June 3, 2012
Welcome to Day 2 of our daily MMRF Newsflash from ASCO 2012. This morning an oral presentation session on myeloma brought us important results for early-phase studies of carfilzomib, MLN9708, and pomalidomide. In addition, a new update of the MRC Myeloma IX study from the UK provided further information regarding the management of myeloma-related bone disease using bisphosphonate therapy.
Results from three phase 1/2 studies of carfilzomib in patients with newly-diagnosed multiple myeloma (NDMM) were presented to kick off the session.
· The first, presented by Dr. Philippe Moreau of the Hôpital de Nantes, France, described preliminary results of the ongoing study of carfilzomib plus melphalan and prednisone (CMP) in patients with NDMM who were >65 years of age and ineligible for high-dose therapy and transplant. The regimen was well-tolerated with little peripheral neuropathy, and an overall response rate (ORR) of 89% was seen in 35 patients evaluable for response. Though early, this impressive response rate is similar to the rate seen in the initial Velcade-MP trials. Larger trials with longer follow-up are needed.
· The second study, presented by Dr. Joseph Mikhael from the Mayo Clinic in Arizona, evaluated the use of cyclophosphamide, carfilzomib, thalidomide, and dexamethasone (CYCLONE), a previously untested combination, in patients with NDMM. At a median follow-up of 8.2 months, the phase 2 ORR was 96% in 27 patients, including 75% with at least a very good partial response, and no peripheral neuropathy >grade 1 was observed. The initial results are impressive but questions arose as to whether similar results can be seen with three drugs combinations.
· The third study, presented by Dr. Andrzej Jakubowiak from the University of Chicago, reported updated results of an MMRC-supported phase 1/2 study of carfilzomib, Revlimid, and low-dose dexamethasone (CRd) in patients with NDMM. Patients received 8 months of induction treatment followed by 16 months of CRd maintenance, and then Revlimid maintenance. As of this analysis, 98% of 53 patients have responded, with 81% achieving at least a very good partial response and 42% achieving a stringent complete response. Dr. Jakubowiak noted that responses were rapid, typically seen after 2 cycles of therapy, tended to deepen over time, and were durable. Toxicity was similar to that seen in prior reports of carfilzomib, with no grade 3+ peripheral neuropathy, and Dr. Jakubowiak noted that toxicity did not appear to be increased for elderly patients.
Dr. Melissa Alsina from the Moffitt Cancer Center described results of PANORAMA 2, a phase II study of panobinostat in combination with Velcade and dexamethasone in patients with relapsed and Velcade-refractory multiple myeloma. In this study of 55 heavily-pretreated patients, an ORR of 31% was seen, with the most common grade 3+ adverse event being thrombocytopenia, seen in 62% of patients. While significant, the thrombocytopenia did not require treatment discontinuation and was managed using platelet transfusions and dose reductions/interruptions. The results were consistent with other Velcade-based triplets in Velcade-refractory patients, and PANAROMA 1, an ongoing phase 3 study comparing panobinostat, Velcade, and dexamethasone with Velcade and dexamethasone for patients with relapsed myeloma, will shed more light on this potential treatment strategy.
Dr. Gareth Morgan of the Royal Marsden Hospital, London, reported updated results of the MRC Myeloma IX randomized trial, comparing Zometa to clodronate for the treatment of bone disease in 1960 newly diagnosed myeloma patients initiating antimyeloma therapy. Prior reports of the study have demonstrated fewer skeletal-related events (SREs) and an improved overall survival for patients receiving Zometa; in this new analysis at 5.8 years follow-up, these benefits were confirmed. Bisphosphonate therapy is reportedly associated with increased renal failure and osteonecrosis of the jaw (ONJ). In this analysis, renal events were similar for both arms, confirming that Zometa does not increase the risk of renal failure compared with the oral clodronate.However, ONJ was increased in the Zometa arm, with a cumulative incidence 3.7% versus 0.5%. Dr. Morgan noted that most cases were lower-grade, and that 1/3 of patients fully recovered. An additional 1/3 of patients saw partial improvement. Most incidents were seen between 12 and 24 months, and those who had pre-existing dental challenges and/or had dental surgery during treatment were at much higher risk for ONJ. Dr. Morgan suggested that dental preventative measures might improve the incidence of ONJ.
Dr. Ravi Vij described a pre-planned subset analysis of patients with relapsed/refractory myeloma treated with pomalidomide with or without low-dose dexamethasone, a trial conducted in collaboration with the MMRC. The subset analysis examined activity in patients who were refractory to Revlimid (87 patients), Velcade (82 patients), both of these drugs (69 patients), or both drugs plus autologous stem cell transplant (47 patients). Encouragingly, regardless of prior treatment, the response was similar. Finally, Dr. Sagar Lonial described results of a phase 1 study of twice-weekly MLN9708. The drug was well-tolerated in 56 patients enrolled to date, with early evidence of activity. Dr. Lonial noted that a once-weekly schedule is also being studied, and a phase 3 randomized trial using the once-weekly schedule (NCT01564537) will be enrolling soon.
During her discussion, Dr. Irene Ghobrial from Dana-Farber highlighted the encouraging data emerging for both pomalidomide and MLN9708, and suggested that both drugs may potentially have a role in both the upfront and the maintenance setting, and perhaps even for smoldering myeloma requiring treatment given their reasonable toxicity profiles.
Stay tuned for our final newsflash tomorrow!
June 2, 2012
The MMRF team is on site at the 2012 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.
This morning, a myeloma poster session highlighted new data from the investigational oral proteasome inhibitor MLN9708; additional data for the investigational proteasome inhibitor carfilzomib; data from several other treatment regimens; and a look at second primary malignancies.
Highly anticipated data from two studies of the investigational oral proteasome inhibitor MLN9708 were presented today. One was a phase 1/2 study in combination with Revlimid and standard-dose dexamethasone for previously untreated patients (led by Dr. Paul Richardson from the Dana-Farber), and a phase 1 study as monotherapy in the relapsed/refractory setting led by Dr. Shaji Kumar of the Mayo Clinic. Both studies used a once-weekly dosing schedule and both confirmed a maximum tolerated dose (MTD) of 2.97 mg/m2. The recommended phase 2 dose was 2.23 mg/m2 according to the overall safety and efficacy results of the phase 1 portion of the combination study. A twice weekly schedule is also being investigated using a 2.0 mg/m2 dose. Dr. Sagar Lonial from the Winship Cancer Institute at Emory University will present results using this schedule for patients with relapsed/refractory disease at a myeloma oral presentation tomorrow.
The phase 1 monotherapy study had a promising adverse event (AE) profile in 52 total patients. No significant neuropathy was observed. The most common AEs were transient thrombocytopenia (with platelet counts recovering towards baseline levels following dosing in each cycle) and gastrointestinal symptoms, requiring study discontinuation for 2 patients. The phase 1/2 combination study reported an overall response rate of 98% in 46 patients, with a complete response seen in 26% and a very good partial response or better in 39%. The drug appeared generally well-tolerated in this study as well, with the most common AE being rash, none of which required drug discontinuation. One patient experienced a grade 3 peripheral neuropathy (the first peripheral neuropathy greater than Grade 2 seen with this drug) at a dose greater than the recommended phase 2 dose. Based on these data, a global, randomized, phase 3 study of this combination compared to Revlimid and dexamethasone alone for relapsed/refractory MM has been registered at www.clinicaltrials.gov (NCT01564537) and enrollment will begin soon.
One poster on carfilzomib was presented today (with Dr. David Siegel from the John Theurer Cancer Center at Hackensack University as first author). It described a sub-analysis of 266 patients refractory or intolerant to both Velcade and immunomodulating agents (thalidomide or Revlimid), who were enrolled in PX-171-003-A1, a phase 2b monotherapy study of patients who had relapsed/refractory myeloma that was conducted in collaboration with the Multiple Myeloma Research Consortium (MMRC). These patients were heavily pre-treated, with 82% receiving at least 4 prior therapies. The overall response rate was 22.9% (15.4% for 169 patients refractory to both Velcade and Revlimid).
Another two posters described analyses of second primary malignancies (SPMs) following myeloma treatment. One analysis of 1175 patients confirmed other recent analyses of SPMs in multiple myeloma, demonstrating that the rates of SPMs were as expected for this patient population, although follow-up was relatively short at just over 12 months. The incidence of SPMs was similar in patients under 65 versus 65 and older, and no correlation was seen according to different treatment regimens. In contrast, a study of 869 patients receiving an autologous stem cell transplant at the City of Hope revealed what was described as a high incidence of SPMs, at a cumulative 10-year incidence of 15.9% (primarily solid tumors), with a trend towards increased risk in patients receiving thalidomide. There were insufficient numbers of patients receiving Revlimid for any correlations to be seen, but the authors suggested that there may be a class effect. Clearly the issue of SPMs in myeloma requires further long-term analyses, though, most believe that, based on the current data, the survival advantage that has been seen in one study and the delayed disease progression are benefits that outweigh any potential risks. Long-term follow-up will continue.
Stay tuned for additional updates including a summary of oral abstracts being presented tomorrow morning!
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!