December 8, 2012
Welcome to our first day of on-site coverage of the 2012 American Society of Hematology (ASH) Annual meeting.
Highlights from today included a Multiple Myeloma Education session and a poster session focusing primarily on new agents.
Key takeaways from the Education Session which featured Drs. Gareth Morgan from Royal Marsden in London, Antonio Palumbo from the University of Torino in Italy and Vincent Rajkumar at Mayo Clinic-Rochester were:
- For the majority of patients, and especially those with any risk factors like deletion 17(p) or t(4;14) should receive triple therapy, eg, Revlimid-Velcade-dexamethasone (RVD) or VCD (Velcade-cyclophosphamide-dex) as first-line therapy (the minority being some elderly patients and those with low risk disease)
- High-dose chemotherapy followed by autologous stem transplant early in the course of disease appears to still offer patients the greatest benefit in terms of length of remission
- Maintenance therapy appears to be beneficial for most patients, particularly those with lower risk disease, where the benefits of progression free survival and perhaps overall survival outweigh the risk of secondary cancers
- There is still a great need to identify those patients at highest risk for relapse and determine the treatment regimen that could prolong remission time
There were several key posters presented:
- Dr. Paul Richardson presented a poster on the phase II part of the PANORAMA 2 study assessing the histone deacetylase (HDAC) inhibitor panobinostat in combination with Velcade and dexamethasone. Patients progressed on two or more prior therapies, and all had been exposed to immunomodulatory drugs (IMiDs). The overall response rate (ORR) in 17 patients was 43%, primarily partial responses, though another 28% had minor responses. Progression free survival (PFS) and time to progression (TTP) were both 5.4 months. The most common grade 3 or 4 adverse event was thrombocytopenia, occurring in 64%. Peripheral neuropathy was generally mild, and occurred in 27.3%.
- Dr. Keith Stewart presented the early results of the phase I MMRC trial assessing the aurora kinase inhibitor MLN5237 in combination with Velcade in relapsed/refractory disease. No steroid was included in the regimen. Nineteen patients have been enrolled, and 16 had prior treatment with stem cell transplantation. Phase 1 is complete, with a maximum tolerable dose of 50 mg twice daily, days 1-7 of a 28-day cycle. The ORR was 26%. Adverse events of grade 3 or greater occurred in 68%. These included myelosuppression, neuropathy, hair loss gastrointestinal (diarrhea, nausea, vomiting), and infection.
Sunday will be a busy day with the start of the oral presentations. Stay tuned!
June 4, 2012
Welcome to the third and final day of our on-site coverage of ASCO 2012. Highlights today included a clinical sciences symposium discussing immunotherapy for multiple myeloma and a poster session shortly later, covering many myeloma topics.
The oral session included three presentations of monoclonal antibodies for the treatment of myeloma:
· Dr. Robert Orlowski from the MD Anderson Cancer Center presented results of a Phase II, randomized, double blind, placebo-controlled study comparing the antibody siltuximab, which targets interleukin-6 (IL-6), in combination with Velcade compared to Velcade alone, in 281 patients with relapsed/refractory disease. Despite promising early data, the experimental arm did not show any benefit in delaying the disease or prolonging survival. Additionally, the experiemtnal arm experienced modestly higher (although generally manageable) adverse events. However, Dr. Vincent Rajkumar from the Mayo Clinic suggested that perhaps this heavily pre-treated population may have lost sensitivity to IL-6 and that the antibody may still have a role in the upfront or even smoldering setting. Trials are underway to study the antibody in these contexts.
· Dr. Torben Plesner from Vejle Hospital in Denmark reported Phase 1 results from a Phase 1/2 study of single-agent therapy with the antibody daratumumab for patients with relapsed/refractory myeloma. To date, 29 patients have been treated at doses from 0.005mg/kg to 16 mg/kg, with a plan to enroll patients in a 24 mg/kg cohort. Infusion-related adverse events were relatively common but were reduced with appropriate pre-medications. In this heavily pre-treated patient population, 7 patients (24%) achieved PR, and an additional 4 patient achieved a minimal response. The results are extremely early, but worth watching based on these preliminary results.
· Dr. Philippe Moreau of the Hôpital de Nantes, France, described results of the Phase 2 portion of a Phase 1/2 study of the anti-CS1 antibody elotuzumab, in combination with Revlimid and low-dose dexamethasone in patients with relapsed/refractory myeloma. The Phase 1 portion of this study was recently published in the Journal of Clinical Oncology (June 2012). The Phase 2 study randomized 73 patients to 10 mg/kg or 20 mg/kg elotuzumab plus Revlimid and dexamethasone. The study was generally well-tolerated and showed remarkable efficacy: response rates were 84% overall, 92% in the 10-mg/kg group, and 76% in the 20-mg/kg group; response was higher for patients who had only received one or two prior therapies. Progression-free survival (PFS) at 17 months of follow-up was not reached for the 10-mg/kg group and was estimated at 18.6 months for the 20-mg/kg group; PFS was significantly lower for patients with higher-risk cytogenetics (about 9 months). Two Phase 3 studies are currently underway using the 10-mg/kg dose, comparing this combination with Revlimid + low-dose dexamethasone in the upfront (ELOQUENT 1) and relapsed/refractory (ELOQUENT 2) setting.
A poster session following these oral presentations included new data for carfilzomib, analyses of potential prognostic risk factors, and various subgroup, follow-up, or retrospective analyses.
Dr. James Berenson of the Institute for Myeloma and Bone Cancer Research presented results of an interesting Phase I/II study of carfilzomib for 27 patients who progressed on or within 12 weeks of receiving a Velcade-containing combination regimen. These patients received the same treatment regimen upon progression but with carfilzomib as a replacement for Velcade. 14 of 22 evaluable patients (64%) subsequently achieved at least a minimal response, and 11 patients (50%) achieved at least a very good partial response. Additionally, in a pooled analysis of 4 Phase 2 studies of carfilzomib in relapsed/refractory myeloma, Grade 3/4 hematologic AEs were infrequent and transient, and serious events were rare.
Several posters described retrospective analyses (using existing medical records) of the effect of early stem-cell transplants (as consolidation therapy after induction):
· A poster with Jonathan Kaufman from Emory University demonstrated that achieving at least a VGPR following stem cell transplant and then RVD maintenance resulted in significantly improved progression free and overall survival.
· A related poster by Charise Gleason from Emory University demonstrated the ability of RVD induction, consolidation stem cell transplant, and then maintenance to improve progression-free and overall survival.
· Fnally, the value of a second stem cell transplant as salvage therapy was demonstrated by Dr. Wilson Gonsalves from Rochester, noting that time to progression for the first transplant was associated with higher progression-free and overall survival following a second transplant.
We hope you found these updates useful!
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.