December 13, 2011
This final day of ASH 2011 brought us some interesting retrospective and follow-up analyses of prior MM studies, which addressed several key questions in myeloma treatment.
We cite two below:
First, Dr. Hervé Avet-L’oiseau presented a pooled analysis of almost 2000 patients treated with various regimens by the Intergroupe Francophone du Myélome (IFM) to analyze the impact of cytogenetics on prognosis and outcome for elderly patients. Dr. Avet-L’oiseau reported that the translocation of chromosomes 4 and 14 or t(4;14)was significantly less common in elderly patients (>65 years) compared to younger patients, while the deletion of chromosome 13 - del(13) - and the deletion of part of chromosome 17 -del(17p) – frequencies were similar. As is the case with younger patients, a negative survival impact was observed for patients with (4;14) or del(17p), regardless of treatment.
Second, Dr. Antonio Palumbo provided further data on the frequency of second primary malignancies (SPMs) in patients treated with Revlimid, using a pooled analysis of 9 clinical trials conducted by the European Myeloma Network, and consisting of approximately 2200 patients with at least one year of follow-up. Dr. Palumbo cautioned that, due to very small numbers of patients with SPMs, the findings must be interpreted with caution; however following a median of about 3 years of follow-up, data suggest that patients who received melphalan in combination with an immunomodulatory agent (Revlimid or Thalomid) approximately doubled their risk of an SPM. Dr. Palumbo noted that the resulting incidence rate was still quite low and that all incidences were similar to that expected for the general population. Dr. Palumbo emphasized that the risk of death due to treatment toxicity was actually higher than the risk of SPM, and he reiterated that the risk of disease progression is much more significant, at 10 to 15 times the risk of an SPM. He concluded that, according to evidence currently available and at the current follow-up of 3 years, the benefits of treatment outweigh the risks, particularly when there has been an overall survival benefit seen in some trials when Revlimid is used as maintenance. Dr. Palumbo encouraged ongoing study of this important issue.
Finally, our own Sandra Wear, Associate Director of Operations at the MMRC, presented metrics affirming the MMRC’s speed at opening and closing clinical trials based on a retrospective review of 25 multiple myeloma trials conducted with MMRC project management resources from May 2006 to July 2011. The data also included comparisons between a set of baseline trials (June 2006 - September 2008) and recent trials (September 2008 - July 2011) run through the Consortium, with the recent trials based on the model the MMRC and MMRF have established to accelerate drug development.
- The recent trials opened 28% faster than the baseline trials, which opened at times consistent with industry standards (131 calendar days for recent trials vs. 181 calendar days for baseline trials);
- All MMRC trials opened 20% faster when comparing all participating MMRC centers on any MMRC trial (189 days for recent trials vs. 236 calendar days for baseline trials);
- MMRC trials enrolled 10% more patients than their pre-study enrollment commitment, with 89% of trials meeting their commitment; and
- MMRC trials enrolled patients 10% faster when compared to their baseline enrollment timeline, with 67% of trials meeting their pre-study enrollment commitment 34%, or 4.5 months, faster than their baseline enrollment timeline.
With these strong metrics, working in collaboration with our investigators and industry partners, we have accelerated the development of several important treatments in late-stage clinical trials such as carfilzomib, elotuzumab, pomalidomide, and Zolinza, all of which were the focus of ASH abstracts at this year’s meeting.
December 12, 2011
Monday was a big day for MM research at ASH 2011, with numerous preclinical and clinical oral presentation sessions. We couldn’t cover them all, but we did cover 4 excellent clinical sessions describing advances in current treatments and the development of novel agents.
Highlights include data from pivotal front-line trials:
- Final, 5-year follow-up data from the VISTA study of Velcade (bortezomib), melphalan, prednisone (VMP) versus melphalan and prednisone (MP) in patients with previously untreated MM, confirming the OS benefit seen originally at 3 years of follow-up (published by Dr. María-Victoria Mateos and colleagues in 2010 in the Journal of Clinical Oncology). Unlike the original follow-up report, a survival benefit was not seen for patients with high-risk cytogenetics. The report also confirmed the preferential benefit of receiving Velcade during induction rather than after progression. Additionally, no safety signal for second primary malignancies was observed.
- Updated data on maintenance therapy following 3 years of follow-up for the GEM2005MAS65 Spanish study of VMP vs VTP induction followed by maintenance with VP or VT, and confirmed the benefit or both maintenance regimens for all patients except those with high-risk cytogenetics.
- An update from the MM-015 study of melphlan-prednisone (MP) versus MP plus Revlimid (lenalidomide) followed by Revlimid maintenance (MPR-R) in newly diagnosed, transplant ineligible MM patients, which demonstrated statistically and clinically significant improvements in progression free survival (PFS) for the MPR-R arm. Including Revlimid in induction also appeared to significantly benefit this patient population, in contrast to older patients (>75 years), where MPR and MP showed similar response rates and PFS.
- Final results of the community-based, phase 3b UPFRONT study of VD, VTD, or VMP in newly diagnosed patients ineligible for transplant were presented by Dr. Ruben Niesvizky, demonstrating similar response and survival for all patient groups. Triplet therapies tended to result in greater dose reduction and discontinuation; Dr. Niesvizky noted that relatively high comorbidities were seen in this community study, which highlights that the more intensive triplet therapy may not add benefit for these patients.
Additional data were presented on novel agents in clinical trials, all of which have been studied through our affiliate organization, the MMRC:
- Final data from the global phase 3 study of the histone deactylase (HDAC) inhibitor Zolinza (vorinostat), which is FDA-approved for a type of lymphoma, in combination with Velcade for patients with relapsed/refractory MM, presented by Dr. Meletios Dimopoulos, demonstrated a statistically significant though clinical modest improvement in PFS for the combination. High-grade fatigue was more common in the Zolinza arm. An additional phase 2b study of Zolinza with Velcadeas salvage therapy for patients who were resistant to Velcade was presented by Dr. David Siegel. The MMRC had partnered with Merck to contribute patients to this large, multi-national trial which showed that a significant number of Velcade-refractory patients had relatively high response rates, indicating that retreatment is possible.
- Three presentations described phase 2 data for carfilzomib as single agent or in combination with Revlimid/low-dose dexamethasone or Thalomid (thalidomide)/dexamethasone. The combination with Revlimid in particular showed rapid and almost universal responses which deepened over time. Each study demonstrated impressive responses in patients with high-risk cytogenetics.
- Four presentations described new phase 1/2 data for pomalidomide alone or in combination with dexamethasone, cyclophosphamide-prednisone, or clarithromycin-dexamethasone, showing good response especially in combination, and efficacy in subsets of patients refractory to Revlimid or with high-risk cytogenetics.
- Dr. Sagar Lonial provided updated data for a phase 2 study of the monoclonal antibody elotuzumab with lenalidomide and low-dose dexamethasone, which resulted in excellent responses (>80%) in relapsed/refractory patients. The possibility of an effective monoclonal antibody for MM is quite exciting!
Equally exciting is the rich pipeline of drugs in development for MM. Oral sessions today described promising phase 1 and phase 2 data for a dizzying variety of agents: the HDAC inhibitor panobinostat; the bifunctional alkylator bendamustine; novel proteasome inhibitors MLN9708 and marizomib (NPI-0052) – both of which are currently being studied in the MMRC; BT062, an anti-CD38 monoclonal antibody conjugated to the maytansinoid cytotoxin; the MEK 1/2 inhibitor AZD6244; the dendritic cell vaccine APC8020; and the AKT inhibitor perifosine. The large number of drugs in the pipeline bodes well for the future of MM treatment.
Stay tuned tomorrow for our final blog from ASH 2011!
December 11, 2011
The MMRF team is on site at the American Society of Hematology (ASH) Annual Meeting in San Diego and is pleased to share with you highlights from key sessions over the next 3 days.
On Friday, the MMRF kicked off the meeting with a standing-room-only CME symposium, which more than 560 healthcare professionals attended. Dr. Paul Richardson chaired the novel format which included presentations from leading specialists Drs. Herve Avet-L’oiseau, Andrzej Jakubowiak, Maria-Victoria Mateos, and Philip McCarthy. Live cases from community physicians were presented for audience response and faculty discussion.
MM Education Session
On Saturday, the multiple myeloma scientific sessions began with a scintillating educational session chaired by Dr. Ken Anderson with Drs. Sergio Giralt and Donna Reece as additional speakers.
- Dr. Reece covered the latest data related to first-line treatment as well as post-transplant maintenance. Overall, she concluded that with incorporation of novel agents Revlimid and Velcade, as induction, as well as consolidation and maintenance, with high-dose chemotherapy and stem cell transplant, we are seeing unprecedented response rates, with complete responses in the 65% range. There are proven benefits in terms of progression-free survival (PFS – the amount of time a patient remains disease free) and strong hints of a survival benefit particularly with the incorporation of Revlimid maintenance post-transplant. With regard to maintenance, we still need to understand who is most likely to benefit and who may be at risk for second primary malignancies (SPMs). We are also continuing to see that these agents, particularly Velcade, can overcome some of the adverse features of MM, such as translocation of chromosomes 4 and 14 (t(4;14)).
- Dr. Giralt looked at the role of high-dose chemotherapy in the age of novel agents. To date, there are no data showing the superiority of one or the other, but, in truth, trials asking those types of questions are still underway. He introduced several thought-provoking questions that have yet to be answered such as:
- Does everyone need triple therapy upfront or are there patients with lower risk disease that would benefit from a doublet?
- What is the optimal duration of induction therapy?
- Is there an optimal timing for high-dose chemotherapy and stem cell transplant?
- Dr. Anderson focused on the future – though much of the future is now! – for myeloma therapy. Right now, there is an unprecedented number of treatments in clinical trials – some second-generation treatment like carfilzomib and pomalidomide, as well as agents with totally new mechanisms of action such as HDAC inhibitors (eg, Zolinza and panobinostat), Akt inhibitors (such as perifosine), antibodies (such as elotuzumab and siltuximab), and MEK inhibitors among many others. He concluded by discussing the future of personalized therapy whereby a patient’s treatment regimen is determined by his/her molecular profile – exactly what the MMRF is seeking to do with our CoMMpass StudySM.
Oral and Poster Sessions
Poster sessions on Saturday and Sunday covered risk stratification, risk of optimizing current frontline treatments, SPMs, and the development of novel therapies, including several for which the MMRC has played a significant role.
Both oral abstracts and posters presented by researchers at several institutions including the Mayo Clinic-Scottsdale and the University of Arkansas for Medical Sciences looked at genetic markers to predict response and side effects to various therapies and to optimize risk stratification. Risk stratification remains a goal in MM, and research to develop risk-based tools for improving prognosis and therapy continues. Dr. Leif Bergsagel credited the MMRF’s Genomics Initiative with uncovering potentially important new targets for drug development.
SPMs have become an important topic for patients receiving Revlimid in combination with akylating agents such as melphalan, as several recent studies reported higher incidences of SPMs following Revlimid treatment. Dr. Jesus San Miguel analyzed the risk of SPMs following Velcade treatment using data from 4 large phase 3 trials, and demonstrated rates of SPMs similar to that expected for the general US population. Several papers on SPMs following Revlimid treatment will also be presented at ASH this year, providing further evidence that recurrence of myeloma is much more of an issue than is the development of SPMs following Revlimid; however, the topic is important and continues to be investigated.
Several posters addressed optimizing the use of current treatments in the upfront setting:
- Most notably, Dr. Antonio Palumbo presented final data from a phase 3 study of melphalan, prednisone, and Revlimid (MPR) versus high-dose melphalan (MEL200) and autologous stem cell transplant in newly diagnosed MM patients younger than 65 years. As described previously at ASCO this year, responses were similar but significant PFS improvement was seen in the transplant arm. MEL200 was associated with greater side effects, although few patients in either arm discontinued as a result.
- Dr. Ajai Chari presented data from a small study of treatment of newly diagnosed MM with Revlimid, Velcade, and dexamethasone (RVD) therapy on a 28-day cycle with Velcade 1.3 mg/m2 given on days 1, 4, 11, and 18, in contrast to the typical 21-days; peripheral neuropathy appeared to be reduced without loss of efficacy in the 38 patients analyzed.
Finally, there were many posters Sunday describing novel treatments for MM. Two of the most anticipated new drugs continue to be carfilzomib, the novel proteasome inhibitor that has been developed with the facilitation of the MMRC, and pomalidomide, the novel immunomodulatory agent that has been tested in multiple MMRC trials. Data for both agents continue to be impressive; both drugs are now in phase 3 development. At Saturday’s poster session, data were presented indicating that even patients with higher risk features such as deletion of chromosome 13 or t(4;14) responded as favorably as patients with lower risk disease.
Additional agents are showing exciting early results in the relapsed/refractory setting. Several posters demonstrate that Treanda (bendamustine), which is approved for CLL and NHL also studied in an MMRC trial, continues to show promise in relapsed/refractory MM patients with Velcade- and Revlimid-based regimens. Posters demonstrated impressive early efficacy data for novel kinesin spindle protein (KSP) inhibitor ARRY-520 (also being studied in an MMRC trial) in phase 1 and phase 2 studies, as single agent and in combination with standard therapies. Additional posters described early but intriguing data for PD 0332991, a novel cyclin-dependent kinase (CDK) 4/6 inhibitor; GSK2110183, a novel Akt inhibitor which just entered an MMRC-facilitated trial; daratumumab, an antiCD38 antibody; and BLP25 liposome vaccine.
Stay tuned for continued updates over the next couple of days as more data are presented!
June 6, 2011
Welcome to the final day of live coverage of the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago. Today, a poster session on multiple myeloma covered new drugs in development; refinement of the regimen for Velcade-based treatments; and additional data from the landmark MRC trial looking at the use of bisphosphonates.
Data for several new drugs in development were presented during this poster session, including panobinostat, pomalidomide, elotuzumab, and Treanda (bendamustine), all of which have been and/or are being studied in MMRC-facilitated clinical trials. First, Dr. Jesus San Miguel and colleagues presented data from a phase Ib study of panobinostat combined with a lower dose of Velcade that showed synergy between the two drugs in terms of efficacy and a lower incidence of peripheral neuropathy. Pomalidomide, which is in late-stage development for myeloma, showed encouraging activity when combined with low-dose dexamethasone in a large phase II study of heavily pretreated patients (including those refractory to both Revlimid and Velcade), and phase I data from the phase I/II study of elotuzumab combined with Revlimid and dexamethasone, presented during yesterday’s myeloma oral session, again showed encouraging data for this agent. Finally, Dr. James Berenson reported promising preliminary efficacy and safety from a phase I/II study of Treanda plus a reduced dose of Velcade, which, similar to Dr. San Miguel’s trial, appears to reduce the occurrence of peripheral neuropathy.
A poster by Dr. Nikhil Munshi and colleagues reported on a study of once-weekly Velcade dosing in the upfront setting for newly diagnosed myeloma patients not eligible for transplant. His data strongly suggest that a once-weekly regimen for four weeks with one week off reduced the risk of peripheral neuropathy. The authors suggested that this treatment regimen should allow for Velcade use as maintenance therapy.
A poster by Dr. Ruben Niesvizky and colleagues described a sub-analysis of the UPFRONT study, which compared three different Velcade regimens for patients with newly diagnosed myeloma. Dr. Niesvizky examined the impact of various baseline characteristics of patients, including age, sex, the presence of comorbid illness, and International Staging System (ISS) score, on the safety and efficacy of these regimens. While Velcade was active in all patient subgroups based on these characteristics, the likelihood of achieving a VGPR or better was higher in patients under age 75, and there were also significantly fewer adverse events in these patients. Similarly, CR and nCR rates were significantly higher for patients with no comorbidities; VGPR rates also tended to be higher for these patients, but the difference was not significant. Velcade had similar safety and efficacy regardless of sex and ISS score. These results demonstrate the ability of Velcade to overcome multiple risk factors, but they also highlight once again the ongoing need for improved treatment options for elderly patients.
We reported yesterday on two oral presentations describing sub-analyses from the MRC Myeloma IX study of Zometa versus clodronate in upfront multiple myeloma; today, a poster by Dr. Faith Davies again suggested that early and ongoing use of Zometa reduced the incidence of skeletal-related events (SREs) for newly diagnosed myeloma patients and improved OS in patients presenting with bone disease. However, incidence of osteonecrosis of the jaw (ONJ) was significantly increased in patients receiving Zometa after about 3.5 years of follow-up, ONJ occurred in about 3.5% of patients compared to about 0.3% in patients receiving clodronate. The authors reported that these were mild to moderate in severity. But, as Dr. Roodman mentioned the day before, given the preliminary data and increased incidence of ONJ, it would be premature to refine any guidelines around bisphosphonate use at this time.
June 5, 2011
Welcome to day 2 of live coverage of the ASCO Annual Meeting in Chicago. Today was a big day for multiple myeloma!
First, a session of oral abstracts – those deemed by the scientific organizers to have the greatest impact on patient care - dedicated exclusively to myeloma discussed critically important topics: the risk of second primary malignancies (SPMs) following Revlimid treatment; the role of bisphosphonates in myeloma; and studies of new drugs in development. Three speakers discussed the potential risk of SPMs following Revlimid treatment. This issue was first brought up at last year’s annual meeting of the American Society of Hematology (ASH), in which three randomized phase III studies—MM-015, IFM 2005-02, and CALGB 100104—reported SPMs in a small number of patients receiving Revlimid maintenance. The common feature among all of these trials, as opposed to other trials where SPMs have not emerged as a potential issue, is that patients first received high-dose melphalan or the MPR regimen.
At today’s session on SPMs:
- Dr. Antonio Palumbo, principal investigator for MM-015, described a retrospective analysis of approximately 1800 patients from nine studies of various myeloma therapies. Following a median of 30 months of follow-up, Dr. Palumbo observed a 7% increased risk of SPMs in patients receiving Revlimid maintenance therapy.
- Dr. Adriana Rossi and Dr. Ruben Niesvizky reported similar data from retrospective analyses; Dr. Rossi analyzed continuous therapy using the BiRD regimen (clarithromycin, Revlimid, and dexamethasone) after almost six years of follow-up, and Dr. Ruben Niesvizky analyzed the MM-009 and MM-010 studies of Revlimid and dexamethasone. Neither found any increased risk of SPMs. Importantly, though, neither regimen included melphlan.
- All three presenters believed that, at present, the benefits of Revlimid therapy, overall as well as in the maintenance setting, outweigh any potential risk of SPMs. Nevertheless, it is important for patients to discuss with their doctor the risk of SPMs, as is the case for all potential adverse effects of treatment.
Next, two speakers discussed the role of bisphosphonates in myeloma treatment, using data from the MRC Myeloma IX Trial that compared Zometa (zoledronic acid) and clodronate with chemotherapy for patients with newly diagnosed myeloma.
- Dr. Gareth Morgan reported that patients with and without bone disease at presentation benefited from Zometa; following almost four years of follow-up, both groups of patients had a reduced incidence of skeletal-related events (SREs). Improvements in progression-free survival were also seen compared to the clodronate arm, but these were limited to patients with bone disease.
- Dr. Faith Davies reported that patients continued to see a reduced incidence of SREs at least up to three years of Zometa based on a landmark analysis, and that overall survival benefits increased over time.
- Both authors recommended changes to the current guidelines for bisphosphonate therapy, which currently recommend two years of treatment for patients with bone disease only.
In a discussion following these talks, Dr. Roodman expressed his view that it was premature to change current practice regarding the use of bisphosphonates as no survival benefit was seen in patients without bone disease in this study, and the risk of osteonecrosis of the jaw (ONJ) remains a significant consideration.
Finally, three speakers discussed results of studies in the relapsed and/or refractory setting of novel antibodies in development for the treatment of multiple myeloma:
- Dr. Noopur Raje described a phase I study of LY2127399, an anti-BAFF antibody, whose preclinical development was supported by grant funding from the MMRF, combined with bortezomib. This is an early trial but the combination is worth watching given its preliminary safety and efficacy profile.
- Dr. Jesus Berdeja described a phase I study of lorvotuzumab mertansine (IMGN901) in combination with Revlimid and dexamethasone. Similar Dr. Raje’s presentation, while these are very preliminary results, they looked promising.
- Dr. Philippe Moreau from France reported updated data from a phase I/II study of elotuzumab, which has been studied in MMRC-facilitated trials, combined with Revlimid and dexamethasone in relapsed patients. This study has large patient numbers and demonstrated an impressive 82% response rate; a median progression-free-survival rate that has not been reached as of nine months of follow-up; and a manageable toxicity profile. A phase III study of this combination is underway in relapsed patients.
In his discussion of these presentations, Dr. Nikhil Munshi expressed enthusiasm for the future of monoclonal antibody therapy in myeloma and excitement regarding the elotuzumab phase III study, noting that “we may have more than one ‘rituximab’ (Rituxan – which transformed the care of patients with non-Hodgkin lymphoma) for myeloma” in the future.
Immediately following this oral session, the MMRF interviewed Drs. Rafael Fonseca and David Roodman, who provided a fascinating and informative discussion of what these and other presentations at ASCO mean for patients and their families. Stay tuned for the MMRF Myeloma Update webcast of these interviews, and for our final ASCO update tomorrow!