April 6, 2013
This morning, Sagar Lonial, MD, summed up the purpose of the IMW in comments preceding his presentation on Pomalyst (pomalidomide) today: “…what we do here is all about improving outcomes for patients.” This sentiment has been palpable throughout the first couple of days as clinical and translational researchers from around the world have come together to discuss the most pressing research questions related to multiple myeloma.
Over the last few years, an emerging area of focus is the treatment of smoldering multiple myeloma patients. The largest study to date from Mateos et al in Spain has shown a survival benefit for patients treated with Revlimid and dexamethasone, but while promising, more data from additional trials are needed to understand the overall risk-benefit ratio of treating patients earlier, and, most importantly, and there was a certain amount of consensus here, how can we prospectively identify high-risk smoldering patients – those most likely to convert to active myeloma within two years – as opposed to lower risk patients who may not convert for up to 10 years.
There have also been updates on the newest therapies – Pomalyst and Kyprolis (carfilzomib). For Pomalyst, a sub-analysis of the pivotal Phase II (which was conducted in partnership with MMRC) showed that patients with deletion 17p (chromosomal abnormality), a group of patients who are not as likely to respond to standard therapies, can benefit from treatment with this drug. Further, Pomalyst provides end-organ function benefit. For Kyprolis, Andrzej Jakubowiak presented a sub-analysis from the MMRC Kyprolis-Rev-dex trial in newly diagnosed patients that showed that elderly patients were just as likely to obtain high response rates (85% NCR and CR) though they were also more likely to need dose reductions. There was also very preliminary work presented looking on the combination in high-risk SMM patients.
Finally, the question of maintenance therapy continues to be an important one, and as more data emerge, it is clear that there is a consistent decrease in risk of disease progression, though there is a slightly increased risk of secondary cancers (primarily MDS/AML). However, the risk of disease progression is much higher. Building on a theme mentioned in yesterday’s entry, we really need to identify which patients are likely to have the greatest benefit with the lowest risk. Data show that those patients in a complete response (CR) following high-dose chemo and stem cell transplant do not really benefit from maintenance (as opposed to those who do not initially reach CR). Once again, we are back to really needing to better match patients to treatments that are most likely to benefit them and are associated with the lowest risk of side effects – which is exactly what we are working to accomplish using CoMMpass data combined with data from similar initiatives. We are getting closer!
April 5, 2013
Mid-way through day two of the 14th International Myeloma Workshop (IMW) and already we have heard many thought-provoking presentations and several lively debates on key questions facing the myeloma community. Follow live MMRF posts from IMW on Twitter by searching for #IMW2013. The program at IMW is primarily centered around discussing – even debating – the best approaches for classifying and treating patients which is vastly different than the annual meetings of the American Society of Hematology (ASH) or American Society of Clinical Oncology(ASCO) where the primary focus is new data.
Oral presentations on the first day of the workshop focused primarily on biology, new imaging techniques and related malignancies. The day was capped off with the presentation of the prestigious Waldenstrom’s Award, the highest honor provided to a multiple myeloma expert which is given to one individual at every IMW, to Nikhil Munshi of the Dana-Farber Cancer Institute (DFCI). The MMRF has been privileged to collaborate with Dr. Munshi since our inception, and we are pleased that his commitment to the community and his research focus, primarily in immune therapy, has been appropriately recognized by his peers.
Day two kicked off oral presentations on clinical issues and particularly provocative were presentations around risk-adapted therapy – or as the presenters positioned the question – “should all MM patients be treated with a one-sized fits all approach?”. There were two key debates in this area:
1) for front-line therapy, should there be a one-sized fits all approach or should clinicians pursue a “risk-adapted” approach – debated by Pieter Sonneveld from the Netherlands (no) and Vincent Rajkumar from the Mayo Clinic (yes); and
2) should all eligible patients receive high-dose chemo and stem cell transplant upfront or can it be delayed for some patients – debated by Philippe Moreau from France (yes) and Paul Richardson from DFCI (no).
The key takeaway from both debates was that it is clear that some patients do appear to be “high-risk” and have a worse outcome from initial treatment, but there is a lack of widespread consensus on how to prospectively identify these patients. As one presenter pointed out, there is little overlap between the various risk “signatures” from a number of different groups both in the US and Europe, so, according to one group, a patient could be high-risk and according to another, that same patient could be low-risk. A growing number of experts, led by Antonio Palumbo of Italy, are calling for an end to classifying patients by low-, medium-, and high-risk but instead to classify patients based on specific features.
Another key point was that the vast majority of patients would benefit from a triplet, eg, Revlimid-Velcade-dex or Cytoxan-Velcade-dex, but there are no large randomized trials completed to determine superiority of a specific regimen. Further, most groups do recommend early transplantation for all eligible patients but we do not yet know whether there are specific patients who could safely delay the procedure and still experience the same benefit.
It is clear that currently available classification systems are not sufficient to match patients to treatments most likely to benefit them – with as few side effects as possible – and that multiple myeloma is truly many diseases “collectively called multiple myeloma” (Rajkumar). This is precisely why the MMRF launched the CoMMpassSM study to characterize the disease using the most cutting-edge, robust technologies available to identify the different patient subtypes which will allow the field to better predict prognosis based on a patient’s molecular profile, and, most importantly, identify from diagnosis the best treatments for any given patient based on his/her subtype.
We – the myeloma community – do not yet have the answers but by amassing high-quality data from 1,000 patients in the MMRF CoMMpass study and other similar efforts, by the next IMW, in Rome in 2015, we should have much more predictive models and treatment algorithms which will lead to better outcomes for patients.
It is not too late to sign up for our telephone/web education program Highlights From 14th Annual International Myeloma Workshop being held later today, April 5, 2013 at 5:00-6:00 PM ET / 2:00-3:00 PM PT by visiting: http://www.cancereducation.com/cancersyspagesnb/a/mmrf/mm1303/Register.html
December 11, 2012
Welcome to our fourth and final day of coverage of the 2012 American Society of Hematology (ASH) Annual meeting. Today during the oral session, treatment for patients with relapsed/refractory disease and papers on infection and kidney impairment, common in multiple myeloma, were presented.
Pomalidomide Extends Overall Survival
The phase 3 trial of pomalidomide plus dexamethasone vs dexamethasone that was predominantly conducted in Europe was accepted by ASH as a late-breaking abstract. This means that data were not available when original abstracts were due but the data were so compelling that the abstract was accepted after the deadline. Dr. Meletios Dimopoulos from the University of Athens, Greece presented data from this study that showed pomalidomide plus low-dose dexamethasone significantly increased progression-free survival (PFS) and overall survival (OS) compared with high-dose dexamethasone in patients who were refractory to Revlimid and Velcade! Median PFS was nearly four months for the pomalidomide arm versus about two months for the dex arm. Median overall survival for the pomalidomide arm had not yet been reached. We hope to hear positive news from the FDA on the potential accelerated approval of this promising new treatment in the coming weeks.
Treanda (bendamustine) is a chemotherapy treatment that is widely used outside the US to treat multiple myeloma. In the US, Treanda is FDA approved to treat a type of lymphoma. Several studies were presented at this meeting, including an MMRC trial of Treanda plus Revlimid and dexamethasone, showing promising activity when combined with Velcade and/or Revlimid. In an oral presentation today, Dr. Heinz Ludwig of the University of Vienna, Austria presented results from a trial of Treanda combined with Velcade and dexamethasone in patients with relapsed/refractory multiple myeloma. There were 66 evaluable patients, most of who had received 1 or 2 prior therapies; 43 of these patients had responses (response rate of 65.2%) including 14 patients with a complete response; all patients had a clinical benefit to this treatment. Median progression-free survival was 9.7 months when all patients were considered, but was 12.9 months in patients with 1-2 prior treatments. Median overall survival in the entire cohort was 21 months. Prior treatment with Revlimid had a negative effect on response rate to this treatment. Toxicities to this regimen included a low incidence of infections and gastrointestinal events, with a few cases of peripheral neuropathy.
Dr. Dimopoulos also provided an update on second line treatment of patients who relapsed in the phase III trial, MM-015 that compared melphalan plus prednisone and Revlimid followed by Revlimid maintenance (arm 1) with melphalan and prednisone (arm 2), or with melphalan, prednisone, and Revlimid (arm 3). After frontline treatment, fewer patients from arm 1 (54%) progressed compared with patients in arms 2 (77%) and 3 (83%), confirming the benefit of maintenance therapy. After progression, patients could opt to receive open-label Revlimid plus dexamethasone or another treatment. Revlimid-based second-line treatments were active in these patients, regardless of which treatment they received as the first-line therapy. Importantly, this study showed that maintenance treatment with Revlimid does not appear to result in disease that is resistant to this agent at relapse.
About half of myeloma patients have some impairment of the kidneys, and an estimated 20% have “myeloma kidney” or severe renal failure at diagnosis. This condition can cause patients to have more toxicity from treatment. However, several novel agents have been incorporated into new treatments for myeloma and have improved the survival of this disease.
Dr. Meletios Dimopoulos presented a study of impact of these novel therapies like Velcade and Revlimid on the survival of myeloma patients with impaired kidneys. In total, 1773 patients with symptomatic myeloma who were treated in the Greek Myeloma Study Group were included. Patients were divided into 5-year groups between 1990 and 2004 according to the date of their initial treatment, then from 2005 onward. The response and median survival to frontline therapy for all myeloma patients improved in the years after 2000 compared with the prior years as a result of the availability of these newer treatments. When looking only at patients with impaired kidney function, the study showed that survival of these patients also improved after the introduction of novel therapies, especially for patients with severe kidney impairment.
Myeloma Preclinical Studies
Several studies presented today, too numerous to detail here, covered potential risk assessment strategies and tumor biology studies, which will help us identify better drugs in the future, and also help us to achieve our aim of personalized medicine! This is certainly an exciting time in myeloma research.
For additional information on what was covered at this year's ASH meeting, please view our interview with Gareth Morgan, MD, PhD, and Antonio Palumbo, MD.
It is also not too late to sign up for our patient telephone/web education program Highlights From the 2012 American Society of Hematology (ASH) Annual Meeting for Patients and Caregivers on Tuesday, December 18, 2012 at 1:00-2:00 PM ET/10:00-11:00 AM PT by visiting www.cancereducation.com/cancersyspagesnb/a/mmrf/mm1209/Register.html
December 10, 2012
Welcome to our third day of onsite coverage from the 2012 American Society of Hematology (ASH) Annual meeting. Oral sessions today covered new therapies for patients with newly diagnosed multiple myeloma, as well as for those with relapsed/refractory myeloma. The day concluded with more presentations and posters some featuring compounds in very early development for myeloma.
Dr. Shaji Kumar from the Mayo Clinic-Rochester presented data from a phase I/II trial on the ixazomib, (MLN9708) a new oral proteasome inhibitor from Millennium, combined with Revlimid (lenalidomide) and dexamethasone in previously untreated myeloma patients. The overall response rate in this trial was 100%, with 23% complete responses (CR). Importantly, the incidence of peripheral neuropathy was very low, with only one grade 3 occurrence. The most common side effects were fatigue, nausea and vomiting. Based on the positive results, a phase III trial is planned.
Dr. Jonathan Kaufman (Atlanta, GA, USA) presented results from a phase I study of Revlimid, Velcade (bortezomib), and dexamethasone combined with the histone deacetylase (HDAC) inhibitor Zolinza (vorinostat) as first-line therapy. Commonly seen toxicities included Grade 1 or 2 constipation, diarrhea, fatigue, and nausea. The overall response rate was 97%, including a very exciting number of very good partial responses (VGPR) and complete or near complete responses (CR). Although Zolinza does not have an FDA-approved indication for multiple myeloma, it is approved for a type of lymphoma.
Dr. Antonio Palumbo from the University of Torino, Italy, presented results on a trial evaluating pomalidomide, cyclophosphamide, and prednisone in relapsed/refractory patients followed by pomalidomide and dexamethasone maintenance therapy. This trial is ongoing. At the time of this presentation, 55 patients had received at least 1 treatment cycle. Patients with relapsed/refractory disease who had received at least 1 to 3 prior therapies were eligible to participate. The overall response rate was 51%, with 6% achieving a CR and 24% a VGPR.
Dr. Noopur Raje from Mass General presented data for a phase I trial of the new anti-BAFF antibody tabalumab, combined with Velcade and dexamethasone. Forty-eight patients were enrolled, who had a median of 3 prior treatments. Adverse events observed were similar to those seen with Velcade. Two patients had a CR, 20 had a PR or VGPR, 21 had stable disease, and 3 progressed. The phase II trial is ongoing. The MMRF funded some of Dr. Raje’s early preclinical research on this target.
Dr. Jatin Shah from MD Anderson presented the results of a phase II trial assessing ARRY-520, a novel KSP inhibitor, with or without dexamethasone. Patients were heavily pre-treated, with a median of 6 prior treatments. Grade 3 and 4 toxicities were low, there was no cumulative toxicity, and the treatment was well tolerated. Responses ranged from PR to SD, with no CR in these heavily treated patients, and 34% had progressive disease. Interestingly, responses to this agent corresponded to serum levels of alpha-1-acid glycoprotein, which can act as a marker for patients who may respond to this agent.
Dr. Sundar Jagannath from Mt Sinai in New York City presented results of an age analysis from the phase II trial of pomalidomide with low-dose dexamethasone (in which the MMRC participated) in patients with relapsed/refractory multiple myeloma who have received prior therapy with Revlimid and Velcade. The results showed no significant differences in responses between the groups.
At tonight’s poster session, our own Chief Medical Officer Dr. Michael Needle presented data from the MMRF’s CoMMpass Study, for which he is co-principal investigator. The CoMMpass study will analyze the tumor and normal genomes from 1,000 patients with newly-diagnosed active multiple myeloma from their initial diagnosis over an at least five years. The clinical study opened in July 2011 and includes 55 sites in the United States. CoMMpass will provide researchers insight into patients’ disease progression and their responsiveness to specific treatment regimens, thereby characterizing the subtypes of multiple myeloma and accelerating individualized treatment approaches, which will be so important in this heterogeneous disease.
As mentioned, there were many new compounds representing many different classes in early development for myeloma presented at this year’s ASH meeting. Excitingly, there are too many to discuss on this blog, but I recommend that you check out the MMRF’s webcast with Dr. Antonio Palumbo and Professor Gareth Morgan.
December 9, 2012
Welcome to our second day of on-site coverage of the 2012 American Society of Hematology (ASH) Annual meeting. Today there were several exciting oral and poster sessions specifically focusing on new treatments for multiple myeloma.
Dr. Paul Richardson from Dana-Farber presented an update on a phase II study of the monoclonal antibody elotuzumab (which targets CS1) given at 2 different doses (10 mg/kg or 20 mg/kg) combined with Revlimid and low-dose dex to treat patients with relapsed/refractory multiple myeloma who had not received Revlimid. The overall response rate of patients was 84% with slightly higher responses seen at the lower dose. As we saw with pomalidomide, the response rate is higher in those patients who have had fewer prior treatments, which means that understanding sequencing of treatments is critical. Patients with high-risk disease did not differ in their responses but had a significantly lower progression free survival, again underscoring the need to understand which patients will benefit most from which treatments. The most common side effects that patients experienced were similar to those seen with Revlimid treatment. This treatment is in phase III trials in both relapsed and newly diagnosed patients.
Dr. Torben Plesner from Denmark presented the results of a phase I study of the new monoclonal antibody, daratumumab, which targets CD38. Patients with advanced disease who had received several previous treatments including immunomodulatory agents (IMiDs), proteasome inhibitors, and stem cell transplantation were enrolled in the trial and received single-agent daratumumab. There were several responses and importantly, there were minimal side effects. Although the results are preliminary, they are promising. Sanofi also has an antibody against the same target in a phase I trial at UCSF.
Dr. Jatin Shah from MD Anderson presented results from a phase 1 study looking at two of the newest agents in combination - Kyprolis (carfilzomib) plus pomalidomide and dexamethasone – in a highly refractory population. All patients (n=32) were refractory to Revlimid, and 31/32 were refractory to Velcade. Side effects were manageable, primarily low blood caounts, and notably, no grade 3 or 4 periperal neuropathy was seen. The overall response rate was 50 and nearly every patient had a minor response or stable disease. And, importantly, though the numbers of patients were small, even those patient who were high-risk (eg, with a deletion of chromosome 17p) responded as well as those patients who were not high-risk. Progression-free survival was 7.4 months, and the 1-year overall survival was 90%. These data continue to show that there are new treatments that can work even in the most heavily refractory and pre-treated population.
Dr. Tomer Mark from Weill-Cornell presented results from nearly 100 patients treated with clarithromycin (Biaxin) plus pomalidomide-dex again in a heavily pre-treated and refractory population. The overall response rate was 57% with a median progression free survival of 8.67 months. There was no difference in responses or progression-free survival between low and high-risk patients. The study is also looking at overall survival, and median survival had not yet been reached. Interestingly, during the Q&A, Dr. Mark mentioned that there are much more pronounced responses with this combination as opposed to the earlier clarithromycin plus Rev-dex trial. The study is continuing to enroll patients.
Dr. Martha Lacy from the Mayo Clinic presented updated results on a number of small trials conducted there with pomalidomide, and her data supported what was seen in Dr. Shah’s and Dr. Mark’s data – that pomalidomide can work even in those heavily pretreated and refractory patients – though, not surprisingly, the higher responses were seen in patients who had had fewer prior treatments. Regardless of dose or population, side effects were again quite manageable, which again is promising in this population.
Two more days to go. Stay tuned!