Most new developments in cancer research tend to occur in increments, thus we see a fair number of improvements in survival (whether PFS or OS) in the 1-4 month range over the existing standard of care. However, as we saw recently at European Conference for Clinical Oncology (ECCO) in September and the San Antonio Breast Cancer Symposium (SABCS) last month with the BOLERO-2 nad CLEOPATRA trials, every once in a while something comes along that shifts the efficacy curve by six or seven months and people rightly get very excited about this.
Imagine then, an improvement in median overall survival by 13 months? Or rather, 13.3 months to be precise? That’s both very exciting and huge for patients and physicians alike.
What was the drug that produced this stunning seismic shift?
VISTA in newly diagnosed elderly patients with MM
At the 2011 American Society of Hematology (ASH) meeting, Professor Jesús San Miguel (Salamanca, Spain) presented the five year results of the VISTA (VELCADE as Initial Standard Therapy in Multiple Myeloma) study. This trial compared triple therapy with bortezomib, mephalan and prednisone (VMP) to the current standard of care, melphalan plus prednisone (MP) in previously untreated multiple myeloma (MM) patients (N=682) who were ineligible for high-dose therapy.
The analysis demonstrated that after a median follow-up of 60.1 months, the median OS was 56.4 versus 43.1 months for patients randomised to VMP and MP, respectively, giving a significant survival advantage of 13.3 months for the VMP arm (p=0.0004).
This is how the survival curves look:
Unfortunately, I wasn’t able to see the actual presentation live as it clashed with so many concurrent presentations on the ‘manic Monday’ of the meeting, but I did talk to Prof San Miguel, who excitedly described the findings as “impressive” despite the fact that “the control arm did very well,” however, “we now know that VMP is the best option in this patient population.”
This was one of those rare times when I thought that ‘impressive’ was perhaps an understatement, especially as the majority of patients could be considered elderly, in the 65-75 age range. Based on this eagerly anticipated data and talking to several myeloma thought leaders at the meeting, there is no doubt that VMP will become the new standard of care for upfront treatment in those patients who are ineligible for high dose treatment and a transplant. It’s a result that is full of win all around.
Secondary Primary Malignancies and Revlimid
The other interesting thing about the data was the incidence of secondary primary malignancies (SPM), a topic that was very much to the for last year for Celgene’s lenalidomide (Revlimid).
Dr San Miguel observed that the background incidence in this elderly population is 1.92, based on SEER data. He also noted that in the VISTA trial, the incidence of SPM was 1.66 SPM per 100-patient-years for the VMP arm versus 1.30 for MP alone. This difference wasn’t significant and in fact, both arms were lower than expected from the SEER data, which is reassuring.
Talking of SPMs, I attended Dr Antonio Palumbo (Torino, Italy) presentation on the last day on a retrospective multifactorial analysis of newly diagnosed patients with MM (N=2,283) who had received Revlimid in European clinical trials (N=9). They sought to try and address if we can anticipate when SPMs were most likely to occur and in which combinations. The median follow-up time for in their analysis was 29 months and the median age was 69 years.
Overall, they found 48 secondary cancers including 10 blood cancers and 38 non-blood cancers.
The data clearly showed that the incidence of SPM with IMiDs was higher in melphalan-based regimens than others:
Dexamethasone ± cyclophosphamide 0.40
Melphalan only: 0.42
We can see from this analysis that while the IMiDs per se don’t appear to cause SPMs, there is clearly an interaction occurring between the IMiDs and melphalan that increases the risk, although the mechanism for this phenomenon is unknown.
The future is bright for MM
Multiple myeloma is now becoming a very dynamic area of clinical research beyond Velcade, thalidomide and Revlimid.
Other emerging agents include carfilzomib, pomalidomide, MLN9708, perifosine, HDACs (panobinostat, romidepsin, vorinostat) and many others.
No doubt we will hear more about these new agents in development going forward either as new combinations or sequencing of multiple therapies, all of which may lead to a cumulative increase in survival for patients with multiple myeloma.