DETERMINATION and IFM 2018-04 Clinical Trials and New Approaches to Relapsed Disease
The American Society of Clinical Oncology (ASCO) was held from June 3–7 in Chicago, IL, and the European Hematology Association (EHA) was held from June 9–12 in Vienna, Austria. This year, both ASCO and EHA annual meetings were held in hybrid format. This has been a remarkable year for myeloma research, with great work being done by investigators from around the world.
DETERMINATION Clinical Trial
Only four of the most prominent abstracts (from ALL cancers) were selected to be presented at ASCO’s prestigious plenary session. Typically, the studies presented are large and practice-changing. This year, the final abstract of the ASCO plenary was the DETERMINATION clinical trial (abstract LBA4) presented by Dr. Paul Richardson.
I had the privilege of being the discussant, where an expert in the field puts the abstract into clinical context for the attendees. In this phase III study, patients were randomized to receive the triplet combination therapy of Velcade® (bortezomib) + Revlimid® (lenalidomide) + the steroid dexamethasone (VRd) as induction therapy, followed by transplant, then maintenance with Revlimid until disease progression vs. VRd with no transplant, followed by maintenance with Revlimid until disease progression.
The study met its primary endpoint of improved progression-free survival (PFS) in the transplant group. Patients who had a transplant stayed in remission 21 months longer than those who did not have a transplant—clearly demonstrating the ongoing benefit of transplant in myeloma. This also supports the use of long-term maintenance therapy with Revlimid.
However, when overall survival (OS) was compared between the two study groups, it was essentially the same. So, although transplant patients stayed in remission longer, this did not translate into a survival advantage in the long term.
Published a few years ago, the Intergroupe Francophone du Myélome (IFM) clinical trial also demonstrated that transplant improved PFS but not OS, although nearly 80% of patients in the non-transplant arm in that study had a transplant at first relapse, suggesting that transplant can be done upfront or at first relapse. In the DETERMINATION study, only 28% of patients in the non-transplant arm had a transplant later – and there was still no OS advantage.
So, what does this mean? There are many opinions about this study and how necessary transplant really is in myeloma. Transplant remains an important part of therapy, but it may not be required at frontline and could be considered at relapse. Given the growing trend of increased treatment options in myeloma, one-size-fits-all no longer fits every patient. This further emphasizes the need for discussion between the healthcare team and the patient to decide what may be best for the individual patient.
Another important feature to the DETERMINATION clinical trial is that 19% of patients were of African descent – this is unprecedented in a large clinical trial in myeloma. Although African Americans comprise 20% of all myeloma patients in the United States, they are typically underrepresented in clinical trials, with an average of 8% – and often even lower in phase III studies. As we seek to reduce the healthcare disparities in myeloma, this greater inclusion is more reflective of the true myeloma population and is to be commended.
IFM 2018-04 Clinical Trial
Another study of note presented at ASCO was the IFM 2018-04 clinical trial (abstract 8002) evaluating the combination therapy of Darzalex® (daratumumab) + Kyprolis® (carfilzomib) + Revlimid + dexamethasone (D-KRd) in high-risk myeloma patients. Although there were only 50 patients in the study and the follow-up remains short, it is encouraging to see deep responses with this quadruplet approach in patients who typically have lower response rates and duration of response. This study also showed that we should plan on collecting stem cells after 3 cycles of D-KRd, as it was harder to collect stem cells after 6 cycles as initially planned. As more quadruplet therapies are being used in myeloma, this study will be helpful to guiding our choices in the frontline setting.
New agents, new combinations
The majority of myeloma-related abstracts presented at both ASCO and EHA meetings included new agents and new combinations in relapsed disease. Blenrep® (belantamab mafodotin) is highly effective when given as monotherapy, but causes keratopathy in the majority of patients, many of whom experience dry eyes or reduced visual acuity. The DREAMM-5 clinical trial (abstract 8019) showed that when given with a gamma secretase inhibitor (nirogacestat), a lower dose of Blenrep results in less keratopathy but maintains the response rates.
Other studies presented included the DREAMM-6 arm-A interim analysis of Blenrep in combination with Revlimid (abstract 8017) and the DREAMM-4 clinical trial with pembrolizumab (abstract 8018). We will likely see Blenrep used in more combination therapies, following the trend of a drug proving itself as monotherapy, then validating its use in combination with other agents.
Arguably, the most exciting area of research in myeloma right now is in CAR T-cell therapy, and we saw many advances discussed at ASCO and EHA, such as the following:
- Making it “at home” (abstract S103) – There was a fascinating presentation at EHA of an academic center manufacturing CAR T cells themselves, without an outside industry partner. If centers could manufacture them locally, this could potentially herald greater access to CAR T-cell therapy. Interestingly, they were also able to provide a booster dose of CAR T cells, which may be able to prolong the benefit of the therapy.
- Using it earlier (abstract S185) – Two types of CAR T-cell therapy have been approved by the FDA for myeloma patients who have had at least 4 prior lines of therapy. Carvykti™ (ciltacabtagene autoleucel) is being evaluated in patients with 1–3 prior lines of therapy. The CARTITUDE-2 study data was updated to show that the very deep and durable responses we see in late-line therapies are now being reproduced in earlier settings.
- Modifying the product – Manufacturing CAR T cells is a very complex process with many variables that can be altered to enhance it. One study (abstract 8005) produced CAR T cells much faster (in 3 days) but it still took several weeks for the process to be completed. Another study (abstract 8003) used a different method of manufacturing to potentially create a more durable CAR T-cell product.
- Targeting new antigens (abstract 8004) – The two CAR T-cell products already approved by the FDA bind to B-cell maturation antigen (BCMA) on myeloma cells. Now CAR T cells are being developed that can bind to G protein- coupled receptor, class C group 5 member D (GPRC5D). This may be particularly important when patients have previously been treated with a BCMA-targeting therapy.
In the prior edition of Myeloma Today, I explored the emerging treatment of bispecific antibodies. The pace of their development is striking as we saw abstracts updating us on many molecules:
- Teclistamab (abstract 8007) is the most advanced bispecific agent. Updated results continue to show a response rate of approximately 60% in patients with heavily relapsed myeloma with side effects that are mostly predictable and manageable, including cytokine release syndrome (CRS).
- Elranatamab (abstract 8006), another bispecific that targets BCMA, was studied to reduce CRS by using
- a step-up dosing strategy that may make the drug easier to give.
- REGN 5458 (abstract S189), another bispecific that targets BCMA, showed reduced rates of higher-grade CRS.
- Talquetamab (abstract 8015) and RG6234 (abstract S180) are two bispecifics that target GPRC5D. Having multiple targets on the myeloma cell will likely improve our ability to control myeloma for longer periods of time.
Several clinical trials are exploring combinations of bispecifics with other drugs, with even a prospect of using two bispecifics together. This will continue to expand the options we will have for our patients in the coming years.
Many other studies are demonstrating the incredible research being conducted in myeloma. New agents like iberdomide (abstract P865) and modakafusp (abstract S181) might be available soon, while the FDA-approved anti-CD38 monoclonal antibody Sarclisa® (isatuximab) is currently being developed for subcutaneous administration (abstract 8025).
It is both exciting and gratifying to see the sheer volume of myeloma studies, with many new drugs being developed at an incredible pace. We trust this will continue as we seek to find the cure for this awful disease and, until such time, to prolong the survival of patients with the best quality of life possible.
(This article was published in the 2022 Summer Edition of the IMF's quarterly publication, Myeloma Today. Read the full publication here.)