Joshua Richter, MD

Question

What are some of the novel treatment approaches in multiple myeloma discussed at the 2018 American Society of Hematology Annual Meeting?

Answer

Two big areas of novel therapy classes that are currently under evaluation are CAR-T (chimeric antigen receptor T-cell) therapies and bispecific antibodies.

CAR-T targeting CD19 and more recently, BCMA, are in the forefront of clinical trials, however, G-protein coupled receptor family C group 5 member D (GPRC5D) is a novel target that is currently being utilized in both the bispecific and CAR-T realms.¹ It is highly expressed on plasma cells and is an extremely promising target.

CAR-T therapy may ultimately not be appropriate for all patients due to toxicity, cost, availability, and time needed to engineer the cells. Bispecific antibody constructs are extremely exciting as potential ‘off-the-shelf’ treatments. AMG 701 is one of the leading compounds in this space.² [Although] many of the CAR-T and bispecific agents in the pipeline target BCMA, what is not clear is not only which therapy is potentially best for which patient, but also, what is the role of sequencing for BCMA-based treatments? Can a BCMA CAR-T work after [treatment with] a BCMA bifunctional antibody and vice versa?

Selinexor is currently before the US Food and Drug Administration with a PDUFA [prescription drug user fee act] date of April 6th, 2019, is a new class of agents called selective inhibitors of nuclear export (SINE). This is an exciting new drug for penta-refractory myeloma. The STORM data were presented, evaluating the double of selinexor and dexamethasone in heavily pretreated patients. The ORR was 26.2%. The ongoing BOSTON study (selinexor + Vd versus Vd) and the STOMP trial (combinations of selinexor with other myeloma agents, ie, IMiDs [immunomodulatory imides], mAbs [monoclonal antibodies], PIs [proteasome inhibitors]) will ultimately yield a new area of active combinations for patients where there is currently no standard of care.

Question

Were there any data presented that will influence the decisions you make for your patients with multiple myeloma?

Answer

The MAIA study is practice-changing. This trial evaluated Rd [lenalidomide and dexamethasone] vs DRd [daratumumab, lenalidomide, and dexamethasone] in upfront transplant-ineligible patients. The median progression-free survival (mPFS) for Rd was 31.9 months, with a mPFS of ‘not reached’ for the DRd combo.⁴ With a hazard ratio of 0.55, and given the current shape of the PFS curves, the likely mPFS should read out to be between 50 months to 60 months; potentially longer. For newly diagnosed patients, this represents a new level of disease control.

The other practice-changing trial was the Rd-R vs Rd continuous trial.⁵

In this study, we saw patients transitioning from the Rd standard based on the FIRST trial (MM-020) to an approach that follows Rd with R maintenance. In this study, we saw no difference in PFS [progression-free survival] or OS [overall survival]; however, the Rd-R arm had a better safety profile. This supports what many patients are asking in the clinic—”When can we stop the steroids?”

Question

Should all multiple trials be stratified by prior relapse? Why or why not?

Answer

Trials that are stratified by prior relapse (such as the trials mentioned above) are crucial to one of the biggest questions in myeloma: sequencing. We have many new therapies available and many new ones on the way. There has been little headway into our understanding of how to properly sequence these regimens. [Drug sequencing] data give us better insight into which therapy is likely to work better, at the bedside, [and] in an individual patient with a unique treatment history.

It is cumbersome to design all trials this way. As more and more therapies [become] available, there is an ever-increasing heterogeneity [of] treatment sequencing, especially in the relapsed setting. This makes it harder to enroll patients with complex inclusion criteria. That being said, post-hoc analytics, and real-world datasets looking into the sequencing paradigms can offer an important view into how we can better use the tools we currently have at our disposal.

Question

Were any of the presentations you attended surprising in terms of findings/outcomes?

Answer

Following the FDA halting the pembrolizumab and IMiD trials, there has been a knowledge gap in myeloma as to what the true role and benefit of checkpoint inhibition is. Dr Cho presented data on the combination of atezolizumab, daratumumab, and IMiD-based regimens.6 These data showed durable responses and more importantly, no new safety signals. I am hopeful that this will reinvigorate the research into [checkpoint inhibition] in multiple myeloma.

Question

A recent Nature article suggested immunotherapies are being developed too quickly and are being pushed through the pipeline too fast to be able to ensure safety. Was there any discussion about this at the meeting? What are your specific safety concerns?

Answer

Although I did not attend any session specifically [geared toward] this, it was a hot topic amongst clinical researchers. There is still a large unmet need in myeloma, both in terms of management of R/R MM, as well as [about] the ‘brass ring’ of a potential cure. CAR-T therapies are an exciting modality, which for many researchers and patients, offer the potential for deep and durable remissions and perhaps, in the right context, a cure.

That being said, there is more that we don’t know than we do know. We do not know the ideal target, vector, cell dose, lymphodepletion schema, induction prior, bridging prior, CRS [cytokine release syndrome] management regarding risks and benefits (ie, is a little CRS beneficial to induce long term remissions?).

There is a high likelihood that this type of therapy will be approved in myeloma before any of these questions are answered. Until such time [when] we have deeper insights into this, we need to, as a myeloma community, be diligent about choosing the most appropriate patients for these therapies, [administer] them [at] institutions that are appropriately trained and equipped to manage the [associated] toxicities, [and] properly inform the patients of the risks and benefits. And, continue to collect as much information (especially post-FDA-approval) to allow for continued learning about the optimal strategies in this area.

Question

Are medications being trialed in a logical manner in multiple myeloma in regard to drugs in the maintenance setting? Were there any new developments from ASH or studies that look most promising for medications in this setting?

Answer

The TOURMALINE-MM3 data were presented, looking at ixazomib in the maintenance setting.⁷

A 26.5-month vs 21.3-month PFS was seen for ixazomib vs placebo, [respectively]. This provides another option for patients in the maintenance setting posttransplant. We are still awaiting more data to mature, but at the current time, this does not supplant lenalidomide maintenance as the standard approach. That being said, some patients do not tolerate IMiDs and this is simply another clinical tool. Furthermore, there is ongoing research looking into doublet- and triplet-based maintenance approaches in the post-ASCT [autologous stem cell transplantation] setting. This trial opens up the possibility of IR [ixazomib, lenalidomide] or IRd [ixazomib, lenalidomide, and dexamethasone] as a maintenance strategy for patients with high-risk cytogenetic features.