Initial Success, Frequent Recurrence

EBO: Today’s generation of multiple myeloma treatments result in high rates of initial remission. However, virtually all patients experience relapse. What do we know today about the mechanism of relapse in myeloma?

Dr Siegel:

You’re asking a very complicated question and it’s not an easy one to answer. The mechanism of relapse is that you don’t completely eradicate the clone. That might seem a silly, almost superficial answer, but it actually is more complicated than it might seem.

Myeloma is probably an inappropriate term, because it implies that we’re talking about a single disease, and almost certainly we are not. We used to talk about lymphomas a generation or two ago in a similar way. Now, we have identified 50 different species of what we used to call intermediate-grade lymphomas. Today, we understand that the biology of the various lymphoma types is entirely different and that the therapies used to treat them should be and are different.

What we call myeloma today is just a catchphrase for a bunch of diseases that are characterized by the accumulation of clonal plasma cells in the bone marrow. In some of those subtypes, the actual malignant cell—meaning the cell that is capable of repopulating the cancerous population—is a plasma cell, but in others it is not. It may be some other cell that has the capacity to spin off well-differentiated plasma cells but in fact is not a plasma cell itself.

That results in problems in how we judge the efficacy of our therapy. Today, this is done by measuring either the plasma cells themselves or the by-products of the plasma cell. That may not be the appropriate determinant or predictor of success. The ability to kill the clonal cells is not necessarily the same thing as the ability to kill the plasma cells. In fact, we know that in some patients, complete remissions are not necessary in order to have sustained disease control. They are treated with a particular approach, they achieve some level of response, and then the disease remains quiescent for the next decade. That’s not a common thing, but clearly that needs

to be explained. It can be explained by the fact that we did not kill the plasma cell in that particular patient but we’ve managed to kill some other precursor that mattered. Or have we managed to reconstitute the patient’s immune system in some way that allows it to keep the disease well controlled? It may be both of those things, depending on the particular version of myeloma that we’re dealing with.

Well, maybe we’ve killed all the “myeloma” cells, but we’re not addressing the right cells. We get relapse because this other group of cells is in fact the repopulating group.

Relapse occurs in many situations—from complete remission and from stable disease in other situations. Duration of stable disease may be the most interesting outcome, and depth of response may not be the most important arbiter of success.

EBO: How far into the future will it be before we’re able to identify and differentiate the various types of myelomas?

Dr Siegel:

Well, some people have started to do that. It depends which tool you are using to distinguish them. A group in Arkansas has the most extensive database,

based on gene-expression profiling, and they have identified 8 different subsets of myeloma that seem to have unique gene-expression signatures. We’ve begun to do whole genome sequencing. With this technology, we can begin to assess myeloma differences between patients. We’re not far off.

The Multiple Myeloma Research Foundation’s CoMMpass (Relating Clinical Outcomes in MM to Personal Assessment of Genetic Profile) study will include whole genome sequencing on 1000 patients with myeloma, and then follow what happens with those patients. This is one of the seminal efforts in cancer biology, and has not yet been done in this way for other cancers. This can dramatically change how we think about myeloma.

EBO: What do you think will be the effect of genome sequencing on therapeutics?

Dr Siegel:

Knowing that you have a B-RAF mutation might very well direct your therapy some time in the future, but not today. There is some suggestion

that patients with certain characteristics do better when they get bortezomib than when they don’t, but all patients with myeloma get bortezomib eventually, so that piece of knowledge has not yet really affected patient outcomes. It will require long-term follow-up of this large group of patients before we can understand what these data mean.

All the gene-expression profiling, the molecular and cytogenetic and FISH [fluorescence in situ hybridization] characterization of patients that we do routinely at the current time helps us to understand how well the patients will do in the long term, but they haven’t yet translated into directing whether a given patient should get a particular therapy. These current strategies, along with the more sophisticated strategies, like whole genome sequencing, will ultimately allow us to: (1) understand what mutations have led to the development of myeloma; (2) predict which MM patients are likely to do better than others; and (3) design therapies that are specifically active for a particular patient’s version of MM.

EBO: Let’s talk a bit about theavailable medications and those on the immediate horizon. Some novel agents in the pipeline show encouraging results in patients who have been heavily pretreated or have relapsed. From your view,which are some of the most promising investigational agents?

Dr Siegel:

Carfilzomib—the proteasome inhibitor that just received FDA approval after an accelerated review— is a major accomplishment. (To some extent it is hard for me to answer your questions without bias, because I was involved in the carfilzomib trials.) It received a limited approval and hopefully will achieve a more broad-based approval in the near future.

Carfilzomib is an exceptionally active drug—perhaps the most active drug that we have seen to date. It has a number of advantages over pre-existing drugs, and certainly represents a significant step forward, although it won’t immediately supplant any of the existing agents. We don’t even know how far this drug can ultimately go in terms of improving outcomes, nor the appropriate maximum dose. It is a very important addition to our armamentarium.

Carfilzomib is a noncompetitive and irreversible inhibitor of the proteasome. Bortezomib is a competitive, reversible proteasome inhibitor. That means that unlike bortezomib, where once the drug diffuses away, the proteasome becomes active again, once carfilzomib is no longer in the system, the cell needs to synthesize new proteasomes in order to recover its activity.

EBO: What about other promising agents in later-stage trials?

Dr Siegel:

A bunch of oral proteasome inhibitors are in clinical trials, some farther ahead than others, so we may soon have new oral alternatives to this very active group of drugs.

There is also a new derivative of thalidomide, like lenalidomide, that is in late-stage clinical trials and may also get accelerated approval from the FDA in the near future. It is also an exceptionally active drug with a good toxicity profile. This drug, pomalidomide, will be an important, highly active drug that has shown activity when other immunomodulatory derivatives (like thalidomide and lenalidomide) do not.

EBO: Will these agents be used commonly in combination?

Dr Siegel:

Yes. Carfilzomib has been used with lenalidomide. Carfilzomib will also be used in combination with pomalidomide. Pomalidomide may be used in any number of combinations. There is a huge need for a rituximablike drug in myeloma—a monoclonal antibody against lymphomas that has activity in a huge spectrum of lymphomas. No drug like this exists today for multiple myeloma.

The first monoclonal antibody that may get approved for use in multiple myeloma is elotuzumab, and it certainly looks like it has activity, particularly in combination with both bortezomib and lenalidomide. It is another, entirely new class—very, very exciting, because we don’t know what to expect as we combine it with other antimyeloma drugs.

The other drugs that have been widely used in clinical trials in multiple myeloma are the small-molecule kinase inhibitors, the mTOR inhibitors, and the AKT-kinase inhibitors, but none of them look like they are a home run in myeloma yet. That may be because we just haven’t figured out the right combination or the right scenario. That’s been one of the major disappointments: these small-molecule kinase inhibitors have not demonstrated the efficacy in multiple myeloma that they have in other B-lymphoid malignancies.

A huge number of drugs are being tested in clinical trials, many in very early phase testing. It’s very hard to judge their activity, but I am completely confident that some of them will turn out to be fantastic. Which ones? I don’t know.

EBO: Has research in the area of peptide vaccines yielded promising results in myeloma?

Dr Siegel:

There has been a very, very long history of tumor vaccine strategies in multiple myeloma dating back probably 15 to 20 years. Unfortunately, none of them to date have really translated into significant clinical activity. Yes, you can get the immune response, but know that immune response doesn’t translate into anything that is clinically relevant. We get more sophisticated both in terms of identifying the antigens, the potential targets, and in manipulating the situation to be optimal in terms of creating a clinical response. I think the work that’s being done at the University of Pennsylvania is certainly cutting edge in that regard. They are using cancer/testis antigens as vaccination targets for multiple myeloma, something that many, though not all, myelomas express. They’ve also generated a T-cell receptor that can recognize these antigens, and they can engineer the patient’s T cells to express that receptor and therefore attack the myeloma target. They used a similar strategy in chronic lymphocytic leukemia and attained clinical success already. Using this alternative target, will they be able to have similar kinds of success in multiple myeloma? It’s still too early to know.

EBO: One of the most common complications of multiple myeloma is peripheral neuropathy (PN)—it seems to be associated with both the disease itself and its therapies. In terms of the big picture, how many patients are affected and how debilitating is it?

Dr Siegel:

As you pointed out, there are a number of antimyeloma drugs that cause PN, bortezomib being the number 1 culprit, but thalidomide and lenalidomide can both cause PN. More than 50% of patients taking these drugs will develop PN additional to their baseline neuropathy. A small percentage of those patients (16%) will develop debilitating PN that is caused by the drugs we prescribe.

We have learned strategies to minimize that. One of the primary examples is that we now recognize that bortezomib can be administered subcutaneously, which significantly decreases the probability of developing PN. That’s a very important advance.

Carfilzomib causes far less PN. In fact, the drug has not needed to be discontinued because of peripheral neuropathy in clinical trials. That is a major breakthrough.

Unfortunately, we haven’t figured out a strategy to treat the PN caused by the therapies we use. We can discontinue the drugs and hope that it gets better, and that occurs in approximately 60% of patients, but for those in whom the PN doesn’t improve, there are very few effective options.

EBO: Is there any way to predict which patients may be at higher risk for treatment-related PN before administering the therapy?

Dr Siegel:

Not really, but we do know that certain patients (eg, those with diabetes) are at higher risk for PN because of their other condition.

EBO: Managed care organizations are scrutinizing the utilization of autologous peripheral stem-cell transplants today and are concerned about its costs in the future. Will transplant utilization increase or will these newer pharmacologic therapies provide better value?

Dr Siegel:

Autologous peripheral blood stem-cell transplants are the most effective therapy for multiple myeloma. A percentage of patients who undergo autologous peripheral blood stem-cell transplants will have remissions that last for decades, and no other intervention that we utilize today can provide as optimistic a prognosis.

The other advantage to an autologous peripheral blood stem-cell transplant is that there is virtually zero long-term toxicity. There is no neuropathy, there is no chronic bone marrow suppression, and there is no particular set of toxicities which you expect to persist beyond recovery from the transplant. Once you recover from the transplant (of course, the actual transplant is an uncomfortable experience), the expectation in the overwhelming majority of patients is that you will recover to your baseline or better than your baseline.

And peripheral blood stem cell transplantation is much less costly than the alternatives. The cost of a transplant is basically the cost of 3 or 4 months of therapy with any one of the frontline drugs for the management of multiple myeloma. Multidrug combinations, like bortezomib and lenalidomide, can be $16,000 to $20,000 per month. If you consider the cost of the drugs, the cost of the monitoring, the professional costs, and everything that goes into that pharmacologic therapy, it is a relatively expensive proposition.

EBO: Should stem-cell transplants be promoted as a primary intervention?

Dr Siegel:

I believe we should be using more stem-cell transplants. It’s very cost-effective.

EBO: Is there benefit to using lenalidomide as a maintenance therapy post-transplant?

Dr Siegel:

A couple of studies recently have suggested that lenalidomide used as maintenance therapy in patients who have undergone peripheral blood stem-cell transplant prolongs remission. That is true, but the survival advantage has not been as clearly demonstrated. Of 3 clinical trials, 2 do not show increased survival with maintenance lenalidomide therapy, but it should be recognized that none of these trials were actually designed to show a survival advantage.

It does not seem that maintenance therapy is significantly advantageous. For what is certainly at best a marginal survival advantage, we would be spending an enormous amount of money on chronic drug treatment, not to mention any additional toxicity that may occur as a result of the chronic pharmacologic therapy.

The trend in US practice has been to do just this. Without more definitive data, I don’t believe in it. The value of doing a stem-cell transplant is, to some extent, the advantage of not having to be on these alternative drugs. If we are going to put the patients on these alternative drugs anyway, the economic value of doing the transplant will be eroded.

One of the main reasons I prescribe a stem-cell transplant is that after they recover from the transplant, and assuming you do not give them additional drug therapy, they will feel the best they have since they were diagnosed with multiple myeloma—for that 1 year, 2 years, 3 years, and sometimes 20 years post-transplant. This will be the only time that they will be left alone medically. In my opinion, you better be pretty damned sure that maintenance therapy is valuable before you deprive the patient of this quality time.

Participant Affiliation: From the Division of Multiple Myeloma, John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ.

Funding Source: None.

Participant Disclosure: The participant reports receiving honoraria from Celgene, Millennium, and Onyx Pharmaceuticals.