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Hello, my name is Stefan Knop I'm with Würzburg University Hospital in Würzburg, Germany, and we arrived here at ASCO 2017 in Chicago. In the following minutes I will summarize the main results from our DSMM 14 study. The DSMM 14 trial was originally designed to compare two induction regimens. One with two versus one with only one novel drug. As you know, still in 2017, multiple myeloma is best being treated by induction chemotherapy, autologous stem cell transplant, and maintenance. However, we don't have yet, a definite standard for induction defined.
There were convincing results for progression free survival utilizing Revlimid, autologous stem cell transplant, or Revlimid maintenance. And also with bortezomib induction, autologous stem cell transplant, and bortezomib maintenance. The combination of bortezomib, lenalidomide and dexamethasone was particularly effective in the setting. And very recently the French group could also demonstrate that its efficacy is still enhanced by autologous stem cell transplant.
We have pioneered a phase two study utilizing lenalidomide, Adriamycin, and dexamethasone followed by double stem cell transplant, and one year fixed duration lenalidomide maintenance. And this was the basis for the current DSMM 14 protocol, which was designed according to a two by two factorial design.
The first randomization compares three induction cycles, lenalidomide, Adriamycin, dexamethasone, RAD, versus three cycles of bortezomib, lenalidomide, and dexamethasone, VRd. All patients proceed to uniform autologous stem cell transplant.
The second randomization randomizes patients who have achieved at least very good partial response, to immediate maintenance versus the second auto transplant followed by lenalidomide maintenance.
While, in the third randomization, patients who have not yet received VGPR after the first autologous transplant are randomized between a second auto versus auto/allo- transplant. Both transplant regiments followed by lenalidomide maintenance treatment.
This slide summarizes the induction regiments on the upper half of the panel you can see the RAD protocol. Lenalidomide was administered in the conventional fashion, three weeks on, one week off. Four days of consecutive Adriamycin push infusions, and two 160 milligram blocks of dexamethasone from days one to four and 17 to 20. All patients were to receive pegfilgrastim to prevent chemotherapy induced febrile neutropenia.
On the lower hand of the panel you can see the VRd protocol. Lenalidomide was administered for 14 days followed by one week off. The conventional fashion of bortezomib on days one, four, eight and 11. Then 20 milligrams of dexamethasone on each bortezomib day and the day after.
The primary endpoint of this study phase was the rate of complete remission or stringent complete remission at first restaging, which means after three cycles of induction regiment. The other endpoints are not yet mature. The second co-primary efficacy endpoint is a progression free survival at three years for those groups of patients who did not yet achieve very good response or better.
This table summarizes the patient characteristics as typically in such a patient cohort, the median age was well below 60 years of age. With around 18-20% of patients with adverse serologic factors, which means elevated beta-2 microglobulin or elevated LDH. High-risk cytogenetics in terms of deletion 17p or translocation 4:14 are present in approximately 11 to 12% of patients. All the patient characteristics were well-balanced between the two treatment arms.
Now let's move to the primary endpoint of the study phase. Post-induction CR and stringent CR rate. The table in the right upper half of the panel summarizes rates for either induction regiment. You can see VRd induced CR and stringent CR rates in 13% of patients, while RAD treated patients achieved CR and stringent CR in 11.8%, and this of course was not statistically significant. The cumulative rates of VGPR and better were slightly higher in a percentage value for the VRD patients, 46%, which is perfectly in the middle for the two arms from the French group, 45 versus 47. While in our study, patients who had received RAD induction achieved 39% of VGPR and better.
The median restaging procedure was performed quite briefly after end of the third induction cycle in a median of 33 days beginning the third RAD cycle, versus 29 days from start of the third VRd cycle. With only very few early progression events, and stable diseases only in the range of five to seven percent of patients.
The next efficacy measured in our protocol was minimal residual disease. We had the opportunity to perform MRD evaluation according to the Euroflow next generation flow protocol with an enhanced composition of two antibody tubes with each eight colors. A target cell count of 10 million events was gated, and in fact, we had 4.3 million events in median for every bone marrow sample, which was analyzed at baseline as well as post induction.
We were able to reach a median sensitivity level of 6 times 10 to the minus 6. 318 paired baseline and post induction samples were evaluable and 278 were informative both at baseline and post induction. Slightly more patients in both arms already reached MRD negativity, when compared to conventional IMWG response. 21% for patients who had received RAD induction versus 27% after VRd, but again this difference was not statistically significant.
What about tolerability? This table summarizes for the set of 469 patients who received at least one dose of studied drug. The grade 3 entire treatment-emergent adverse events. The induction mortality was surprisingly low. One patient in the VRd arm died due to a cardiac event. For an overall unsteady mortality of 0.2% during the induction phase. With comparable rates of hematologic toxicities between both arms. Round about 1.5% febrile neutropenia and about 2.5% of thrombocytopenia. With a slightly higher rate of grade 3 and higher infections and infestations, namely pneumonia with RAD versus VRd. We had a rate of about 1.5% of venous thromboembolic events with no advantage for one protocol over the other. With a low rate of cardiac events however, one patient in the VRd arm died due to a cardiac arrest, and we had a slightly higher, but still acceptable rate of 2% of grade 3 and higher bortezomib induced polyneuropathy.
So in conclusion, after we had established RAD as an induction protocol in a prior phase two study, thereby, identification of low-risk disease group by the absence of high-risk cytogenetic factors as well as low expression of mRNA levels regarding Ikaros, the transcription factors. We move with this protocol to phase three. In the current study, we had a post induction complete response rate, as a co-primary endpoint. And surprisingly there was no statistically significant difference for either treatment arm.
There was a tendency toward a higher VGPR and better rate for patients who had received VRd versus RAD induction, but without reaching the level of statistically significant differences. The safety profile was excellent for either induction protocol. The treatment related mortality was 0.2%. One patient had died in the VRd arm due to cardiac events and interestingly, bortezomib needed the most frequent dose reductions during the induction period of all four induction drugs utilized. Of course, we need to await the time dependent endpoints progression free and overall survival to see whether one could speculate VRd of the induction protocols might emerge as superior over the other. And with saying this, I wish to thank you for your attention.