Report from the 49th Annual Meeting of the American Society of Hematology (ASH)
by Greetje Goossens
The 49th Annual American Society of Hematology (ASH) Meeting was held in Atlanta, Georgia from 8-11 December 2007. This meeting provided hematologists from around the world a forum for discussing current and critical issues in hematology. The latest research and treatments for blood disorders, including multiple myeloma, were presented at this meeting.
Being a multiple myeloma patient myself, I had the opportunity to attend this huge conference and was able to observe the activity, the commitment and the motivation of those specialists. Thanks to their persistent work, the treatment options for multiple myeloma patients are expanding in a spectacular way.
The introduction of novel agents such as lenalidomide (Revlimid) and bortezomib (Velcade) and the use of thalidomide, either alone or in combination, have largely extended the treatment possibilities of the disease.
Some highlights from the meeting are provided below:
1. Primary treatment for newly diagnosed patients.
1.1. Transplant candidates:
Lenalidomide (Revlimid) based regimens
- Lenalidomide (Revlimid) and dexamethasone:
There were reports from 2 large phase III trials, the SWOG-study (Southwest Oncology Group)and the ECOG-study (Eastern Cooperative Oncology Group)1 about the use of lenalidomide and dexamethasone in the front-line setting (so for newly diagnosed patients). Those 2 trials build on the already existing information from a phase II trial using lenalidomide plus dexamethasone for newly diagnosed patients.
The results of the SWOG and ECOG-studies continue to show a high level of activity of the Revlimid/Dexamethasone combination with high response rates as well as high (> 90%) one-year survival rates. This oral regimen is able to achieve disease control in many patients with as an important finding that lower doses of dexamethasone are more efficient and much more tolerated than the administration of high doses. The "Len + low dose dex" combination is a promising induction treatment for the patient who is a candidate for stem cell collection.
- Lenalidomide (Revlimid), bortezomib (Velcade) and dexamethasone (VRD)
The aims of this phase I/II study, presented by Dr. Richardson were to determine the maximum tolerated doses of Revlimid, Velcade and Dexamethasone in newly diagnosed patients and to assess safety and efficacy of the treatment. In the study , the doses of lenalidomide and bortezomib were successfully escalated2, the dose of dexamethasone was set at 20 mg, on the day of bortezomib and on the day after. Noteworthy is the absence of significant peripheral neuropathy and a very low rate of deep vein thrombosis.
The preliminary results on response rates of this combination are very exciting, making it very likely that this regimen will move forward in the upfront treatment setting.
The team of Dr. Wang performed a study with the 3-drug combination: bortezomib/lenalidomide/dexamethasone (BLD) and it was found that this combination gave a rapid control of previously untreated multiple myeloma (after 1 or 2 cycles). This treatment induced high remission rates (in 87% of patients). Toxicity was infrequent due to the short exposure to the drugs. This combination allows an early access to intensive therapy supported by autologous stem cells. Important is that the reduced exposure to the drugs in this trial may help to preserve disease sensitivity to later treatments upon relapse.
- Cyclophosphamide, lenalidomide (Revlimid) and dexamethasone (CRd)
The combination of lenalidomide and dexamethasone has shown to be a highly effective treatment for multiple myeloma. This phase II trial adds cyclophosphamide to the combination lenalidomide and low-dose dexamethasone as an initial therapy of newly diagnosed MM.
The CRd combination has excellent activity in this setting with an estimated overall response rate of 79%. The use of cyclophosphamide is interesting because as an alkylating agent it is less stem cell damaging when compared to melphalan. So it is more suitable as a primary treatment component for patients who are potential stem cell transplantation candidates.
Bortezomib (Velcade) based regimens
- Bortezomib (Velcade)/Dexamethasone versus VAD (Vincristine, Adriamycin, Dexamethasone)
Dr. Harousseau presented results on the ongoing IFM3 phase III - study comparing the combination Velcade/Dexamethasone versus the classic VAD as induction therapy. The combination Velcade/Dexamethasone shows superior response rates as well as superior CR (complete remission) rates. The improved response rates before autologous transplantation translate into a significant higher CR rate after autologous transplantation, which is expected to correlate with a prolonged survival benefit.
This well tolerated regimen could become a standard induction regimen for transplant candidates.
- Bortezomib (Velcade)/thalidomide/dexamethasone (VTD) versus thalidomide/dexamethasone (TD)
In this study conducted by the Italian Myeloma Network (GIMEMA) collaborative group, this Velcade based induction regimen achieved a fourfold increase in the CR rate. Complete remission is widely recognized as a predictor for long-term survival according to Professor Cavo, principal investigator of the trial. These exciting findings demonstrate that adding Velcade to the standard induction therapy prior to stem cell transplantation improves the pre-and post stem cell transplantation results dramatically.
- Bortezomib (Velcade)/lenalidomide (Revlimid)/dexamethasone (see lenalidomide based regimens)
In the upfront setting, there are several other studies ongoing with combination therapy and the preliminary results are encouraging.
It is clear that some of the old dictums of myeloma therapy have definitely changed. In the context of the novel agents, the improved induction responses and the quality of the response are important steps to put the patient in an optimal situation where stem cell transplant can be considered either as an upfront modality or where it can be considered further down the treatment line. According to Professor Harousseau the interest in tandem autologous transplantation is decreasing because the same results can be obtained now by a single autologous transplantation, followed by maintenance or consolidation with novel agents.
As to allogeneic transplantation, Professor Harousseau expressed his concern about the toxicity of the procedure, even with reduced-intensity conditioning (RIC) regimens. Since very good results are now obtained either with autologous transplantation or even without autologous transplantation using a novel agent, allogeneic transplantation should not be the treatment of choice in first-line, even for patients who have a HLA-identical stem cell donor. For the moment a mini-allogeneic transplantation (following an autologous transplantation) should only be offered in the context of a clinical trial or for the treatment of relapsed patients.
1.2. Non-transplant candidates
There are a now large number of possibilities for patients who are not candidates for transplantation.
At the ASH conference, several trials with combination therapy were presented in this setting. Often these combinations are MP (Melphalan, Prednisone) based but with the addition of novel agents. MP was, up to recently, the standard of care for elderly patients.
In this report some of these trials are presented, showing the superiority of the combination therapy with the inclusion of (a) novel agent(s) when compared to the standard MP-regimen.
- VISTA-study: Bortezomib (Velcade), Melphalan, Prednisone (VMP) versus Melphalan, Prednisone (MP)
A very striking study is the VISTA-trial, presented by Dr. San Miguel. This trial is one of the largest, international, randomised clinical trials for patients in this setting.
The VISTA-trial compares VMP versus MP, showing clearly the superiority of the VMP regimen in terms of response rates , progression-free survival and overall survival. These results led to the early closure of the trial and are likely to be published soon. The benefits of the treatment are the same in higher risk groups e.g. patients with poor risk cytogenetics, patients older than 75 years or patients with renal insufficiency.
VMP is a highly effective treatment for patients who are not eligible for transplantation.
- Combination Melphalan, Prednisone and thalidomide (MPT)
Another successful MP-based regimen is MP plus thalidomide. Final data from an IFM-study showed that adding thalidomide to standard myeloma treatment prolongs survival in older myeloma patients. Myeloma patients over the age of 75 who received thalidomide in addition to MP reported significantly better survival benefit (17.6 months) over patients who received MP alone. Median progression free survival was also five months longer on the MPT arm. This study is the third randomised trial showing the superiority of the MPT regimen over MP. MPT is today the standard primary treatment for patients who are no candidate for autologous transplantation.
- Combination Melphalan, Prednisone and lenalidomide (Revlimid) (MPR)
Dr. Palumbo looked at the MPR-regimen and high response rates were obtained with this therapy. The results seem to be even better than the MPT experience with the additional advantage that there was less neuropathy associated with the MPR combination.
2. Treatment in relapsed and refractory multiple myeloma
The management of the relapsed or the refractory patient remains a considerable challenge but great progress has been made with the introduction of the new drugs. Combination therapy with novel agents as well as with steroids (e.g. dexamethasone) and conventional chemotherapy continue to improve the patients’ outcome.
Lenalidomide (Revlimid) based regimens
- Lenalidomide (Revlimid)/dexamethasone
The update from the MM-009 and MM-010 phase III trials were presented, comparing lenalidomide plus dexamethasone versus placebo plus dexamethasone. The combination lenalidomide with dexamethasone induced significantly higher overall response rates and complete remission rates as well as longer time-to-progression in comparison with dexamethasone alone.
The combination lenalidomide plus low dose dexamethasone showed improved efficacy and was better tolerated than the high dose dexamethasone regimen. Moreover, the synergy of those two drugs overcomes poor prognosis conferred by chromosome abnormalities such as translocations e.g. t(4;14), deletions such as del 13q (although this is not the case for del 17p), high beta 2mcg in relapsed or refractory multiple myeloma.
Bortezomib (Velcade) based regimens
- Bortezomib (Velcade) plus Pegylated Liposomal Doxorubicin (Doxil).
Dr. Bladé presented the results of a multi-center international phase III study, comparing Velcade plus Doxil versus Velcade alone. The conclusion was that the combination Velcade plus Doxil significantly prolonged time-to-progression, compared to Velcade alone, regardless of the extend of prior therapies or anthracycline (a class of chemotherapeutic agents) exposure.
- Bortezomib plus Dexamethasone
The initial report of the CREST-study demonstrated the substantial activity of Velcade at 2 different doses +/- dexamethasone in patients with relapsed or refractory multiple myeloma.
At the ASH conference, an updated analysis of overal survival after prolonged follow-up of this study was presented. The results showed that the combination of Velcade with dexamethasone is associated with higher response rates when compared to Velcade alone. It was noticed that the highest dose of Velcade gave better results.
- Bortezomib plus Melphalan and Dexamethasone
This combination was used in a phase I/II trial and the results tell us that it is another highly effective regimen with an acceptable safety profile.
We can conclude that the efficacy of bortezomib in relapsed multiple myeloma is confirmed with long term data.
Worth saying is that additional data of some studies, which are not mentioned in this report, show positive effects of bortezomib on renal function and bone metabolism.
Regimen with lenalidomide (Revlimid) and bortezomib (Velcade)
- Bortezomib (Velcade)/lenalidomide (Revlimid)/Dexamethasone (VRD)
Preliminary data from a multi-centre Phase II study in relapsed patients showed high response rates for patients who had VRD in combination. Moreover the VRD combination also offers a favourable side effect profile.
Important to mention is that here also the novel agents seem to have the capacity to overcome the impact of unfavourable cytogenetics (chromosomal abnormalities such as translocations e.g. t(4;14) or deletions e.g. del 13q).
New treatments in the pipeline
Several exciting presentations of new treatments and combinations in myeloma were given at the ASH-meeting and without going in detail, some of the new drugs are mentioned below.
Phase I/II clinical data on the second-generation proteasome inhibitor carfilzomib were presented and the results are intriguing. The toxicity profile of this new drug appears to be very manageable. Interesting is that carfilzomib shows good activity not only in patients who have been previously treated with bortezomib (first generation proteasome inhibitor), but also in patients who even may have been resistant to bortezomib.
The heat shock protein 90 (HSP90) inhibitor tanespimycin in combination with bortezomib (Velcade) shows durable anti-myeloma activity in patients with relapsed and progressive myeloma.
There were also reports on other new agents and this shows that there is a real revolution ongoing in the treatment options for multiple myeloma.
As a patient, being able to witness this exciting period that shows the pace of change in myeloma treatment and research is very encouraging.
The introduction of new treatments help myeloma patients survive longer and it improves their quality of life considerably. More tools are available to combat the disease and we are definitely heading towards a new treatment era in which patients have every reason to be hopeful.
It is truly an exciting time in the field of myeloma!
See also the webcasts of the MMRF and the IMF:
www.cancereducation.com/cancersyspagesnb/a/mmrf/mm0704/index.cfm
myeloma.org/main.jsp
1 The ECOG-study compared lenalidomide plus high dose dexamethasone versus lenalidomide plus low dose dexamethasone (Rajkumar et al).
The SWOG-study compared lenalidomide plus high dose dexamethasone versus high dose dexamethasone alone (Zonder et al).
2 The dose of lenalidomide was escalated to 25mg/week, 2weeks on and 1 week off and the dose of bortezomib was standard (1,3 mg/m2 on day 1,4,8,11)
3 FM : Intergroup Francophone du Myélome