Another hectic ASH has concluded. My pre-ASH expectations were largely confirmed with the full oral and poster presentations. But some important changes in philosophy and strategies for myeloma management emerged. These changes were key discussion points at various educational sessions, including the IMF’s Satellite Symposium on Friday, December 5th and the IMWG Conference Series Debate program on Monday, December 8th.
Considerable attention was focused upon the new IMWG Diagnostic Criteria, with Dr. Vincent Rajkumar as the first author, published in Lancet Oncology in November. This represents a paradigm shift in the approach to early disease. Patients with myeloma-defining events are now considered eligible for treatment. These defining events, which are biomarkers of malignancy, are: bone marrow plasma cells (clonal) of 60% (S = sixty); serum Freelite ratio of ≥100 (LI for light); >1 focal on MRI studies (M for MRI). At the Conference Series Debate, Dr. Joseph Mikhael quipped that we now have “SLIM”-CRAB! Joking aside, this is a major shift to standardize early intervention and improve outcomes for myeloma patients.
The follow-up question is: how should we be managing high risk smoldering myeloma (HR-SMM) patients (excluding the ultra-high risk patients now considered to have myeloma)? This led to an active discussion by the panel on Monday evening. Interestingly, the new aggressive approach to early disease transitioned over to the HR-SMM patients also. There was much more interest in recommending a full myeloma treatment approach to achieve the very best outcomes – within the context of a clinical trial, of course. Options considered included the three-drug carfilzomib/Revlimid/dexamethasone (CRd) approach of Dr. Ola Landgren, as well as a completely new approach of using daratumumab.
The discussions of what options to use for frontline therapy were the most revealing. Based upon the many presentations at ASH this year, some options were clearly preferred. In the transplant setting, a triplet including a proteasome inhibitor was a unanimous choice. Velcade/ Revlimid/dexamethasone was preferred, although Velcade/Cytoxan/dexamethasone (CyBord) was considered an acceptable back-up option. Dr. Landgren referred to the notion of a paradigm shift here, too. Based upon excellent results, many investigators are now using Kyrpolis versus Velcade in this frontline setting, and many were interested to see Dr. Antonio Palumbo’s data with one day per week Kyprolis (along with Cytoxan plus dexamethasone) with results equivalent to the twice per week Kyprolis schedule. This makes the Kyprolis triplets so much more user friendly. This shift in thinking (#175 and #4739) was strengthened by the very robust results of the ASPIRE trial in which Kyprolis Rd was compared with Rd in the 1-3 relapse setting (#79). The superior results with KRd here reflected a likelihood of similar excellent results as already seen in the frontline setting.
For non-transplant patients, the choices were also simplified by the ASH presentations. The update of the FIRST trial consolidated Rd (continuous versus 18 months) as a “standard of care choice” in the elderly (#81) including ≥ 75 years of age. For “fit” elderly patients, however, there was a strong preference for a triplet to achieve the best outcomes, with options including VRD-lite (#3454), CyBord or VMP (#178) (in Europe): very similar to the pre-transplant induction options. And what about up-front transplant? Dr. Philippe Moreau at the educational sessions made a very strong case for the need and value of upfront ASCT. Detractors included Dr. Paul Richardson and Dr. Ola Landgren, for example, who indicated that newer “novel combinations” should provide equal benefit. The problem is that despite probably everyone wanting this to be the case, there is no such “novel combination” which has emerged so far. Thus, for now I am still firmly in the camp of offering up front ASCT to all those who are eligible.
The next question was where might a really effective “novel combination” come from? Considering the relative merits of all the new agents in the pipeline, there was strong agreement that the anti-CD38 antibodies (daratumumab and SAR 650984) offer the best hope of truly enhancing depth of response and improving outcomes (#83, #84, #178, #3474, #4729). Although likely to be approved in patients with relapse/refractory disease (to fulfill “unmet need”), the greatest optimism was to incorporate anti-CD38 therapy into frontline strategies. These results will be for a future ASH.
Of the other new agents presented, there were mixed feelings among ASH attendees about the HDAC inhibitors in the wake of the negative ODAC vote for panobinostat (#32; #33) There was speculation about whether or not the three-month extension for panobinostat review at the FDA will lead to a reversal with an FDA yes vote. The major benefit with CAR-T cell immune therapy in other malignancies has led to some optimism about use in upcoming myeloma trials. The data on the Karyopharm agent selinexor were also noted (#4773). The 67% response rate using selinexor plus dexamethasone in patients with very advanced disease means that investigators will be watching closely as larger studies proceed.
Note was also made of the results with the oral proteasome inhibitors ixazomib and oprozomib, especially in the maintenance setting. Results presented by Dr. Shaji Kumar with ixazomib were especially promising with extended PFS and improvement in response during the maintenance treatment (#82). With the oprozomib (#34), there were concerns about the formulation of this oral agent, which is now provided with a “stepped-up” version—an extended-release 240 mg/day capsule designed to overcome the GI and other toxicities. Initial results are encouraging with the new formulation.
There was quite a bit of interest in a new approach to new drug evaluation presented by Dr. Philippe Moreau, who combined daratumumab with many of the standard novel combinations to assess efficacy and toxicity. This is a rapid way to screen many different combinations. In this case, it was especially interesting that daratumumab combined with pomalidomide plus dexamethasone was very effective, producing one stringent CR. Tolerance was assessed as well as the ability to harvest stem cells after such combination therapy.
We will touch on a number of other trends in upcoming blogs, but hopefully this will give you a flavor of how “fine-tuning” is leading to clearer decisions and recommendations for better outcomes for patients. So as always stay tuned.