June 4, 2011
The MMRF team is on-site at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago and is pleased to share with you highlights from key sessions over the next 3 days. Today, the first data related to multiple myeloma was presented in a series of poster presentations focusing on new data for carfilzomib, a next-generation proteasome inhibitor that is being developed through a partnership with the Multiple Myeloma Research Consortium (MMRC); stem cell transplantation; and advances in personalized medicine.
Posters describing four studies of carfilzomib were presented today. In a phase II study, interim data were presented for 51 of 52 patients with relapsed and/or refractory MM treated with carfilzomib, Revlimid, and dexamethasone; 78% of patients responded and 48% achieved a very good partial response or better. The most common serious side effect was neutropenia, seen in 23% of patients. Peripheral neuropathy (PN) was not reported for this study; however, a poster by David Siegel describing long-term follow-up of an earlier study of a similar patient population treated with carfilzomib alone demonstrated a very low incidence of new or worsening PN. Notably, only 3 of 266 patients experienced severe PN, and no patient discontinued due to PN. Responses were promising and durable in the study, consistent with other studies of carfilzomib, regardless of patient risk factors. Several additional studies showed similar, promising results. A phase III study of Revlimid and dexamethasone ± carfilzomib is underway and will be described during ASCO’s Trials in Progress poster session on Monday.
A poster presented by Mario Boccadoro from Italy described a phase III study of melphalan/prednisone/Revlimid (lenalidomide) (MPR) versus high-dose melphalan and autologous transplantation (MEL200) in patients with newly diagnosed multiple myeloma, all of whom initially received induction therapy with Revlimid and dexamethasone. Progression-free survival was significantly higher for the patients receiving MEL200; however, these patients also experienced significantly more serious side effects including neutropenia, thrombocytopenia, infections, and gastrointestinal events.
An interesting poster by Erica Campagnero and colleagues described an analysis of survival outcomes for elderly MM patients treated in 4 phase III trials conducted by the Eastern Cooperative Oncology Group (ECOG), representing 30 years of myeloma treatment, in order to examine survival outcomes for elderly MM patients. Similar analyses in the past have suggested that the survival improvements seen in MM have largely been limited to patients younger than 65 years; this analysis did see improved survival for patients over age 65, but the gains lagged behind younger patients. The authors emphasized the importance of understanding specific contributions to this difference.
Finally, a poster by Rafael Fonseca described a novel, automated tool for gene expression profiling, which allows for simultaneous analysis of multiple risk stratifications measures—an example of the ongoing research towards personalizing treatment for patients, based on biological factors that contribute to disease prognosis.
The MMRF symposium for physicians will be held later this evening, where a packed room of myeloma clinicians from around the world will hear from Chair Ken Anderson, as well as Herve Avet-L’oiseau, Sergio Giralt, Sundar Jagannath, David Roodman, and Jesus San Miguel.
Stay tuned for continued updates over the next couple of days as more data are presented!
May 8, 2011
The XIIIth International Myeloma Workshop that was held this past week in Paris, France featured nearly four full days of presentations and discussions on the latest multiple myeloma research. The organizers created an incredibly comprehensive and thought-provoking program featuring the world’s leaders in the field. The MMRF was on-site all week to listen to the latest data and hypotheses, bring you highlights, and meet with current and potential collaborators. For those of who you interested in more substantial coverage, we encourage to watch archived webcasts and read our blog.
For those interested in a few key takeaways, following is our attempt to synthesize so much information into the points we found to be most relevant to patients:
- New data shed further light on the benefits of Revlimid when used as maintenance therapy following high-dose chemotherapy and stem cell transplant. One large randomized trial, performed in the US, showed a survival benefit for those patients who had received Revlimid (vs. those who had received a placebo). Other large trials have not (yet) shown a survival benefit, though they have shown a delay in disease progression for Revlimid. While there does continue to be a slightly increased incidence of secondary cancers seen when Revlimid is used after melphalan, more data are needed, and for most patients, the consensus among many of the researchers is that the benefits likely outweigh the risks.
- Next-generation proteasome inhibitors (like Velcade) and IMiDs (like Revlimid and Thalomid) continue to show promise in clinical trials. Carfilzomib, a second-generation proteasome inhibitor that has been studied in MMRC-facilitated clinical trials, appears to work in Velcade-refractory patients and lacks the associations with peripheral neuropathy. Similarly, pomalidomide, an IMiD, has been shown to work in patients who are refractory to Velcade and Revlimid, and the MMRC has been proud to help to accelerate the early phase trials. Both drugs are in Phase 3 clinical trials, though they also stand a chance at an accelerated approval based on their ability to work in such a difficult to treat patient population.
- New classes of drugs continue to emerge, from histone deactylase inhibitors like Zolinza and panobinostat to antibodies like elotuzumab, that appear to significantly enhance the effectiveness of currently available treatments like Velcade and Revlimid and, for some patients, overcome resistance to those drugs.
- It is increasingly clear that multiple myeloma is not a single disease, but many diseases. There are numerous genomic mutations and alterations, which will mean that in the future, there will be a number of subsets of patients, each of which is treated according to the features of their disease. Understanding this segmentation has been and continues to be a priority for the MMRF in terms of research investment, beginning with the Genomics Initiative, which resulted in the complete sequencing of the myeloma genome, and continuing into the future.
- The international myeloma research community remains steadfastly and intensely committed to improving outcomes for patients extending their lives and eventually finding a cure. The MMRF is proud and grateful to partner closely with such collaborative and dedicated researchers and clinicians, as well as pharmaceutical and biotech companies.
Stay tuned for further updates next month from the American Society of Clinical Oncology (ASCO) Annual Meeting!
The Multiple Myeloma Research Foundation
May 7, 2011
The final day of this international meeting began with a comprehensive review of the latest International Myeloma Working Group consensus on criteria for diagnosis and treatment and retreatment of patients with multiple myeloma. In addition to discussing the importance of utilizing correct diagnostics, there were key discussions concerning the management of anemia, bone disease, vein thrombosis and the use of vaccination and infection prophylaxis.
Several abstracts of note were presented during the final plenary session, including:
- An Italian clinical trial that one compared the use of aspirin to low molecular weight heparin (enoxaparin) to prevent deep vein thrombosis in myeloma patients receiving Revlimid-based treatments, and found that both were similar in effectiveness.
- A Phase 3 trial from researchers in Sweden looked at the use of Velcade for consolidation after high dose melphalan and found that it appeared to prolong disease remission post stem cell transplant.
- Updated data from the MMRC-facilitated Phase 1 and 2 pomalidomide trial were presented by Dr. Paul Richardson; the data continue to show the promise of pomalidomide in working in some patients who are refractory to both Velcade and Revlimid.
- Updated data from the MMRC-facilitated Phase 2 carfilzomib trial, looking at heavily pre-treated patients, were presented by Dr. David Siegel. These encouraging results, showing efficacy in patients who had failed Velcade, could form the basis for an accelerated approval from the FDA in 2012.
- The final talk given by Dr. E. Libby on the declining rates of mortality in both the young and elderly. For the young, we saw an earlier decrease in mortality (starting in 1995) with the introduction of high dose chemotherapy followed by bone marrow transplant. However, this was not a treatment prescribed for those over the age of 65 because of the higher risk this posed for the population. The real shift for young and old started with the introduction of Thalomid. Once other new compounds like Velcade and Revlimid came to market, the decrease in mortality has been essentially equalized with lives being substantially prolonged regardless of one’s age.
On this last day, it was wonderful to see our very own Sara Tyghter address the Congress on behalf of the MMRF and MMRC. She graciously thanked the meeting organizers, physicians, nurses and most importantly the patients who make research possible by participating in clinical trials of high importance. Following this, there was a presentation by Dr. Kaz Shimizu who was setting the stage for the IMW Meeting in 2013 which will be held in Kyoto, Japan. In two years, so much can happen and so the excitement is already building for this meeting two years from now!
May 6, 2011
Day 3 of IMW began with an overview of treatments for newly diagnosed patients aged 65 and older. Several trials were presented, each with a slightly different approach to providing patients in this population with the best treatment while limiting toxicities. Overall, with the integration of newer agents like Velcade and Revlimid, we are now starting to see responses resembling those seen in younger patients who can tolerate tougher treatments - high dose chemo and transplants.
Additionally, several updates were provided regarding drug classes currently used to treat MM, specifically proteasome inhibitors and IMiDs. Data on carfilzomib, a second generation proteasome inhibitor which has been studied in four MMRC- facilitated clinical trials, continued to show very low incidence of PN (peripheral neuropathy) and responses in patients that have relapsed or are refractory to Velcade and/or Revlimid. Additionally, use of subcutaneous Velcade has been shown to reduce PN by approximately 50% while new oral formulations of proteosome inhibitors are currently in clinical trials which should provide a much easier route of administration when compared to intravenous delivery, including Millennium’s MLN9708. Pomalidomide, a more potent IMID, was also highlighted for its ability to overcome resistance to Velcade and Revlimid, as shown in trials facilitated by the MMRC and the Mayo Clinic.
Newer classes of drugs such as histone deacetylace inhibitors (HDAC) were highlighted for their ability to amplify Velcade’s activity and in some cases, overcome Velcade resistance. The MMRC participated in a key Phase 2 trial combining Zolinza, another HDAC inhibitor, and Velcade, as well as early trials of panobinostat, both of which are in Phase 3 clinical trials.
Monoclonal antibody therapy was also discussed. In particular, elotuzumab, which is entering a Phase 3 clinical trial in combination with Revlimid and dexamethasone, was also studied within the MMRC. This compound also helped amplify the effectiveness of Revlimid in the relapsed/refractory patient population. Other exciting monocolonal antibodies in earlier development include those targeting IL-6 and anti-CD38.
Perhaps the most highly anticipated session focused on the use of Revlimid maintenance. Encouragingly, for the first time, data from the US CALGB study showed an overall survival benefit. Grade 3 toxicities were reported for the Revlimid maintenance arm and were manageable. There continued to be an increase in the incidence of secondary malignancies in the Revlimid arm; however, given the survival benefit, the researchers presenting during this session agreed that, particularly for patients who did not achieve at least a very good partial response following high-dose chemotherapy and stem cell transplant, based on currently available data, the benefits do appear to outweigh the risks. It will be critical, however, to continue to follow these patients as well as those participating in other trials that combined Revlimid with melphalan to better understand the benefits and risks over time.
May 5, 2011
Day 2 kicked off a full day of sessions beginning with a discussion around the treatment of newly diagnosed patients who are not eligible for high-dose chemotherapy and stem cell transplant (SCT) with leading clinicians from around the world – US, France, Germany, Italy, Netherland, Spain and the UK sharing their individual perspectives. While treatment patterns differ by country, particularly because some treatments like Revlimid are not widely available outside the US for first-line treatment, encouragingly, when treatments like Revlimid and Velcade are used – regardless of the combination, we are virtually seeing everyone achieve a response though the depth and duration of response does vary between individuals.
So, the ongoing question remains whether, now that we have such highly effective combinations that include proteasome inhibitors and immunomodulatory agents (IMiDs) as backbone therapies, the high dose chemotherapy and SCT should remain as a standard treatment for younger patients (see tomorrow’s highlights for more discussion on this topic). And, as recently as the ASH meeting in December 2010, the impressive results in terms of delayed disease progression from the use of prolonged maintenance therapy post-SCT has given rise to more questions about whether we need to consider incorporating this into standard of care for patients. Possible answers may come out of a newly opened trial being led in the United States by one of MMRC’s member institutions – Dana-Farber Cancer Institute and in France, by the IFM. The IFM/DFCI randomized trial will enroll 1,000 patients in the US and France and will examine the role of high dose chemotherapy followed by SCT in the era of novel agents (is high dose chemo + transplant + novel agents needed, or not, to achieve a good level of response when compared to using novel agents alone?) and is maintenance therapy something we must seriously consider for use in future (is it effective or not at prolonging a patient’s initial response, regardless of the initial treatment and, for how long should it be administered?).
High risk myeloma was also covered in depth at this meeting with the MMRF’s Nature paper with sequencing results from the MMRF-funded Genomics Initiative once again garnering recognition for its contribution to our increased understanding of myeloma tumor cell biology. High risk presentations highlighted how complicated the MM biology really is – and not just at time of diagnosis as there can be multiple myeloma “clones” within one individual, and, as an individual’s disease progresses, new clones can emerge. New genomic discoveries have provided early direction in terms of druggable targets not previously explored in MM. Briefly, we can focus on drugs to address abnormalities of the BRAF cellular pathway and over-expression of a protein called MMSET which is clearly present in patients that have t(4;14) multiple myeloma. Although the myeloma tumor cell by nature is a ‘survivalist’, the only real way we can keep it at bay is by deepening our understanding of how it operates and have ready at hand all of the tools needed to overcome its peculiarities every step of the way.