The IMF team just returned from an extremely busy and exciting meeting of the American Society of Hematology (ASH) in Orlando. What are the key takeaways from the myeloma research presented at this important event? Here is the news I found to be the most important.
There is a consensus that the new criteria for high-risk smoldering multiple myeloma (HR-SMM) can reliably guide our classification of patients with smoldering myeloma for now. The 2/20/20 system (M protein spike greater than 2 g/dL; bone marrow plasma cells greater than 20%; and free light chain ratio greater than 20) has been validated by the International Myeloma Working Group (IMWG). It has been enhanced to include a scoring system (for which there will soon be an IMF app) and can be more broadly applied to identify patients with HR-SMM as a basis for decisions about their management. ]
The results of the first CURE trial, the CESAR Trial, were presented at ASH. Results continue to be very good, with progression-free survival (PFS) of 94% at close to 3 years, and 98% of patients alive. Since 62% of patients achieved MRD-negativity at 10-to-the-minus-6 level (as measured by next-generation flow [NGF]), there are high expectations that sustained remissions will occur in a substantial percentage of patients.
With such promising early results, there is less enthusiasm about single-agent or less aggressive treatment approaches to HR-SMM that do not offer this level of benefit. HR-SMM is very early active myeloma and should be considered and treated in that fashion.
To help evaluate the potential of the curative approach used in BSRI-supported CURE trials, mass spectrometry testing was performed. It showed that this extremely sensitive method for measuring myeloma protein in the blood can help indicate if the disease is truly eliminated in all sites. One patient, who was found to be MRD-negative by NGF, had protein detected by mass spectrometry. This was the only patient who relapsed.
More follow-up is required, but there was a lot of interest and excitement about the value of mass spectrometry testing and its applications throughout the spectrum of myeloma disease monitoring, including its use in key clinical trials.
The pressing question in the frontline setting is whether a four-drug cocktail (a quadruplet) will be the new standard of care in myeloma. Multiple studies at ASH presented information about various quadruplet options, including: dara-VRd (the Griffin study), dara-VTd (the Cassiopeia study), dara-VMP (the Alcyone study), dara-KRd, and dara-IRd.
Although three-drug combinations are clearly very effective, there is added benefit—with deeper and more sustained responses—with the quadruplets. Since it is ideal to achieve the very best response as the primary approach, there is a sense that this is what should be attempted, despite concerns about logistics, costs, and potential added toxicities and/or tolerance issues.
Will quadruplets actually be used in practice? It is hard to say. However, such triplets as VRd or DRd represent excellent treatment options and they will remain the global standards for quite some time to come because of access issues. Treatment selection will also continue to be driven by patient perspective, risk status, age, frailty score, and co-morbidities at the individual patient level.
Will more detailed precision-medicine approaches emerge? At ASH this year there was a focus on the impact of the 1q+, t(4;14), and t(11;14) chromosomal abnormalities. It seems clear that a combination of 1q+ plus t(4;14) is a definite high-risk group that deserves special attention. In addition, the follow-up analyses of the t(11;14) patients in the Bellini trial demonstrated the substantial benefit of venetoclax (combined with bortezomib (Velcade®) plus dexamethasone for this subset. Since t(11;14) patients may or may not have very high Bcl 2 expression, there is a sense that the major focus should be on the t(11; 14) abnormality. Further follow-up and additional trials are required.
Dominant Immune Therapy Presentations
As I noted in my ASH 2019 Preview blog, there was tremendous interest in the results obtained with CAR T-cell therapies, the bispecific T-cell engagers (variously called TCEs, BiTEs, and BEATs), and monoclonal-antibody approaches. So, what are the takeaways for these approaches, which all use the B-cell maturation antigen (BCMA) target?
- First, there was strong appreciation for the follow-up of the original Chinese Legend CAR T-cell presentations and data, and for the U.S. CARTITUDE study data on JNJ-4528, the Legend CAR T product now under development by Janssen. The results with JNJ-4528 replicated the Chinese findings of a high response rate and excellent tolerance. The FDA awarded JNJ-4528 “breakthrough” status, which will move it closer to potential approval in 2020.
- Second, the results with the new bispecific T-cell engager (TCE-CC-93269) were also very promising, with excellent dose-related responses and no unexpected toxicities.
- And third, as in the past, the results with GSK2857916 (belantamab mafodotin or “bela,” for short) also continued to be very promising, with a high response rate in refractory patients and good tolerance, except for concerns with corneal irritation and some degree of neutropenia.
How will these agents move into clinical practice? This is the $64,000 question! The GSK antibody-drug conjugate, bela, will probably move forward most quickly. It will be attractive as a widely available, off-the-shelf product against the BCMA target known to be so important for patients for whom all other drugs have failed. It also has the advantage that it is active at lower levels of BCMA expression because the internalized drug conjugate, a cellular toxin, helps destroy myeloma cells.
Nonetheless, the CAR T-cell data are very strong, showing rapid, deep responses. This is a decisive new approach with incredible potential. The downside is that it is not off-the-shelf, requires three to four weeks’ engineering and processing time, and is intrinsically much more cumbersome and expensive to make broadly available. The duration of the response will be key (especially in light of the cost) in highlighting the comparative benefit of this therapy. Moving forward, it is obvious that additional and better CARs will be developed very rapidly and may have even more powerful and lasting benefit. The future is bright but uncertain as we head into 2020.
Results are also promising for the new T-cell engagers. Their efficacy may challenge CARs, even with new CARs coming down the pike! Their off-the-shelf availability will also prove attractive. They may provide an opportunity to use this BCMA approach after a CAR-T therapy. Likewise, the GSK compound may be helpful after CAR-T therapies in order to eliminate clones with lower BCMA expression. The sequencing of these agents will be a major focus of upcoming clinical trials, as well as laboratory research investigating resistance mechanisms.
Lots of information needs to be gathered, and the IMWG is committed to establishing a registry for the therapies targeting BCMA, as well as standardizing MRD testing and assessment of toxicities, such as cytokine release syndrome (CRS).
I will need to renew my membership in the Futurist Society to predict how uses of these new treatments will truly emerge in practice. But the future is very bright: the use of these powerful immune therapies will undoubtedly save the lives of many relapsing patients and contribute to decisive responses and potential cures when integrated into our already strong armamentarium of other agents available earlier in the disease course.
New Agents and Combinations
Also seen at ASH: many newer agents and combinations, plus studies with completely new agents. The results of the CANDOR trial, which compared carfilzomib (Kyprolis®), dexamethasone, and daratumumab (Darzalex®) (KdD) to carfilzomib and dexamethasone (Kd) in relapsed/refractory patients, were presented as a late-breaking abstract. Median PFS was not reached for KdD versus 15.8 months for Kd, a highly significant benefit. KdD is especially attractive for patients exposed to and/or refractory to lenalidomide (Revlimid), a population that requires good new options. It will be possible to consider a once-a-week schedule for the Kyprolis and subcutaneous injection (versus intravenous) for the daratumumab.
Other interesting agents include melflufen (a newer type of alkylating agent) and iberdomide, a CELMoD (similar to, but more potent than, an IMiD).
The Bottom Line
This was a very productive ASH, with much new information to digest, an abundance of data that can lead to new FDA approvals, and numerous agents showing promise in clinical trials. Undoubtedly, 2020 will be an exciting year!
Dr. Brian G.M. Durie founded and now serves as Chairman of the International Myeloma Foundation and serves on its Scientific Advisory Board. Additionally, he is Chairman of the IMF's International Myeloma Working Group, a consortium of nearly 200 myeloma experts from around the world. Dr. Durie also leads the IMF’s Black Swan Research Initiative®.