MULTIPLE MYELOMA UPDATE
FROM THE AMERICAN SOCIETY OF HEMATOLOGY (ASH)
NOVEL BIOLOGICALLY-BASED THERAPIES
Kenneth Anderson, MD
Dana-Farber Cancer Institute, Boston, MA
December 8, 2002
DR. STEPHEN SALETAN: We're here in Philadelphia at the 44th annual meeting of the American Society of Hematology with Dr. Kenneth Anderson. Dr. Anderson is Kraft Family Professor of Medicine at Harvard Medical School and Director of the Jerome Lipper Myeloma Center at the Dana- Farber Cancer Center. Dr. Anderson, we've heard a lot about very exciting and fast-moving area of novel, biologically based therapies for multiple myeloma at this meeting. Can we begin with Velcade, PS-341, also known as bortezomib ... can you tell us a bit about this agent, what kind of agent is it and how does it work?
KENNETH ANDERSON, MD: Surely. Velcade, or bortezomib, was originally called PS-341 and it is a proteasome inhibitor. The way it works in myeloma isn't completely clear, but we do know that it attacks not only the myeloma cell and kills it, even the cells that are resistant to standard treatments, but it also blocks the ability of the myeloma cell to bind to the bone marrow and inhibits in the neighborhood or bone marrow microenvironment the production of factors, cytokines, that the myeloma cell needs to grow and survive. The excitement is that this drug not only works in the laboratory and in animal models against human myeloma cells, but in phase I trials was found to be very well tolerated and to have early hints of myeloma activity. And at this meeting, now in Philadelphia, the full phase II trial, where we really tested the efficacy of this drug against myeloma is for the first time being reported.
In 202 patients with relapsed refractory myeloma, whose myeloma was growing in spite of having 6 prior therapies and individuals who had their myeloma 4 years before getting on this Velcade trial, remarkable antimyeloma activity was observed. There were 4% complete responses, which means complete absence of protein and normalization of the bone marrow. And there were a number of individuals who had near-complete responses, whose bone marrow normalized, but they just had residual protein. The total number, therefore, is 10%, complete responses or near- complete responses.
There was another approximately 20% of patients who had a partial response, which means, in fact, that their protein fell 50% or more and, again, it lasted for at least 6 weeks. So the response rates by strict criterion were in the range of 30% in these very refractory/relapsed patients. Fully another 30% of patients had stable myeloma, which means that their myeloma protein, which had been rising before they began treatment, stabilized (see Slides 1-3).
So the first important message is the extent and the degree of responses observed. The second important message is that these responses were durable. The response duration or the time until myeloma progressed on average in this population was a little bit more than 10 months ?in data released since, the response duration is actually 12 months?. And, in fact, this is a quite a remarkable durability of responses in this very refractory/relapsed patient population. So the aspects are the extent of response and that they are durable.
The third important feature of this trial is that these responses were associated with clinical benefit. And clinical benefit was associated with an improvement in the hemoglobin or hematocrit and a related decrease in the need for red blood cell transfusions, improvement in quality of life, improvement in performance status, and importantly, an improvement in the normal antibodies that are usually low in myeloma at the same time that the abnormal myeloma antibody or protein was going away.
So the 3 features, just to summarize for you, are these ... this drug achieved a remarkable degree of responses in patients in whom it had not previously been possible, including complete responses. The responses were durable and they were associated with clinical benefit.
DR. STEPHEN SALETAN: Well, these are very exciting results, indeed. Can you tell us a little bit about the side effects that are seen with the drug?
KENNETH ANDERSON, MD: The side effects are primarily well managed and well tolerated. The 2 major concerns that had been advanced in terms of side effects were neuropathy and low platelet count, or thrombocytopenia. These 2 complications occur primarily in patients in whom these conditions were preexistent. So that is the major side-effect profile. Also at this meeting will be reported another trial of Velcade in earlier-stage myeloma, people who have had up to 3 prior therapies, not 6 prior therapies, as I just mentioned for the previous study. And in this earlier patient population of individuals who had only 3 prior therapies before they made it to Velcade, the response rate in 52 patients was 50%. So it was a little bit higher response rate in the setting of an earlierstage of disease. And I mention it now because the side-effect profile was also more favorable. Both the neuropathy and the thrombocytopenia, which had been significant in the advanced-stage patients, was also less in this earlier trial (see Slides 4-6).
DR. STEPHEN SALETAN: What kind of results have we seen with Velcade used in combination treatment?
KENNETH ANDERSON, MD: At this meeting there are 3 different drugs that have been combined with Velcade and which will be reported on at least in preliminary way. Firstly, in the big phase II trial of Velcade alone of 202 patients, if patients did not respond or progress to Velcade alone, Decadron was added. And that occurred in 78 patients. And in these 78 patients in whom Decadron was added to the Velcade, 17 patients out of the 78 patients ... or I believe that's 26% of patients ... actually had an additional benefit when the Decadron was added to the Velcade. And so there are some patients, who appear to be a minority, who may benefit from the addition of steroids to Velcade.
The second important other drug class that's been added to Velcade that's reported at this meeting is the anthracyclines, specifically Doxil. And Dr. Robert Orlowski from North Carolina will report that in a small number of patients who were refractory to anthracyclines, they responded markedly to the combination of anthracycline, specifically Doxil, plus Velcade. And this experience mirrors our laboratory prediction that you can overcome resistance to alkylating agents like anthracyclines or like melphalan that we use to treat myeloma if you simply add Velcade.
The third drug class that is being reported in a preliminary way here in combination with Velcade is thalidomide. This study is done by Dr. Zangari in collaboration with Dr. Barlogie in Arkansas, where they are starting with Velcade and adding thalidomide to it for those individuals who have either stable disease or don't respond to the Velcade alone. Preliminary analysis shows marked responses and not increased incidence of neuropathy that we might worry about, given that either drug can cause this complication by itself. So in summary, as I like to say, Velcade is a member of a new team and the team will consist of old conventional drugs such as Decadron and anthracyclines and new drugs such as thalidomide.
DR. STEPHEN SALETAN: Velcade is actually in phase III testing at this point, is it not? Can you describe that for us, briefly?
KENNETH ANDERSON, MD: Surely. The phase III trial in Velcade represents something that we've all wanted in our myeloma communities for a long time. There is a trial now that was initially going to involve 66 centers around the world, which is now going to involve probably 80 or 85 centers. So it represents a massive effort internationally in myeloma. The trial will compare Decadron alone versus Velcade alone in patients with relapsed myeloma. The idea with all of the centers, with this patient number requirement, is that we will finish accrual to this trial by mid-2003.
We will be looking for an improvement in time to progression in comparing Decadron and Velcade in this trial and importantly, we'll look to be sure that we can confirm activity of Velcade in this earlier patient population in order to hopefully expedite approval of this drug, both in the United States, and since this is an international trial, also in Europe, roughly within the same time frame (see Slide 7).
DR. STEPHEN SALETAN: Can we talk now about another exciting new agent, Revimid, also known as CC-5013? What kind of drug is Revimid and how does it work?
KENNETH ANDERSON, MD: Revimid is a member of a class of drugs called the immunomodulatory drugs or IMiDs, in which class thalidomide also resides. The difference between Revimid and thalidomide is Revimid is much stronger. Probably at least a thousand times stronger in our laboratory assays. Revimid works not only by killing myeloma cells that are resistant to standard treatments like melphalan, Adriamycin, and steroids, but importantly, also inhibits the ability of the myeloma cell to bind to the bone marrow and inhibits in the bone marrow the production of factors, cytokines, again, that are needed for the myeloma cell to grow and survive.
Excitingly, these laboratory observations have rapidly gone from the bench to the bedside. Phase I studies reported at ASH last year showed that this drug had remarkable antimyeloma activity. In 25 patients, 80% of them had either stabilization or drop in their myeloma protein, all of whom had had a rising protein before beginning treatment. Even more importantly, there were not the side effects that we see with thalidomide, which include insomnia and constipation and neuropathy.
Now, at this meeting, my colleague Paul Richardson is reporting on a phase II trial of Revimid that has been conducted primarily at our center in Boston in collaboration with the Mayo Clinic, the Moffitt Cancer Center in Tampa, Florida, and in New York City with St. Vincent's Medical Center and Dr. Sundar Jagganath. In this population of patients, again, remarkable disease responses were observed. In particular, there were 4% complete responses. There were 17% partial responses and there were 33% minimal responses. There were an additional 30% of patients who had stable disease. Putting it more plainly for all of you, only 7 of 46 patients treated with Revimid in this phase II trial progressed. The majority of patients benefited in terms of either stabilizing their disease or responding.
DR. STEPHEN SALETAN: All right. We've heard that Revimid is not associated with several of the more troubling side effects that thalidomide is associated with. What side effects has Revimid treatment been associated with?
KENNETH ANDERSON, MD: That's a terrific question. There is no free lunch in life and so Revimid does have some complications. It's primarily low blood counts, both low white blood cell count and low platelet count. But these can usually be addressed by reducing the dose of Revimid and/or utilizing growth factors such as GCSF to augment the patient's white blood cell count. However, this phase II trial that I've just mentioned has added further support to the original findings of the phase I trial that there really are not somnolence, constipation, or neuropathy in most patients.
DR. STEPHEN SALETAN: What kind of results have we seen using Revimid in combination treatments?
KENNETH ANDERSON, MD: Well, there's very little to date that has been done utilizing Revimid in combination with other agents. I will tell you that in our phase II trial in those patients who had stable disease or progressed with Revimid alone, Decadron was added. That was done in 7 patients out of the 46 patients that I've mentioned to you and 4 out of the 7 patients had response that they had not had to Revimid alone, upon addition of Decadron (see Slides 8-12).
DR. STEPHEN SALETAN: Can you tell us something about the phase III trial program for Revimid?
KENNETH ANDERSON, MD: Yes, I surely will because this represents another international trial proving actually that we in the world can work together in myeloma to rapidly test novel agents and get them from the bench to the bedside to patients internationally. This will be a 50-site trial, which will compare Revimid and Decadron in 1 cohort with Decadron alone. The endpoint of this study is an improvement in time to progression of multiple myeloma. As I stated, this trial will open in early 2003 and we predict very rapid accrual internationally, hopefully finishing the trial by the end of 2003 for accrual purposes (see Slide 13).
DR. STEPHEN SALETAN: And Dr. Anderson, what are some other novel myeloma therapies you can tell us about?
KENNETH ANDERSON, MD: Well, at this meeting of the American Society of Hematology, in myeloma as well as the other blood cancers, targeted therapies of very many types are being reported for the first time. In the category of targeted therapies that act on circuits inside of myeloma cells, there is the compound Genasense, which has nearly completed clinical trials and inhibits survival circuits inside of myeloma cells. Other representative compounds being reported here are the farnesyl transferase inhibitors, the histone deacetylase inhibitors, and the HSP 90 inhibitors. These 3 drugs, in addition to Genasense, represent targeting circuits inside of cells that show promise in myeloma.
There are also classes of new drugs that target myeloma cells on the cell's surface. And these include the insulin-like growth factor receptors, the vascular endothelial growth factor receptors, and a compound called TRAIL, all of which target circuits at the cell's surface which induce drug death in multiple myeloma in preclinical trials and are rapidly moving to the bedside for clinical testing. And finally, there are drugs which act not only on tumor cells, but also to inhibit the tumor cell interaction in the microenvironment. In this category is arsenic trioxide. A new class of drugs called the LPAAT beta inhibitors and the p38 MAP Kinase inhibitors. Again, all of these represent targets not only in the evil myeloma cell, but in the microenvironment to overcome drug resistance (see Slide 14).
DR. STEPHEN SALETAN: Well, Dr. Anderson, this clearly has been an exciting meeting for myeloma research and is an exciting time for myeloma research. Thank-you very much.
KENNETH ANDERSON, MD: You're very welcome.
cancereducation.com |
