The ASH 2013 abstracts were released on November 7th. As usual, there are a staggering number of myeloma abstracts: this year, 830. The IMF team has been reviewing them studiously, trying to identify what is new, interesting, and important. We have identified 131 abstracts worthy of specific comment: 38 oral presentations and 93 posters.
The first key point is that a myeloma abstract is one of the top "plenary session" abstracts for ASH overall this year. Abstract #2 (I believe this may be its priority ranking for 2013 ASH) will be presented by Dr. Thierry Facon of the Intergroupe Francophone du Myelome (IFM) and details the results of a Phase III trial involving 1,623 patients over age 65 years (a huge study) which compares lenalidomide (RevlimidÂ® [R]) low-dose dexamethasone (d), given until disease progression (ARM A) with Rd give for 18 cycles (ARM B) with the combination of melphalan, prednisone, andthalidomide (MPT) for 12 cycles (ARM C).
This study thus compares two drugs (Rd) - with and without maintenance - with three drugs (MPT). According to the abstract, there is a 28% reduction in the risk of progression with the Rd (ARM A) versus MPT (ARM C), which is statistically significant. There was also a trend toward survival benefit: 22% reduction in the risk of death. A topic of keen interest is also the rate of second primary cancers (SPMs). The question has been whether SPMs are more linked to Revlimid use versus melphalan, as for example, in the MPT regimen. The hematologic SPMs were 0.4% with Rd in ARM A versus 2.2% in ARM C, which certainly trends toward more SPMs with melphalan exposure versus Revlimid. The solid tumor SPMs were 2.8% in both arms, which is now considered to be an expected rate for myeloma patients. I am sure we will hear more at the ASH presentation. Of added importance, it is widely speculated that these results can lead to the approval of the Rd doublet as frontline therapy both in Europe and in the US. This approval is particularly important outside the U.S., where drugs can only be prescribed strictly within the labeled indication.
Of the 131 interesting and important abstracts we have identified this year, 43 involve the approved novel agents thalidomide, lenalidomide (Revlimid), bortezomib (Velcade), pomalidomide (Pomalyst) and carfilzomib (Kyprolis). For thalidomide, aspects presented will include thalidomide consolidation (#537), which improved both progression free (PFS) and overall survival (OS), and thalidomide combined with dose escalation of carfilzomib (#688), which proved to be a rapidly effective regimen for newly diagnosed myeloma. For lenalidomide, there are multiple aspects presented and discussed in numerous abstracts.
An overarching topic, already touched upon with abstract #2, was the benefit of lenalidomide for maintenance and/or as ongoing continuous therapy. Data include the follow-up of the IFM lenalidomide maintenance trial post autologous stem cell transplant (#406), which again showed PFS but not OS benefit, and a meta analysis of lenalidomide maintenance (#407), which assesses PFS, OS, and SPM rates overall. An additional concept explored in the maintenance phase of the MM-015 update (#405) from the Torino team is the value of lenalidomide maintenance considering "PFS 2," which refers to the length of the second response in patients relapsing, with or without prior lenalidomide maintenance. The PFS 2 was markedly improved in the melphalan prednisone Revlimid arm (MPR-R) with Revlimid maintenance versus the melphalan prednisone alone (MP) arm. This added piece of information is now being considered as part of the drug approval process, especially by the European Medicines Agency (EMA).
For bortezomib (Velcade), there are several important observations. First, in abstract #1968, the cumulative dose of administered Velcade in the VMP (Velcade, melphalan, and prednisone) arm of the Phase III VISTA trial is directly linked to improved overall survival outcomes. This is a key educational point in the use of Velcade, which has become much better tolerated with the subcutaneous (SQ) route of administration. Another important abstract (#3187) evaluated cardiac issues (such as heart failure) in myeloma patients in a retrospective analysis of bortezomib (Velcade) trials. Use of Velcade was associated with a low rate of severe (grade â¥ 3) heart failure in both newly diagnosed (2%) and refractory (1.9%) patients. This rate is not statistically different from the expected background rate.
Other interesting abstracts include numbers 1940 and 1969, which report upon the combination of Velcade with pomalidomide and dexamethasone in relapsed myeloma. This is clearly a very active and well-tolerated regimen. Follow-up data are reported on other Velcade combinations, including Velcade/Cytoxan/dexamethasone [CyBord] versus Velcade/Revlimid/dexamethasone [VRd] (#3178), CyBord long-term follow-up (#3192), VTD long-term follow-up (#3221) and Velcade combinations in the elderly with or without autologous stem cell transplant (#3344). Key points here include the impressive efficacy of CyBord (versus VRD: #3178) with a substantially lesser cost and the sustained longer-term benefit of the CyBord regimen (#3192).
Pomalidomide is covered in several abstracts, basically confirming the efficacy in the relapsed/refractory setting (#408, 686, 689, 690, 1979, 3185, 3191, and 3198). Points of note include efficacy with high-risk features, such as 17p- on FISH testing (#689) abnormal cytogenetics (#408) or high-risk GEP (#3191). The combination of pomalidomide with carfilzomib also continues to show considerable promise (#690). Of interest, the combination of Biaxin (clarithromycin) with pomalidomide plus dexamethasone is also remarkably effective (#1955).
Carfilzomib (Kyprolis) was a part of many trials reported this year at ASH. Combinations showing great promise are carfilzomib/Revlimid/dexamethasone (CRd; numbers, 538, 1939, and 3220), Carfilzomib/Cytoxan/dexamethasone (CCd: #585), carfilzomib/MP (CMP: #1933), and carfilzomib along with Biaxin plus Revlimid/dexamethasone (#3216). Response rates are high and deep: prolonged benefit is being achieved. It will be very helpful to learn the full details of these exciting combinations at ASH.
Next week: In part two of this ASH preview, I will cover new drug updates as well as a diversity of other topics, including many details about testing for minimal residual disease (MRD) and new molecular/genetic research findings. So stay tuned!
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