Myeloma Fighters ASH Breakdown, Part 2: Focus on Relapsed / Refractory Multiple Myeloma
Please note: These opinions are my own and do not represent the positions of UW Medicine.
Thank you to all our new subscribers! For the second installation of the MM Fighters ASH 2023 Breakdown, this time I will focus on highlights in relapsed/refractory multiple myeloma. There is always so much content in this area, it’s tough to put into sugar cube sized content that is digestible for most! These are not necessarily the “top” abstracts in this area from ASH, but rather, represent what I feel to be representative of some of the newer agents in relapsed MM that hold promise and are either approved already, or likely to be approved in the future. For each abstract, I go into a bit more depth about the context and background for the trials, so bear with me!
Relapsed Multiple Myeloma - ASH 2023
The CARTITUDE trials from Janssen are pivotal trials investigating ciltacabtagene autoleucel (Cilta-cel / Carvykti), a BCMA directed chimeric antigen receptor (CAR) T cell therapy. As a brief refresher, how do these therapies work? We take T cells from a patient, genetically modify them using a lentivirus to express the “CAR” on the surface (which allows the T cell to bind to and target myeloma cells), expand them, purify them, and then deliver them to a patient after receiving lymphodepleting chemotherapy (LD). The lymphodepleting chemotherapy is critical to prevent your immune system from immediately recognizing the CAR T cell as a foreign object and destroying it. These therapies have been enormously successful in many hematologic malignancies, including multiple myeloma.
Carvykti was approved by the FDA in 2022 (only for patients with >4 prior lines of therapy, including a CD38, proteasome inhibitor, and immunomodulatory agent), and interest has since spread in using this therapy not only in these heavily pretreated patients, but also earlier in a patient’s disease course, when the immune system might be more effective and patients have less cumulative toxicities from therapies - potentially making CAR T cell therapy safer and more effective (although this remains to be proven by trials).
The population of CARTITUDE B, Cohort A, is quite similiar to the population enrolled in the randomized phase 3 CARTITUDE 4 trial, which showed a dramatic benefit to receipt of Cilta-cel in patients with 1-3 prior lines of therapy, as compared to the control arm, which was standard of care treatment regimens. The long term follow up from Cohort A show deep responses, with 85% of patients achieving a stringent complete response (Meaning, negative serum and urine immunofixation, normal free light chains, no new disease on PET, and negative bone marrow biopsy)! Additionally, responses were durable, with a 24 month PFS rate of 75%. Not bad at all.
However, the more interesting data to me were from Cohort B - 1 prior line of therapy AND progressive disease < 12 months after transplant or start of therapy. This population is increasingly referred to as “functional high risk multiple myeloma (FHRMM)” - meaning that regardless of initial risk stratification, these myelomas fare poorly with advanced therapy - see this link for a nice review authored by Dr Banerjee, Cicero, Lee and myself to learn more about this.
Patients in cohort B fared quite well with Cilta-cel. 73% achieved an sCR, and remissions were durable, with a 24-month PFS rate of 73%. Having seen patients struggle with functional high risk myeloma in the pre-cilta-cel era, these results are highly encouraging and give me hope. I think they point the way to better management of FHRMM, and would certainly argue for taking a CAR T approach in a patient with a functional high risk phenotype.
There has been some attention in recent years to a class of medications known as CELMoDs (Cereblon E3 Ligase Modulatory Drugs) - iberdomide and mezigdomide are the two many readers might be familiar with. What exactly are these drugs, how do they work, and why are these exciting developments? Let’s go back to the first drugs on the scene, lenalidomide, thalidomide, and pomalidomide to get some context.
Lenalidomide and pomalidomide were developed from thalidomide, the original immunomodulatory drug. All immunomodulatory drugs and CELMoDs exert their mechanism of action through binding a protein called “Cereblon” - which results in downstream effects such as immune modulation, anti-tumor effects, effects on the tumor microenvironment, and toxicities. CELMoDs such as iberdomide and mezigdomide are unique in that they bind with greater affinity to Cereblon than Len and Pom, resulting more potent downstream effects. I’ll explore iberdomide and the clinical trial data in a future post, but will focus more on mezigdomide for this post. Notably, this property may explain why pre-clinical work has suggested effectiveness of iberdomide and mezigdomide even in len and pom resistant cell lines (1, 2).
Mezigdomide is a CELMoD that in this trial, was combined with daratumumab or elotuzumab and dexamethasone in patients with relapsed multiple myeloma. Enrolled patients needed to have 2-4 prior lines of therapy, and prior CD38 therapy was allowed. All patients had prior exposure to an IMiD. In the Mezi-Dara Dex arm, the overall response rate was 75%, and the most common side effects were hematologic (as we might expect) - with neutropenia, thrombocytopenia, and infections being the most commonly reported. In combination with elotuzumab and dexamethasone, the side effect profile of mezigdomide was similiar.
I think these data are exciting because both mezigdomide and iberdomide are effective therapies even in Len and Pom resistant patients - thus opening up the door for more treatment options, especially in the post-CAR T relapse space. There will undoubtedly be trials of these drugs in earlier lines of therapy, and one post-transplant maintenance trial of iberdomide, conducted by the European Myeloma Network was already reported at ASH this year!
In years past, part of the discussion when a patient relapses after a first autologous stem cell transplant with melphalan conditioning, is whether they would consider a second autologous stem cell transplant with the cryopreserved cells they had from the first transplant. In recent years, due to the availability and effectiveness of therapies for relapsed multiple myeloma with CD38 monoclonal antibodies, carfilzomib, selinexor, elotuzumab, and now both BCMA CAR T cells and BCMA bispecifics, this option has been less and less commonly used. Nevertheless, it remains on the table as an “option”, yet one with undesirable side effects and impact on quality of life, that many are unwilling to subject themselves to twice.
A very interesting randomized clinical trial conducted by the German Speaking Myeloma Multicenter Group (GMMG - a large cooperative group trial network in Germany) actually compared the benefit of a salvage autologous stem cell transplant with lenalidomide maintenance, to standard therapy. The standard therapy arm was lenalidomide and dexamethasone - hardly something we’d use on a routine basis in the US - but they set the bar low! So it was somewhat surprising to me to see that this trial showed essentially no benefit in terms of PFS or OS for a salvage autologous stem cell transplant as compared to standard of care. Notably, they made sure to only include patients who had at least 1 year of remission from the first autologous stem cell transplant in this trial (and over 90% of patients on this trial had already underwent a stem cell transplant). Additionally, the authors showed that time to progression after first autologous stem cell transplant does not predict response to a second transplant.
So, in summary - there does not appear to be a benefit for a salvage transplant, even if you had a very long duration of remission from the first transplant. This obviously will bring to readers minds the fact that we commonly advise people to continue storing stem cells as long as possible! I think these trial data have to now be considered when this discussion occurs, given the cost incurred for stem cell storage.
I also want to highly about this trial - the critical importance of cooperative group trials such as those conducted by the GMMG and others (in the USA - we have SWOG, ECOG, Alliance, and BMT CTN). These trials may help answer clinically and scientifically important questions that may be unaddressed by industry supported clinical trials.
That’s all for today - thanks for reading, and please keep the feedback coming!
Andrew