IMW 2011 Multiple Myeloma Update – Day Three Part 1

Thursday was the third day of the International Myeloma Workshop (IMW) in Paris. There were presentations from early morning through the evening.
Some of the highlights from the first part of Day 3 of the conference are summarized in this article. Highlights from the second part of the day are summarized in a separate article (see related Beacon news).
Treating Older, Newly Diagnosed Myeloma Patients
The first session of the morning was about treating newly diagnosed multiple myeloma patients over the age of 65 years, specifically those who are ineligible for a stem cell transplant. It complemented the session on Wednesday on treating new patients under the age of 65 years.
First, Dr. Vincent Rajkumar from the Mayo Clinic in Minnesota presented the potential treatment options for older newly diagnosed patients, reviewed clinical trial data relevant to those treatments, identified key issues around treating older patients, and spoke about his own personal treatment preferences.
Dr. Rajkumar explained that he chooses a patient’s initial treatment based on whether the patient is standard-, intermediate-, or high-risk.
First of all, he mentioned that he prefers not to use melphalan (Alkeran), despite its long history of use in myeloma. He believes it can reduce the efficacy of future treatments.
Therefore, in the case of standard-risk patients, he recommends treatment with Revlimid (lenalidomide) and low-dose dexamethasone (Decadron) for 18 months. At that point, he discusses with each patient the option of Revlimid maintenance therapy.
He believes intermediate-risk patients should be treated with a combination therapy that includes Velcade (bortezomib). His preference is Velcade, cyclophosphamide (Cytoxan), and dexamethasone – a combination known as VCd or CyBorD – for one year, followed by Velcade maintenance for two years.
For high-risk patients, Dr. Rajkumar typically uses Revlimid, Velcade, and dexamethasone – known as RVd – until the patient (hopefully) achieves a complete response. Then they are put on Velcade maintenance therapy until their disease progresses.
When treating patients with Velcade, Dr. Rajkumar almost always uses subcutaneous Velcade, rather than infused, administered once a week. He feels this method and frequency of administration has shown good efficacy while also reducing the risk of peripheral neuropathy (pain and tingling in the extremities), which is a common side effect when Velcade is infused or given more frequently.
Throughout the rest of the session, researchers from a variety of countries discussed what myeloma specialists in their countries see as key issues related to the treatment of older, newly diagnosed patients, and the trials that are planned – or which have started recently – to shed light on the key open questions related to treating this patient group.
From the presentations, it was readily apparent that there is an extremely broad range of potential treatment options being investigated for older, newly diagnosed patients. The speakers mentioned melphalan and prednisone in combination with one or more novel agents, cyclophosphamide and dexamethasone in combination with one or more novel agents, as well as Revlimid plus dexamethasone possibly with the addition of Velcade.
Many of the trials discussed during the session are carefully analyzing each participant’s chromosomal abnormalities and, in some cases, bone imaging results. However, very few of the trials differentiate treatment based on a patient’s risk classification like Dr. Rajkumar recommends.
Several creative trial designs were also discussed.
For instance, Dr. Antonio Palumbo from the University of Turin, Italy, suggested using standard doses for “standard” patients and then a set of lower doses for patients who may be older or have other co-existing medical conditions.
Dr. María-Victoria Mateos of the University Hospital of Salamanca, Spain, also presented a creative trial design that uses two combination regimens: Velcade, melphalan, and prednisone (VMP) and Revlimid plus low-dose dexamethasone (Rd). One set of patients in her group's study will receive the two regimens in sequence: first several cycles of VMP, then several cycles of Rd. The other set of patients will receive alternating rounds of the two regimens: first a cycle of VMP, then a cycle of Rd, then VMP again, and so on. Dr. Mateos and her colleagues believe the alternating approach may yield better results, but they will have to wait to see what the results say.
Treatments Under Development
The next key session of the day was an exciting set of presentations about new drugs and approaches to treating myeloma. The focus of these presentations was on drugs that are still being researched and which, in most cases, are not yet government approved or generally available to treat myeloma.
Dr. Kenneth Anderson of the Dana Farber Cancer Institute in Boston gave the session’s introductory presentation. It surveyed the field of myeloma drugs that are still under development. Much of the presentation was similar to one he gave on Day 2 of the Workshop (see related Beacon news). However, in this presentation, he also discussed some promising drugs that are in very early development, including BHQ880, PCI-32765, PD 0032891, everolimus, and WT161.
A bit later in the session, Dr. Anderson also delivered an additional presentation that focused on potential new myeloma drugs that are proteasome inhibitors, a class of drugs that includes Velcade.
One of the new proteasome inhibitors, carfilzomib, is already well known among myeloma researchers and patients. But there are many other potential myeloma drugs in this class, and they all appear to be quite promising. Three that are already in clinical trials, or will be soon, are CEP-18770, NPI-0052, and P5091. Three others that have shown promise in the laboratory and may soon start clinical trial testing include MLN9708, ONX 0912 (PR-047), and PR-924.
Another key presentation during this session also focused on carfilzomib. The presentation was given by Dr. Andrzej Jakubowiak of the University of Michigan. He first summarized for the audience the design and results of earlier clinical trials involving the drug (see related Beacon articles). Then he described at length updated results from a trial involving carfilzomib combined with Revlimid and dexamethasone (CRd) in both transplant eligible and ineligible newly diagnosed myeloma patients. The CRd regimen is being used both as initial (induction) therapy as well as consolidation and maintenance therapy.
The response rates observed with this new combination therapy seem very promising. A full 97 percent of patients achieved at least a partial response, and 60 percent of patients achieved either a near complete response or better. After nine months, no patients have progressed, and all patients are still alive. Moreover, the side effect profile of the CRd regimen looks favorable, with only 11 percent of patients reporting peripheral neuropathy, and no cases of peripheral neuropathy have been serious.
Another new myeloma drug that has received significant attention, pomalidomide, was the subject of the session’s next presentation, which was given by Dr. Martha Lacy of the Mayo Clinic.
Pomalidomide is a chemical relative of both Revlimid and thalidomide. Like those other two drugs, it is taken orally as a capsule.
During her presentation, Dr. Lacy reported data that already had been presented in published papers or at previous conferences. Those data primarily come from clinical trials where pomalidomide has been used in relapsed / refractory myeloma patients who have had many different previous therapies. Even in patients that have received six or more different previous therapies, more than 25 percent of the patients taking pomalidomide have achieved at least a partial response.
The one potential challenge pomalidomide may face is its side effect profile. In many of the trials Dr. Lacy reviewed, about a third of the patients taking pomalidomide experienced serious reductions in their white blood cell counts (also known as neutropenia).
After Dr. Lacy finished her presentation, Dr. Enrique Ocio of the University Hospital of Salamanca, Spain, presented information about a potential new class of myeloma drugs, histone deacetylase (HDAC) inhibitors. Two drugs in this class – panobinostat (Farydak) and Zolinza (vorinostat) – are receiving the most attention in clinical trials.
After initially showing only limited efficacy as stand-alone treatments for myeloma, panobinostat and Zolinza are now typically being tested in combination with other myeloma treatments. The initial focus has been on testing these drugs in combination with Velcade, partly because there is a theoretical rationale for such a combination. The results, mainly from trials in relapsed / refractory myeloma patients, have been promising in terms of efficacy, but there have been some issues with the drugs causing low platelet counts (thrombocytopenia) in a number of trial participants.
Panobinostat and Zolinza also are now being tested in combination with Revlimid and dexamethasone, and initial results of these trials are promising, both in terms of efficacy and side effects.
The final presentation during the session on potential new myeloma drugs was given by Dr. Sundar Jagannath of the Mt. Sinai School of Medicine in New York City. He spoke about promising drugs that are monocolonal antibodies.
Antibodies are proteins used by the immune system to identify and destroy foreign objects like bacteria, viruses, and cancer cells. Monoclonal antibodies are produced from a single type of cell, making them completely uniform and able to hone in on a specific target, such as myeloma cells.
Dr. Jagannath explained that there are a number of monoclonal antibodies under development as potential myeloma treatments. However, as has been the case with the HDAC inhibitors, clinical trials have found that monoclonal antibodies are typically not effective on their own. Instead, they have the greatest impact when combined with another myeloma drug, such as Revlimid or Velcade.
Two monoclonal antibodies that are in late stage development are elotuzumab and siltuximab (CNTO-328). Elotuzumab has shown good efficacy in early trials when combined with Velcade in relapsed / refractory myeloma patients, but even better efficacy when combined with Revlimid and dexamethasone. A Phase 3 trial testing elotuzumab combined with Revlimid and dexamethasone in newly diagnosed patients is therefore planned.
Siltuximab also showed solid efficacy when combined with Velcade in early clinical trials, and one Phase 3 trial of the drug in combination with Velcade and dexamethasone in relapsed / refractory patients is already ongoing. Another Phase 3 trial combining the drug with Velcade, melphalan, and prednisone in newly diagnosed patients is planned.
Monoclonal antibodies that are in early-stage clinical trials for myeloma include BHQ880, BT062, daratumumab (HuMax-CD38), and IMMU-110 (hLL1-DOX).
For more detailed summaries of the day’s sessions, see The Myeloma Beacon’s extensive Day 3 coverage in the Beacon forums. For links to abstracts of some of the presentations given during the day, see the IMW programme. News from the final day of the workshop will also be summarized in a daily update like this one.
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- Nelfinavir-Velcade Combination Very Active In Advanced, Velcade-Resistant Multiple Myeloma
- Adding Clarithromycin To Velcade-Based Myeloma Treatment Regimen Fails To Increase Efficacy While Markedly Increasing Side Effects
- Nelfinavir Shows Only Limited Success In Overcoming Revlimid Resistance In Multiple Myeloma Patients
- FDA Approves Once-Weekly Dosing And Revised Safety Information For Kyprolis
Maybe it's just the way it is presented, but I sure as hell hope they do not only use age as an indication of "older" patients and thus treatment. There are a lot of 65 year olds who could do circles around some of the 50 year olds. I also would like to see some of Dr. Rajkumar survival numbers, particularly in the High Risk group with his treatment recommendations. I know he is a proponent of quality of life issues, and I am too, but it always troubles me when an "older" patient is not allowed the same opportunities as younger patients based solely on their age.