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.