Multiple myeloma patients with the the deletion of TP53 need better myeloma therapies. Deletion of TP53 can be found by normal cytogenetics testing (as deletion of 17p) or by FISH testing. In myeloma, the presence of the 17p deletion is not a good indicator. Del 17p can be rare at diagnosis (2-11%) but it increases as the disease advances, occurring in up to 50% of patients with advanced-stage disease. This suggests that TP53 plays a role in disease progression. Patients with TP53 usually have a more aggressive disease with a higher prevalence of extramedullary disease and hypercalcemia.
In a recent article in the American Journal of Hematology, investigators at MD Anderson Cancer Center set out to understand which treatments could potentially be more effective for these patients. Because stem cell transplant is a core myeloma therapy, they studied the impact of stem cell transplant on patients with the TP53 deletion. Dr. Muzaffar Qazilbash and others reviewed the outcomes in patients with this deletion after they had received an autologous stem cell transplant.
They compared patients during a six year period (2008-2014) with and without the TP53 gene deletion who received induction therapy using an IMiD (like lenalidomide) and/or a proteasome inhibitor (like bortezomib), followed by a stem cell transplant.
Their results were as follows:
- 62% of patients with and without TP53 deletion achieved at least partial remission after induction and before transplant
- 68% of patients with TP53 deletion relapsed prior to transplant vs. 42% of patients without the deletion
- Median progression-free survival was 8 months with the TP53 deletion vs. 28 months without the deletion
- Median overall survival was 21 months with the TP53 deletion vs. 56 months without the deletion
- Both patients with the TP53 deletion and relapse before transplant had a higher risk of earlier progression
What could be more effective for these patients? The study authors say that the ability of these drugs, followed by transplant and maintenance may not be able to overcome the negative cytogenetic features. Following are some suggested ideas presented in the paper on success found from other groups:
- The HOVON-65/GMMG-HD4 trial suggested that the adverse impact of 17p deletion could be reduced by incorporating bortezomib in both pre-transplant induction and post-transplant maintenance
- The Italian group (GIMEMA) suggested that pre-transplant bortezomib, thalidomide, and dex (VTD) would be beneficial
- The Myeloma Institute at the University of Arkansas reported that Total Therapy 3 (VTD induction, tandem transplants, VTD consolidation and maintenance) overcame the adverse impact of TP53.
- The Bologna 96 study showed higher complete response rates in patients with multiple myeloma who received tandem auto-transplants than in those who received single auto-transplants (33% single vs. 47% tandem), making tandem auto-SCT a promising approach
- One study by Haessler, et al. showed improved overall survival in a small number of patients whose disease had 17p deletion who achieved complete response after receiving tandem auto-transplant, although this beenfit was not seen in the low-risk group.
What didn’t work? Study authors said that the new agents combined with transplant didn’t accomplish the objective:
- A phase III trial by the Spanish Myeloma Group (PETHEMA-GEM), in contrast to the FIMEMA study, found that VTD did not overcome the 17p deletion in high-risk patients.
- Likewise, the French group (IFM) trial IFM-2005-01 compared bortezomib/dex vs. vincristine/doxorubicin/dex (VAD) induction followed by transplant did not show PFS or OS improvement for del17p patients.
It is clear that there is significant room for improvement in the treatment of these patients and a number of new options are being tested. MD Anderson’s Dr. Orlowski has been working specifically on this high-risk feature by targeting a designer drug to knock out a survivin protein that keeps myeloma cells alive, allowing drugs like bortezomib and pomalidomide to do their job. Other suggestions by a variety of centers could include:
- Intense up-front combo therapy (RVD) followed by immediate transplant, then proteasome inhibitors as maintenance.
- Allogeneic transplant, although controversial, is being explored for high-risk patients
- New conditioning regimens like busulfan and melphalan may improve complete response (MD Anderson)
- Cellular therapy directed agains clonal plasma cells is another exciting approach (MD Anderson)
- New approaches targeting intracellular pathways (like MDM2) for del17p patients is also being explored (MD Anderson)
Study author Dr. Qazilbash noted that the research helped show that patients who transplant after relapse do worse than patients transplanted up front. He said:
Transplanting patients earlier in the course, say, after induction therapy, may also improve the outcome.