June 7, 2010

New data from ASCO provide much hope for myeloma patients

On Saturday (6/5) afternoon and on Sunday (6/6) morning, 13 oral abstracts based on data from clinical trials in multiple myeloma were presented at the ASCO meeting. Selection as an oral abstract signifies that the ASCO scientific committee had deemed these presentations to be the strongest scientifically and potentially most important in terms of their impact on clinical practice and patient care. Saturday’s session featured early-stage (Phase I and II) data on four exciting new compounds – carfilzomib, pomalidomide, panobinostat, and elotuzumab. What was most encouraging – in addition to three of the trials having been partially or fully facilitated by the MMRC – is that every one of these new treatments showed efficacy in patients whose disease had progressed following treatment with Velcade (bortezomib) and/or Revlimid (lenalidomide). Undoubtedly all patients will need (and the vast majority will benefit from) Velcade and Revlimid, but unfortunately, many will relapse, and it will be important to have treatments in our armamentarium that may re-sensitize patients to these treatments (eg, panobinostat) or work in the face of patients who are refractory to both (eg, pomalidomide). The toxicity profiles of these agents were also encouraging, as neither carfilzomib nor pomalidomide appears to be associated with an increased risk of peripheral neuropathy unlike other proteasome inhibitors (eg, Velcade) and ImiDs (eg, Thalomid).

On Sunday, there were three hours of data from trials involving all patient populations. The data that will likely have the most immediate impact on patient care were from two trials that examined the role of single agent Revlimid (typically 10-15 mg) as maintenance therapy following high-dose chemotherapy and stem cell transplant. These two trials, both involving hundreds of patients, were conducted relatively concurrently by the cooperative groups in the US and by the IFM in France. In both trials, patients were randomized to either Revlimid or placebo, and both trials were stopped early following review by an independent data monitoring board, allowing patients in the placebo arm to cross over and receive Revlimid. This is because those on the Revlimid arm enjoyed a sustained remission (both studies found similar reduction in risk of disease progression – 58% and 54%). Both trials found that, regardless of their induction therapy or risk, patients on the Revlimid arm clearly enjoyed a lower risk of progression. While it is too early to assess whether there is a survival benefit, many felt that this benefit would reveal itself over time.

In transplant ineligible patients, updated data from an Italian trial of VMPT (Velcade-melphalan-prednisone-Thalomid) followed by VT maintenance showed higher response rates, in particular complete response rate (38% vs. 24%), and longer progression free survival than VMP. These data suggest that the four drug combination, which featured lower doses of Velcade and Thalomid than are typically prescribed, may become a standard for this population, and that maintenance therapy may also be important to preventing disease progression in this population.

Also included in this session was the much anticipated final data from Dana-Farber’s Phase I/II single arm trial evaluating RVd in newly diagnosed patients. In this final analysis, all patients (66 in the Phase I trial and 35 in the Phase II trial) enjoyed a partial response or better with manageable toxicity. The French group also presented some interesting data suggesting benefit to a reduced dose of Velcade in combination with reduced doses of Thalomid and dex compared to Velcade-dex for four cycles prior to high-dose chemo and stem cell transplant. Patients on the vTD arm had less toxicity – not a single patient discontinued therapy – as opposed to those on the VD arm while enjoying similar, if not better, efficacy. Also interesting, though early, were data presented by the Italian group suggesting that some patients may derive equal benefit in terms of time to disease progression by foregoing high-dose chemo and stem cell transplant – and considerable toxicity – and instead opting for standard therapies (in this case, Rd followed by MPR). It is too early to tell whether there would a difference in progression free survival and/or overall survival but the data will be important to follow.

The session also featured data from another study facilitated by the MMRC – elotuzumab in combination with Rev-dex – presented by Dr. Sagar Lonial of Emory. This trial showed very high (80+%) response rates in a pretty heavily pre-treated population. Moreover, the combination showed the ability to re-sensitize some patients to Revlimid. A Phase II study is now underway and expected to complete accrual in the next couple of months.

The final abstract compares Zometa (zoledronic acid) to clondronate, an oral bisphophonate, in a large UK study of nearly 2,000 patients. The trial not only found that those randomized to Zometa had fewer skeletal related events (fractures, etc) but also enjoyed a survival advantage (even those who did not have bone disease!), suggesting an antimyeloma effect with Zometa. Also encouraging was the fact that the incidence of osteonecrosis of the jaw was low (about 3%) in the group treated with Zometa and the condition was reversible in most of the cases.

In summary, there really is such hope emerging from this meeting. These data indicate that most patients will benefit from extended therapy, provided the benefits outweighs the toxicities – this assessment needs to be made on an individual basis in conjunction with one’s doctor – and that when today’s standard therapies fail, there will be effective options. For more detailed information and expert perspective on these abstracts, be sure to listen to the MMRF webcast which will be posted on the MMRF’s website later this week and features a discussion with Drs. Paul Richardson and Todd Zimmerman.