bone marrow, of continuous maintenance until relapse.

[mikeb]

Re: Controversies in the treatment of multiple myeloma

by mikeb on Tue Feb 23, 2016 12:56 pm

Hi Cheryl G,

Thanks for the post. I was not aware of the PDQ. I like your grouping of the unresolved questions (3 questions). Based on what I've been reading, at this time those certainly seem like the Big Three to me.

At least we know the questions, even if we don't know the answers.

Mike

[Mark11]

Re: Controversies in the treatment of multiple myeloma

by Mark11 on Tue Feb 23, 2016 1:45 pm

Thanks for posting this link.

I know a lot of people will focus on the first controversy (stem cell transplants). But it's not really my intention to stir that pot further.

Fortunately we are not going to argue about this topic in this thread! Note that this is evidence for newly diagnosed patients. Generally speaking I think it is agreed upon that it does not matter if an auto is done upfront or at first relapse with regard to overall survival (OS). So few (12% of newly diagnosed patients in the US in 2010) did an auto in the US during their first year after diagnosis, I am not sure why patients/doctors are constantly discussing the topic of early auto transplant. For such a rarely used therapy as part of initial therapy it seems to take up a high percentage of the conversations.

I did take a quick look at the studies that were listed that said autos did not improve overall survival. Interestingly, none of the 4 used melphalan 200 exclusively as conditioning for the auto group. None of the studies included novel agents.

As an example, I will show what is compared in one of those studies:

In 1993, three North American cooperative groups launched a prospective randomized trial (S9321) comparing HDT (melphalan [MEL] 140 mg/m2 plus total-body irradiation 12 Gy) with SDT using the vincristine, carmustine, MEL, cyclophosphamide, and prednisone regimen. Responders on both arms (> or = 75%) were randomly assigned to interferon (IFN) or no maintenance treatment.

Reference:

B Barlogie et al, "Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321," Journal of Clinical Oncology, Feb 2006 (full text of article)

Basically you are comparing a high dose of melphalan and radiation with standard doses of alkylators, vincristine, and steroids. This seems to be showing that if a patient is a strong responder to alkylators, it may not matter if it is given in a high dose or standard dose.

To KarenaD's point, yes, I think those overall survival stats given are reasonably successful given that they are not using novel agents during induction. That should raise them con­sider­ably.

To CherylG's point in her last paragraph, the topic most of you should be reading about / discussing is maintenance therapy. That affects a whole lot more of you than auto transplants do, especially here in the U.S. Take note when you read about the treatment histories of the long-term survivors, like 15 years plus. What I have noticed that applies to most of them is that they used and responded to alkylators and they take therapy breaks.

[philatour]

Re: Controversies in the treatment of multiple myeloma

by philatour on Wed Feb 24, 2016 5:52 pm

I took this from Mark11's post:

So few (12% of newly diagnosed patients in the US in 2010) did an auto in the US during their first year after diagnosis, I am not sure why patients/doctors are constantly discussing the topic of early auto transplant.

Some of this might depend on the difference between those with high-risk characteristics vs. those with sustainable response to medication-based treatments. For those who do not achieve a sustained response to medication regimens, (i.e., 12% of multiple myeloma patients is a good estimate), early transplant is among the better choices available. Cytogenetic advances make it easier to determine who falls in this category, along with relapse within 12 months of transplant or disease progression within first year of diagnosis. Easier, but certainly not perfect.

This also pertains to the topic of treatment breaks. Not so easy to take treatment breaks when medication based treatment combos fail to hold the multiple myeloma in check after relatively short periods of time. The near continual effect of being in treatment certainly shows up in wear and tear on the body - but patients with very treatment-resistant disease have few other choices.

[Mark11]

Re: Controversies in the treatment of multiple myeloma

by Mark11 on Wed Feb 24, 2016 10:48 pm

Hi philatour,

I hope all is well with you. Basically your first paragraph is making the point I was making. Note what the "controversy" is supposed to be:

Does a high-dose alkylator-induced immune "reset" AFTER INDUCTION THERAPY (i.e., autologous stem cell transplant [ASCT] consolidation) result in long-term benefits that outweigh potential toxicities such as the emergence of resistant clones or second malignancies?

I don't think what you are discussing is what the "controversy" is supposed to be. You would not know after your initial induction therapy if you will achieve a sustained response to medication regimens immediately after induction. They are discussing a treatment plan like 5 cycles of RVD, to auto, to maintenance in a planned manner. An example of planned use of auto is Total Therapy. They do 2 cycles of VTD-PACE to 2 autos. They do not wait to see if they sustain a response to induction before doing the transplants.

You wrote:

The near continual effect of being in treatment certainly shows up in wear and tear on the body - but patients with very treatment-resistant disease have few other choices.

Not necessarily. I was considered a high-risk patient. That is why I did a planned allo (donor) transplant in first complete response. That therapy choice has enabled me to enjoy a 4.5 year (and counting) drug-free remission. I did the therapy that gave me the best chance to have a therapy break. Most myeloma doctors do not treat in an aggressive manner early in disease course. The best chance of getting a therapy break is during the first remission.

Mark

[RondaV]

Re: Controversies in the treatment of multiple myeloma

by RondaV on Thu Feb 25, 2016 3:08 am

Hi Cheryl,

Thanks once again for a thought provoking post.

With standard risk myeloma, I have pursued a fairly aggressive approach for a person in their 70s, with full strength three-drug induction (CyBorD), followed by ASCT (160 mg melphalan because of my age), then four months of consolidation, which left me at a near complete response. I arrived at a complete response a few months later. Since consolidation finished, I have only had Zometa (no side effect or blood problems) 3-monthly, and plan no more drug treatment until relapse.

With the new drugs now available, and more in the pipeline, I think in the future there will be more people having problems because blood and organs will not tolerate available treatments, than there will be with people running out of treatment options.

I have had 18 months so far and hope for more yet to give my body a chance to recover. My quality of life is very good.

Ronda

[JPC]

Re: Controversies in the treatment of multiple myeloma

by JPC on Thu Feb 25, 2016 8:56 am

Good morning:

Thank you, Cheryl, for posting this interesting article. I would respectfully point out, however, that in my view, in reality, the fact that there are "Controversies" is sort of a good thing, in that there are researchers actively trying to get answers. Complete agreement, I do not think, would in reality happen until we are at or are much closer to a cure, which I think is a long way away, and the fact that there are "controversies" reflects the good activity in advancing the science in this area, for which I am appreciative.

Secondly, to Philatour. You are absolutely correct to question the 12% statistic. I had posted on this before. This is a misapplication or misunderstanding of statistics. It appears to be supporting an argument that transplants are at the fringe, which is not accurate. Although the numbers are not clearly broken out for newly diagnosed multiple myeloma, they can be deduced from a couple of sources.

Overall ASCT rates are misleading. Over 50% of patients for one reason or another (age or condition) are transplant ineligible. Keep in mind that the average age of onset of multiple myeloma is 67, and the traditional standard cutoff for an autologous stem cell transplant is 65. With regards to transplant eligible patients, the ratio between transplants and newly diagnosed patients is something like 80%. What this means is that something like 75% (allowing for a small number of people who elect to get tandems) have transplants at initial diagnosis or first relapse.

I had posted these numbers before, but speaking from memory, I believe that in a recent year there was about 25,000 newly diagnosed multiple myeloma patients, and about 10,000 autologous stem cell transplants for multiple myeloma. I could not get the exact transplant ineligible rate. There probably is not one, because its a judgement call, but guessing it's in the 55% to 60% range, then you can see that the approximate numbers I estimated above are at least in the ball park, given a reasonable guess for the rate of transplant ineligible patients.

From a casual reading of the forum, it would appear that transplant is a big issue. That's because it is a big issue for the relatively younger, relatively healthy transplant eligible population, that is most actively involved in the forum. Yes, there is a group, that I guess to be about 25%, that elect to forego transplant. Maybe that will grow in the future with the improvement in novel agents, but for today, and the recent past, even those patients are faced with the choice or option of an ASCT, and I would suggest that it was also an "issue" for them. So yes, Philatour, I agree that transplant is still a big issue for the affected population.