By strange coincidence this morning I was listening in to the Celgene R&D Day presentations including an update on their plans for their iMiD therapies thalidomide (Thalomid) and lenalidomide (Revlimid), while reading a couple of interesting papers about Millennium-Takeda's bortezomib (Velcade) that were just published in the Journal of Clinical Oncology last month and another this week for the treatment of multiple myeloma. All three of these drugs have changed the treatment of multiple myeloma from a certain death sentence to a treatable disease.
I'll post more about the Celgene pipeline in a later post, but the papers are well worth sharing and discussing. One report looked at the phase III data for the VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma) trial. This study was presented at the recent American Society of Hematology (ASH) meeting in December (see previous post), but the paper now includes updated survival data in a large cohort of 682 people:
"With a median follow-up of 36.7 months, there was a 35% reduced risk of death with VMP versus MP (hazard ratio, 0.653; P < .001); median OS was not reached with VMP versus 43 months with MP; 3-year OS rates were 68.5% versus 54.0%. Response rates to subsequent thalidomide (41% v 53%) and lenalidomide based therapies (59% v 52%) appeared similar after VMP or MP; response rates to subsequent bortezomib-based therapy were 47% versus 59%.
Among patients treated with VMP (n = 178) and MP (n = 233), median survival from start of subsequent therapy was 30.2 and 21.9 months, respectively, and there was no difference in survival from salvage among patients who received subsequent bortezomib, thalidomide, or lenalidomide. Rates of adverse events were higher with VMP versus MP during cycles 1 to 4, but similar during cycles 5 to 9. With VMP, 79% of peripheral neuropathy events improved within a median of 1.9 months; 60% completely resolved within a median of 5.7 months."
The bold for emphasise is mine, but anytime you see a greater than 30% reduced risk of death from a treatment, one is bound to sit up and take notice, especially if you have a loved one suffering from the disease.
What do these results mean? Well, in practice they clearly demonstrate that VMP significantly prolongs OS versus MP after lengthy follow-up and extensive subsequent therapy for myeloma. What was particularly encouraging is that first-line bortezomib use does not induce more resistant relapse, which is also important for people sufffering from the disease.
The combination of VMP used upfront therefore appears more beneficial than first treating with conventional agents such as melphalan and prednisone and saving bortezomib and other novel therapies until relapse. Historically, oncologists often leave the big guns in their back pocket, but the data from this trial may well change their thinking about treatment strategies in multiple myeloma, at least.
The second paper examined the effect on minimal residual disease, by qualitative and real-time quantitative polymerase chain reaction (RQ-PCR), of a consolidation regimen that included the combination of bortezomib (Velcade), thalidomide (Thalomid), and dexamethasone (VTD) in people with multiple myeloma who responded to autologous stem-cell transplantation (auto-SCT). Although the results are more preliminary – this was a phase II trial with only a small number of patients (n=39) – they are very encouraging indeed.
This study is particularly important because it may be the first to document the occurrence of persistent molecular remissions (almost undetectable disease) in a proportion of people with multiple myeloma treated without allogeneic transplantation. To put this is context, until now, a transplant was the only known curative treatment that has been shown to induce molecular remission, so to achieve that state with therapy alone is something that will give many people goosebumps.
Because SCT are associated with 20% treatment related mortality alone, so if that number can be reduced by excluding the risk of death, then it offers hope not just for those who are ineligible for a transplant, but as another option for those who are.
The researchers also noted that:
"The major reduction in tumor load recorded by RQ-PCR after VTD suggests that unprecedented levels of tumor cell reduction can be achieved in MM thanks to the new nonchemotherapeutic drugs."
That's all sorts of awesome news, albeit in a small study, but it does augur well for the future if the results can be repeated in a phase III study.
Ladetto, M., Pagliano, G., Ferrero, S., Cavallo, F., Drandi, D., Santo, L., Crippa, C., De Rosa, L., Pregno, P., Grasso, M., Liberati, A., Caravita, T., Pisani, F., Guglielmelli, T., Callea, V., Musto, P., Cangialosi, C., Passera, R., Boccadoro, M., & Palumbo, A. (2010). Major Tumor Shrinking and Persistent Molecular Remissions After Consolidation With Bortezomib, Thalidomide, and Dexamethasone in Patients With Autografted Myeloma Journal of Clinical Oncology DOI: 10.1200/JCO.2009.23.7172
Mateos, M., Richardson, P., Schlag, R., Khuageva, N., Dimopoulos, M., Shpilberg, O., Kropff, M., Spicka, I., Petrucci, M., Palumbo, A., Samoilova, O., Dmoszynska, A., Abdulkadyrov, K., Schots, R., Jiang, B., Esseltine, D., Liu, K., Cakana, A., van de Velde, H., & San Miguel, J. (2010). Bortezomib Plus Melphalan and Prednisone Compared With Melphalan and Prednisone in Previously Untreated Multiple Myeloma: Updated Follow-Up and Impact of Subsequent Therapy in the Phase III VISTA Trial Journal of Clinical Oncology DOI: 10.1200/JCO.2009.26.0638