Expert Selections From ASH 2020: Multiple Myeloma

In this commentary, Shaji K. Kumar, MD, and Sagar Lonial, MD, share insights on selected abstracts from ASH 2020 about multiple myeloma (MM) and how these data are poised to affect clinical practice.

Newly Diagnosed MM

Shaji Kumar, MD:
With the addition of new agents, the treatment of newly diagnosed MM has greatly improved over the past decade. It is interesting to see that, with these regimens in the upfront setting, we are easily looking at 4-5 years of freedom from progression after diagnosis, which is quite significant progress. In the ASCT‑eligible patient population, the IFM 2009, CASSIOPEIA, and GRIFFIN trials all have shown that VRd is a very effective combination regimen. The question now is whether to continue using VRd or to transition to quadruplet therapy with VRd plus daratumumab for initial therapy.

Sagar Lonial, MD:
The phase II GRIFFIN trial included ASCT-eligible patients with newly diagnosed MM who were randomized to receive D-VRd followed by D-R maintenance or VRd followed by R maintenance. In an updated analysis of GRIFFIN presented at ASH 2020, D-VRd followed by D-R maintenance led to significant improvements in sCR and depth of response compared with VRd followed by R maintenance. Many patients had achieved sCR at the 12-month maintenance cutoff: 63.6% of the D-VRd group compared with 47.4% of the VRd group (P = .0253). Responses deepened over time, with more patients in the D-VRd group achieving ≥ CR compared with previous analyses (P = .0014).

I think that the paradigm is moving toward 4- vs 3-drug combinations in fit patients who can tolerate intensive therapy because there seems to be a clear benefit for early intensive therapy based on the rates of sCR/CR and MRD negativity in these trials.

For frail patients, things are more complicated. First, I think we need better tools to define frail patients than the arbitrary age cutoff of 65 years. Second, for the truly frail patient, 4-drug therapies are more difficult due to the increased need to minimize toxicity. Selecting an appropriate therapy from the outset is very important for frail patients because they may not get a second chance at therapy. Regimens such as the one in MAIA clearly demonstrate very long, durable responses. TOURMALINE-MM2 suggests that all-oral approaches can offer significant benefit for frail, elderly, renal‑compromised patients, as well.

The second piece we need to consider for newly diagnosed MM is the continued role of ASCT in patient management. If we were to summarize the big highlights of ASH 2020, bispecific antibodies would be one, but so would the resurgence of ASCT. A few studies clearly demonstrated the benefit of high‑dose therapy not just in achieving deep responses, but also in achieving durable MRD negativity. As I mentioned earlier, durable MRD negativity is becoming a very important benchmark in the clinic. It is clear from many studies presented at ASH 2020 that ASCT allows a more durable, MRD‑negative PFS.

Shaji Kumar, MD:
I agree. It is important to remember, when looking at the various regimens we have available for first-line therapy, to also consider ASCT and appropriate maintenance therapy to maximize the response to induction and maintain this long duration of a disease-free interval for patients with MM after their initial diagnosis.

Treatment Options for Patients with R/R MM: Newly Approved Agents

Sagar Lonial, MD:
At ASH 2020, the goal of the selinexor and belantamab mafodotin combination studies was to bring these recently approved agents into earlier lines of therapy while building on the success of current MM therapy backbones. When combining drugs, we often need to tweak the dosing schedule to make them more tolerable. In the STOMP study, this meant once-weekly dosing for selinexor in combination with pomalidomide/dexamethasone. In the ALGONQUIN study, the dosing frequency for belantamab mafodotin also was different from when it is given as a single agent. These trials help show us how best to combine these newer agents and use them in our daily practice.

Shaji Kumar, MD:
Yes, it is very interesting how these new agents are being used and introduced into earlier lines of therapy. As we discussed for patients with early relapse, we combine anti‑CD38 antibodies with IMiDs or PIs so, by the time a patient experiences a second or third relapse, they are often refractory to these various classes of MM therapies. The trials combining selinexor and belantamab mafodotin with standard-of-care agents can provide important data on the potential for use in earlier relapse.

These data also make me wonder whether these drugs can move even earlier—to the first relapse setting—potentially replacing or being used in combination with anti‑CD38–based therapy, as has been done with selinexor and daratumumab combinations. How we use and combine PIs, IMiDs, selinexor, monoclonal antibodies, and BCMA‑targeted therapies such as belantamab mafodotin are clearly improving the outcomes for patients with MM, and additional trials will continue to build upon this for optimal outcomes.

Treatment Options for Patients with R/R MM: Anti-BCMA Targeted Agents

Shaji Kumar, MD:
Many exciting immunotherapy approaches targeting BCMA for patients with R/R MM were presented at ASH 2020. Several trials assessed different CAR T-cell therapies in addition to other immunotherapy approaches, such as bispecific antibodies and antibody–drug conjugates. The CAR T-cell trials discussed here have clearly shown the proof of principle for targeting BCMA in R/R MM, and the other BCMA-targeted immunotherapies are quickly catching up.

Overall, the results from the CARTITUDE-1 study of ciltacabtagene autoleucel, the CRB-402 study of bb21217, the PRIME trial of P-BCMA-101, and the UNIVERSAL study of ALLO-715 suggest that anti-BCMA CAR T-cells are effective and provoke an immune response in patients with MM. This has been a real concern, as patients with MM are exposed to so many drugs throughout the course of their disease.

This year, the CAR T-cells we mentioned also highlight some of the nuances that healthcare professionals and researchers are considering to improve on the current paradigm for CAR T-cell therapy. Skewing CAR T-cells to a memory phenotype, as was done with bb21217, may improve their persistence. Use of transposons and nanoplasmids as vectors can decrease both manufacturing time and cost. Allogeneic CAR T-cells offer the ability to use an off-the-shelf product. The speed to treatment is especially important in the R/R setting, where patients cannot wait very long to get their own T-cells manufactured and brought back.

Sagar Lonial, MD:
I am impressed with the evolution from the first CAR T-cells into modern CAR T-cell therapies with improved efficacy, durability, and safety.

Many of us were initially disappointed with the long-term efficacy of CAR T-cells in myeloma, but these studies give us hope that there will be subtle nuances that help improve the overall efficacy of this approach.

Shaji Kumar, MD:
I agree. Another key for improving efficacy of the CAR T-cell therapies in MM is going to be using them in earlier settings. I hope there will be more durable responses as these trials progress.

Bispecific antibodies represent another new approach for targeting BCMA that has shown promise in MM. The premise is similar to that of CAR T-cell therapy, in that these molecules harness the power of the body’s own T-cells to develop an anti-MM response that can lead to disease control. Unlike with CAR T-cell therapy, which requires apheresis and manufacturing, bispecific antibodies are designed to bring normal T-cells close to myeloma cells in the body, resulting in an immune synapse formation and cell killing. Bispecific antibodies are recombinant proteins made up of 2 single-chain variable fragments or antibodies linked together: 1 targeting a T-cell surface molecule, such as CD3, and 1 targeting an antigen common to a specific type of cancer cell, such as BCMA for MM. Of importance, bispecific antibodies are available “off the shelf” for patients but do generally require repeated dosing.

Several bispecific antibodies for MM are currently in clinical trials. One of the first bispecific antibodies to be tested in the clinical trial setting was the BCMA-/CD3-targeted bispecific antibody pavurutamab (AMG 701) and its precursor molecule, AMG 420. Although the first-generation bispecific antibodies had to be infused frequently, subsequent generations have modifications and can be given weekly or even less often.

At ASH 2020, results from the dose-escalation phase I study of pavurutamab suggested that a BCMA-targeted bispecific antibody approach with pavurutamab can be quite effective in a heavily pretreated group of patients with R/R MM. Another BCMA-/CD3-targeted bispecific antibody in early clinical trials for R/R MM is teclistamab and results showed that this agent is clearly another active BCMA-targeted bispecific antibody. Data for several other bispecific molecules were presented during the meeting, including REGN5458, and all of these agents show promise for patients with R/R MM.

Sagar Lonial, MD:
In considering these trials of anti-BCMA bispecific antibodies and T-cell engagers, we are currently where we were with anti-BCMA CAR T-cell trials approximately a year ago. Each of these agents has significant activity—more than I expected from this class of therapy, given that the T-cell health of patients with refractory myeloma has historically been poor. Now that we see these feasibility studies, we need data with larger patient numbers and longer follow-up to start to understand whether the subtle structural differences in each bispecific antibody translate into clinical differences, as well.

Shaji Kumar, MD:
The bispecific antibodies open the myeloma field for immunotherapies. One of the disadvantages with the CAR T-cell, in addition to the waiting time with manufacturing, is the fact that only a limited number of institutions have the needed infrastructure for administration of CAR T-cell therapy and management of patients after they receive the therapy.

By contrast, the use of bispecific antibodies will allow many more institutions and hospitals to provide this type of therapy for patients, and it can be given in a timely fashion. Of most importance, these novel treatments can be combined with other anti-MM therapies, which makes them attractive in earlier lines of therapy, including the frontline setting, where we have many other effective drugs. We hope that using these anti-BCMA therapies in combination with various backbones will allow us to get these patients into deep responses.

Sagar Lonial, MD:
More therapies coming to the party in myeloma is a good thing. The last anti-BCMA therapy I will mention is the antibody–drug conjugate MEDI2228, which has a slightly different mechanism of action than belantamab mafodotin. MEDI2228 is linked to a toxin called PBD (pyrrolobenzodiazepine) and, at ASH 2020, data were presented from the first-in-human, open-label, dose escalation phase I study with MEDI2228.^[71,72] Overall, the MEDI2228 data were promising and all of these approaches with CAR T-cells, bispecific antibodies, and antibody–drug conjugates are welcomed to see whether we can make a difference overall.

Treatment Options for Patients with R/R MM: Other Novel Agents in Clinical Development

Sagar Lonial, MD:
One new agent of interest is iberdomide (also known as CC-220): an oral, potent, novel cereblon E3 ligase modulator (CELMoD) that enhances targeted degradation of proteins including the MM-relevant transcription factors Ikaros and Aiolos. In an ongoing open-label, dose-escalation, dose-expansion phase I/II trial, both iberdomide-Dd and iberdomide-Vd have shown a favorable safety profile in pretreated patients with R/R MM. The results also suggested promising antimyeloma activity, even in patients who are refractory to IMiDs, PIs, and/or anti-CD38 antibodies.

Shaji Kumar, MD:
These data are interesting, especially with newer IMiDs coming along. Having the luxury of more than just lenalidomide and pomalidomide in this class of drugs is going to be important for building new regimens, along with other immunotherapies. But I think the importance of iberdomide goes far beyond what has been shown here, because it sets the stage for additional combinations in the upfront setting.

Sagar Lonial, MD:
I completely agree and think it is an exciting time for drug combinations in earlier lines of therapy—and to perhaps challenge the idea that treatment for first relapse is a daratumumab-based combination. We will just have to see how it plays out with phase III studies.

Shaji Kumar, MD:
There are also a number of immunotherapies with novel targets and multiple types of products (CAR T-cells, bispecific antibodies, and antibody–drug conjugates) going through clinical trials. Cevostamab is a bispecific antibody that targets FcRH5, which is a specific marker on the surface of B-cells, including plasma cells, malignant B-cells, and myeloma cells. In early data from a dose-escalation phase I study of cevostamab, we are seeing encouraging efficacy for cevostamab, with some responses lasting well over a year in a heavily pretreated cohort of patients. This speaks to the power of this potential new immune target. It is exciting to potentially have even more options for our patients with R/R MM.

Another recently identified target for myeloma is the G-protein–coupled receptor family C group 5 member D (GPCR5D), which is present on the majority of the myeloma cells. Using the same approach that has been taken for other bispecific antibodies, talquetamab is a first-in-class bispecific IgG4 antibody that targets CD3 and GPCR5D. Data from an open-label phase I trial with step-up dosing of talquetamab was presented at ASH 2020 and also showed promising efficacy with long lasting responses.

In the next 3 or 4 years, we are going to see a dramatic change in terms of which immunotherapies we use and when we use them. ASCT will continue to play an important role in the foreseeable future, but we potentially have therapeutics that can challenge the use of ASCT in the upfront setting, and many of the ongoing clinical trials are addressing this idea.

Sagar Lonial, MD:
I agree. The various BCMA-targeted therapies have shown great promise. To me, the data with both talquetamab and cevostamab are an exciting development. Two more immune targets means that we can potentially alternate treatments early on while using PIs and IMiDs as backbone therapy. I expect there may still be a role for high-dose melphalan and ASCT in certain subsets of patients to try to get to MRD negativity earlier, but it really portends us putting together a modern total therapy approach to eliminate myeloma. It is exciting because these drugs are active in refractory myeloma, but they are going to be equally as active—if not more so—when we use them earlier.

Conclusion
It continues to be a very exciting time for patients with myeloma, with multiple new treatment options being explored. Based on these studies presented at ASH 2020 along with other data and ongoing clinical trials, novel combinations and treatment approaches will likely alter the landscape of MM treatment going forward.

Share Your Thoughts
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