Novel Multiple Myeloma Treatments and Agents in Development

Kenneth Anderson, MD

Today we speak with Dr. Kenneth Anderson, professor of medicine at Harvard Medical School, and medical director at the Dana-Farber Cancer Institute in Boston. Dr. Anderson is one of the leaders of translational medicine research for identifying novel therapies for multiple myeloma patients, and he actively leads and participates in multiple myeloma trials. Multiple myeloma is a type of blood cancer that affects plasma cells, a type of white blood cell that normally produces antibodies. These cells accumulate in the bone marrow and can result in bone lesions and high calcium levels, or hypercalcemia.

-Interviewed by Anna Azvolinsky, PhD

Cancer Network: Dr. Anderson, what are the major ways that symptomatic multiple myeloma is initially treated? And is the goal to have the majority of patients who are eligible receive bone marrow transplants?

Dr. Anderson: Thank you very much for this opportunity to update the progress in multiple myeloma. The first thing to establish when a multiple myeloma diagnosis is confirmed, usually based on monoclonal proteins in the blood and/or urine in association with a bone marrow plasma cytosis, is whether or not the patient does need treatment. The classic features that have been used to make that decision are hypercalcemia, renal disease, anemia, and bone disease-features that once myeloma is confirmed, would initiate or harbinger the need for treatment. More recently, neuropathy and recurrent infections are also reasons why treatment might be needed.

In terms of treating symptomatic myeloma, we think of it in terms of patients who are transplant eligible and those who are not. Transplant patients are usually younger, less than physiologic age 70, who have heart, lung, liver, and kidney function that would make a transplant high-dose therapy and stem cell transplant safe. And then non- or ineligible patients for transplant are those who are older, or who don’t have the adequate liver, lung, heart, or kidney function to allow a transplant to go on. In either population, novel therapies are very important-the immunomodulatory drugs, thalidomide, nowadays lenalidomide and pomalidomide in the future; the proteasome inhibitors (bortezomib now) and, more recently, the second-generation proteasome inhibitor carfilzomib, and others coming along; and then corticosteroids. But why I say this is that in the transplant-eligible population, we commonly combine lenalidomide (one of the immunomodulatory drugs) with bortezomib (the proteasome inhibitor) and dexamethasone for three or four cycles, collect autologous peripheral blood stem cells, and then proceed to high-dose therapy (particularly high-dose melphalan) and a stem cell transplant followed by lenalidomide maintenance. Other regimens that could be used for three or four cycles initially in the transplant-eligible population might include cyclophosphamide (Cytoxan), bortezomib, and dexamethasone, or so-called CyBorD.

In the transplant-ineligible patients, we either use the same regimens and treat for prolonged periods of time, or commonly melphalan and prednisone tablets are used in the elderly population and then followed in either event by lenalidomide maintenance. So the way we treat symptomatic myeloma is with three drugs usually, and they are incorporated in combinations nowadays of targeted treatments. In terms of transplant eligibility, I have already mentioned it, but not everybody is eligible for transplant. It does really depend on their physiologic age and/or organ function that allows it to be safe. The final thing I will say is that when you use a combination of targeted agents, such as lenalidomide, bortezomib, and dexamethasone, the overall and extent of response is so high that we now have clinical trials that are evaluating the role of high-dose therapy in stem cell transplant. Clearly, new drugs before transplant to consolidate and increase the depth of response to transplant, and to maintain the response, have already changed the paradigm, but maybe someday we will just use the combination of targeted therapies, and the transplant will not be needed; time will tell in that vein.

Cancer Network: As you mentioned, many of the current treatments include bortezomib, a proteasome inhibitor, as well as lenalidomide and other immunomodulators in the same family, and these are used in combination either with each other or with other drugs. You touched upon this a bit already, but how do you decide which patients should receive which combination therapy?

Dr. Anderson: Honestly, I think all patients should receive three-drug therapy nowadays. As it turns out, if you combine novel targeted therapies, pretty much all patients will respond initially to an immunomodulatory drug, a proteasome inhibitor, and steroids, and so I think all patients should receive it. The issue is that there are certain patients who do have high-risk multiple myeloma. They would get the same initial therapy, but perhaps subsequently would be treated differently. In particular, in terms of once they have achieved a response, the method used to maintain that response in the standard-risk patient might just be lenalidomide alone, but in the high-risk patient might be a combination again of a proteasome inhibitor together with an immunomodulatory drug.

Cancer Network: As a physician who both treats multiple myeloma patients and works on the latest therapies in development, what do you see as the biggest progress you have seen in terms of diagnosis or treatment of multiple myeloma?

Dr. Anderson: I think the huge difference in the last 10 or 15 years is the appreciation of immunomodulatory drugs and proteasome inhibitors, which target the tumor in the microenvironment, and have, in a major way, changed things. Specifically, if you use novel therapies now as initial therapy, as consolidation therapy, and as maintenance, the survival of patients with myeloma is doubled to tripled. It is not uncommon nowadays for patients now to live a decade or longer, and with maintenance, frankly, we really don’t know, but one can anticipate that it would be much longer.

This has set the stage now for four-drug combinations or even five-drug combinations, where one could add additional agents. The initial treatment is improving, but so is the treatment of relapsed myeloma. We have been very blessed because we have carfilzomib as a second-generation proteasome inhibitor already approved. We have other proteasome inhibitors, MLN9708 and marizomib. On the other side, we have immunomodulatory drugs. Lenalidomide is approved, but we will soon have pomalidomide, a more potent immunomodulatory drug, which together with low-dose dexamethasone will be approved for relapsed myeloma. So the short version here is we have proteasome inhibitors, immunomodulatory drugs as the first generation, but we are already blessed to already have a second generation in each category now. We also have entirely new classes of drugs-monoclonal antibodies such as elotuzumab or daratumumab-multiple combination treatments with either immunomodulatory drugs, such as lenalidomide and elotuzumab or combined with proteasome inhibitors. For example, we have carfilzomib combined with lenalidomide or we have bortezomib combined with the histone deacetylase inhibitors. We have, in other words, first generation new drugs, second generation new drugs in both the proteasome inhibitor and immunomodulatory category. We have entirely new things, such as antibody-based treatments and we have combinations, so the best progress has been with these agents, and now it is a matter of trying to learn how to use them best together and in ways and doses and schedules where we can enhance the efficacy and have optimal tolerability as well. It is a very exciting time in multiple myeloma.

Cancer Network: Just to highlight one of the newer drugs you mentioned, carfilzomib, as you mentioned has been recently approved for relapsed, refractory patients. What is the mechanism of this specific drug and how are physicians incorporating it in their treatment regimens?

Dr. Anderson: So, carfilzomib is a major advance. It is an epoxyketone inhibitor of the chymotryptic site on the proteasome. The depth of inhibition and the duration of inhibition of the proteasome are longer than that obtained with bortezomib, and fortunately, on the side effect side, there is little in the way of neuropathy. So, it has gone forward into clinical trials as you mentioned  on the basis of a phase II clinical trial, and a response rate of about 20%, duration of response of 8 months, and survival of 15 months in patients whose myeloma literally responds to nothing else. That track record was the framework or basis for achieving accelerated approval, and it has clearly been a godsend to those of us who are caregivers and patients alike. Now, it has been combined already with lenalidomide and dexamethasone in the so-called ASPIRE trial in earlier patients with just relapsed myeloma-carfilzomib, lenalidomide, and dexamethasone vs lenalidomide plus dexamethasone. The large trial has been completely enrolled, and it is our hope and expectation that that clinical trial will be the basis for its approval in relapsed myeloma. Already too we have carfilzomib being tried with lenalidomide and dexamethasone as an initial treatment in myeloma. Just as with the prior bortezomib, prior lenalidomide, these agents come along and prove their value in advanced disease, but they get quickly moved into earlier stages of disease as well.

Cancer Network: Thank you so much for taking the time and joining us today, Dr. Anderson.

Dr. Anderson: You are welcome. Thank you very much.