June 3, 2012

MMRF Newsflash from ASCO - 2



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!