ASH 2010 Multiple Myeloma Update – Day Three Afternoon And Evening

This Monday was the third full day of the American Society of Hematology 2010 annual meeting, and it was packed with multiple myeloma-related presentations. The Beacon published an update earlier today covering presentations made Monday morning. This article covers material from Monday afternoon and evening.
The first presentation of the afternoon was by Dr. Ruben Niesvizky of the Weill Cornell Medical College in New York. He reported on the results of a Phase 3 trial using Velcade (bortezomib)-based initial treatment (induction) regimens combined with weekly Velcade maintenance therapy (abstract).
Patients in this trial were newly diagnosed but ineligible for high-dose therapy or stem cell transplantation. All trial participants were randomly allocated to one of three induction regimens: Velcade-dexamethasone (Decadron) ("VD"); Velcade-thalidomide (Thalomid)-dexamethasone ("VTD"); or Velcade-melphalan (Alkeran)-prednisone ("VMP"). After 24 weeks of induction treatment, patients received 25 weeks (five 35-day cycles) of weekly Velcade maintenance therapy.
The shares of patients who had a complete or near complete response after induction therapy were 24, 36, and 31 percent in the VD, VTD, and VMP arms of the trial, respectively. After an additional five cycles of maintenance therapy, the rates of complete or near complete response were 31, 38, and 34 percent, respectively.
A rather large share of patients in each arm experienced some kind of serious side effect – 74, 86, and 80 percent in the VD, VTD, and VMP arms, respectively, after 13 treatment cycles. Peripheral neuropathy (nerve damage to the extremities that can cause pain and tingling sensations) was the most common side effect. Serious levels of it were observed in 18, 28, and 21 percent of the patients in each arm, respectively.
The authors believe, however, that maintenance with Velcade monotherapy after these Velcade-based induction regimens is well tolerated, and patients in the trial are still being monitored to measure progression-free survival and response duration.
Also during the afternoon session, Dr. Antonio Palumbo from the University of Torino, Italy, presented a Phase 3 study in elderly newly diagnosed myeloma patients comparing the addition of Revlimid (lenalidomide) to melphalan and prednisone (abstract).
Patients in the trial received one of three possible treatment regimens. One regimen involved nine 28-day cycles of melphalan and prednisone alone followed by placebo (MP). The second regimen involved nine 28-day cycles of melphalan, prednisone, and Revlimid also followed by placebo (MPR). The third regimen was the same as the second, but, instead of receiving placebo after the first nine cycles of treatment, patients received maintentance therapy with Revlimid (MPR-R)
The trial results Dr. Palumbo presented on Monday are interim results from a 21 month follow-up. Earlier interim results were presented at last year's ASH annual meeting (see related Beacon news).
Responses were more rapid and better with MPR-R than MP, with overall response rates of 70 percent and 50 percent, respectively.
Across all patients in the MPR-R and MP arms of the trial, MPR-R reduced the risk of disease progression by 58 percent compared to MP. Among patients in the MPR-R and MPR arms who did not progress during the first eight cycles of treatment, MPR-R reduced the risk of disease progression by 69 percent compared to MPR.
Side effects of MPR-R were manageable, but a larger percentage of patients on that regimen discontinued therapy due to side effects as compared to patients on MP. The most common severe side effects were low blood cell counts that occurred during the MPR phase of treatment.
To conclude the afternoon session, Dr. Murielle Roussel of Hopital Purpan in Toulouse, France, presented the results of a Phase 2 study in which newly diagnosed patients younger than 65 received initial treatment with Revlimid, Velcade, and dexamethasone (RVD). Patients then received a stem cell transplant using their own stem cells; consolidation treatment with RVD to get the best response possible out of the transplant; and, finally, maintenance treatment with Revlimid to prevent relapse (abstract).
The percent of patients achieving a complete response or near complete response increased with each step of the overall treatment regimen leading up to the maintenance therapy. Following consolidation therapy, the overall response rate was 94 percent.
Side effects were common. Almost all patients experienced low blood cell counts, and two thirds of patients experienced peripheral neuropathy. However, Dr. Roussel claimed that the side effects were manageable.
Treatment with Revlimid can make it difficult for a patient to collect enough stem cells for transplantation. However, all except for one patient in this trial were able to collect enough stem cells after the initial treatment with RVD.
In response to the efficacy of this regimen, RVD is being used in a clinical trial comparing the use of transplantation versus novel agents as upfront treatment of myeloma.
Monday night’s evening session focused on drugs under development as potential multiple myeloma treatments.
There were three presentations during the session about Phase 1 and 2 studies of pomalidomide. The studies compared different doses and dosing schedules for the drug in heavily pre-treated relapsed and refractory myeloma patients. All three presentations are covered in depth in a Beacon news article from yesterday, so only brief descriptions are provided here.
In the first pomalidomide study (abstract), the efficacy and side effects of 4 mg pomalidomide on days 1 through 21 of a 28 day cycle were compared to the same dose on all 28 days of the cycle. Efficacy was similar with both schedules, so further trials are likely to use the shorter dosing schedule.
The second presentation (abstract) compared 2 mg versus 4 mg pomalidomide in combination with dexamethasone. The lower dose appeared to be as – or maybe even more – effective than the higher dose, and fewer patients experienced side effects when taking the lower dose.
The third pomalidomide presentation (abstract) compared four different pomalidomide doses (2, 3, 4, and 5 mg) and found that 4 mg was the maximum tolerated dose. In the second phase of the trial, which is ongoing, half of the patients are being treated with 4 mg pomalidomide alone and the other half are receiving dexamethasone in addition. Results comparing the two regimens are not yet available.
Also during the evening session, Dr. Ruben Niesvizky from the Weill Cornell Medical School in New York gave a talk about a new drug under development called PD 0332991, or just PD for short (abstract). PD is an oral drug that works differently than any of the currently approved myeloma treatments; it inhibits cyclin-dependent kinases 4 and 6.
In this Phase 1 study involving relapsed and refractory patients, PD was tested at different doses in combination with Velcade and dexamethasone. In addition, half of the patients received PD daily for 21 out of 28 days, and the other half received PD daily for 12 out of 28 days.
Side effects were mostly low blood cell counts, which are known side effects of both PD and Velcade. Two of the 21 enrolled patients achieved a very good partial response.
A Phase 2 trial is underway using the maximum tolerated dose from this study: 100 mg PD on days 1 through 12, 1.0 mg/m2 Velcade, and 20 mg dexamethasone.
PD was studied in this combination regimen because tests in mice showed that the regimen is more effective than PD alone. A physician in the audience, however, said that the path to approval for PD could be very difficult if the drug cannot demonstrate single-agent activity against myeloma.
Later in the evening session, Dr. Andrzej Jakubowiak of the University of Michigan presented results from a study of carfilzomib in combination with Revlimid and low-dose dexamethasone in newly diagnosed myeloma patients (abstract).
Previous research has demonstrated that the combination of Revlimid, Velcade, and dexamethasone is highly effective as a myeloma treatment. Dr. Jakubowiak’s group decided to study a combined Revlimid, carfilzomib, and low-dose dexamethasone (CRd) regimen to see if it reduces the incidence of peripheral neuropathy that is common with Velcade-based regimens.
Patients in the trial first received an initial four 28-day cycles of treatment with carfilzomib, Revlimid, and low-dose dexamethasone. Patients who achieved at least a partial response to this initial treatment then underwent a stem cell transplant using their own stem cells, followed by four 28-day cycles of consolidation therapy with CRd, and finally maintenance therapy with monthly CRd.
After eight cycles of treatment according to the trial protocol, all of the approximately 24 patients in the trial achieved at least a partial response, with 67 percent achieving a complete response or near complete response, 16 percent very good partial response, and 17 percent partial response.
No patients have experienced disease progression thus far, and all were alive after six months in the trial.
A carfilzomib dose as high as 36 mg/m2 was well tolerated. Side effects were mostly mild with relatively infrequent low white blood cell counts and peripheral neuropathy in about 10 percent of patients. No patients had severe neuropathy, and dose modifications were infrequent.
The CRd regimen did not have a negative impact on stem cell collection, as all patients were able to collect enough cells.
Dr. Jakubowiak concluded that CRd was highly active and gave rapid and deep responses. This study received a lot of praise from the physicians in the audience: “These are unprecedented complete response rates, and this is very promising"; "Wonderful data"; “Very encouraging indeed.”
A Phase 3 trial is comparing CRd with Rd in relapsed myeloma patients, and other carfilzomib combinations are being tested as well.
Earlier this week, The Myeloma Beacon published “as it happens” updates from the third full day of ASH in this thread in the Beacon’s myeloma forums. Similar “as it happens” updates have been posted for Day Four. A final ASH Daily Update covering Day Four of the meeting will be published tomorrow.
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