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Director, Center for Multiple Myeloma
Massachusetts General Hospital Cancer Center
Professor of Medicine
Harvard Medical School
Noopur Raje, MD, has disclosed that she has received consulting fees from Amgen, Bristol-Myers Squibb, Celgene, Janssen, and Takeda.
There is a pressing need for treatment options to offer our heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM) who have progressed on multiple approved therapies. Although the FDA recently approved selinexor for patients treated with ≥ 4 previous therapies and who have disease refractory to multiple proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), and an anti-CD38 monoclonal antibody, it remains to be seen how accessible and tolerable this drug will be in the general patient population outside of a clinical trial. Other promising options including CAR T-cell therapies, bispecific T-cell engager (BiTE) constructs, antibody-drug conjugates, and MCL1 inhibitors are available through clinical trials. Below, I share my thoughts on the latest data for CAR T-cell therapies in clinical development for RRMM, along with when I recommend clinical trials in this setting.
Phase I Data for Idecabtagene Vicleucel
In 2017, the anti-BCMA CAR T-cell therapy idecabtagene vicleucel (formerly bb2121) received FDA breakthrough therapy designation based on preliminary data from the phase I CRB-401 trial. We recently published results from the first 33 patients treated through CRB-401 in The New England Journal of Medicine. Among these patents with very refractory, heavily pretreated disease (median number of previous antimyeloma therapies: 7; range: 3-23), the ORR was 85%, including 45% with CRs.
I was struck by the relative lack of severe CAR T-cell–associated toxicity compared with CD19-directed CAR T-cell therapies in RR large B-cell lymphoma, where grade ≥ 3 cytokine-release syndrome (CRS) was reported in 23% of patients treated with tisagenlecleucel and 13% with axicabtagene ciloleucel. In CRB-401, 76% of patients experienced CRS, with only 6% having grade 3 CRS and no instances of grade 4. Very few patients required tocilizumab for CRS. Neurotoxicity was observed in 42% of patients, with all but 1 case being grade 1/2. By comparison, grade ≥ 3 neurotoxicity was observed in 18% with tisagenlecleucel and 31% with axicabtagene ciloleucel.
The lower incidence of severe toxicities observed with idecabtagene vicleucel vs currently approved CAR T-cell therapies was likely related to T-cell expansion. Whereas axicabtagene ciloleucel has CD28 as a costimulatory molecule, idecabtagene vicleucel instead uses 4-1BB and has slower T-cell expansion. Furthermore, idecabtagene vicleucel was assessed in heavily pretreated patients who may not have had the healthiest starting population of T-cells, which may have attenuated toxicity.
Of note, we saw a median remission duration of 10.9 months, with all evaluable responders achieving measurable residual disease (MRD) negativity. Overall, the median PFS was 11.8 months.
These data are quite remarkable and support further study in earlier disease states such as in the randomized phase III KarMMa‑3 trial, which is comparing the efficacy and safety of idecabtagene vicleucel vs standard triplet regimens (eg, daratumumab plus pomalidomide and low-dose dexamethasone). This trial is now recruiting eligible adult patients with RRMM, with an Eastern Cooperative Oncology Group performance status of 0/1, who had received 2-4 previous antimyeloma therapies (including daratumumab, a PI, and an IMiD), and who were refractory to their most recent treatment. Of importance, this trial excludes patients with central nervous system involvement and those who have received an allogeneic stem cell transplant or BCMA-targeted therapy (eg, the BiTE AMG 420).
Clinical Data for Other Anti-BCMA CAR T-Cell Therapies
At ASH 2018, we saw promising early-phase clinical data for other anti-BCMA CAR T-cell therapies in RRMM. Shah and colleagues reported preliminary results of a high ORR of 83.3% and durable responses in 12 patients who received bb21217, which has the same CAR construct as idecabtagene vicleucel but a different manufacturing process that enriches for a memory-like phenotype by exposing the T-cells to a PI3 kinase inhibitor.
Zhao and colleagues shared an updated analysis of the ongoing LEGEND-2 trial evaluating LCAR-B38M in 57 patients with relapsed MM. This construct, which has 2 BCMA-targeting domains, was associated with a high ORR of 88%, and most patients achieved MRD-negative CRs. The safety profile was consistent with other CAR T-cell therapies, with 90% of patients experiencing CRS (predominantly grade 1/2).
We also saw initial data on JCARH125, which has the 4-1BB costimulatory and CD3ζ activation domains, like idecabtagene vicleucel. Mailankody and colleagues reported that the ORR was 82% in RRMM, with 80% of patients experiencing CRS that, again, was mostly grade 1/2.
Despite these promising results, it is premature to compare therapies because these data are from early-phase studies involving dose escalations.
Which Patients Should Enroll on CAR T-Cell Clinical Trials?
Now that we have an FDA-approved option and many agents in trials for heavily pretreated patients with RRMM that progressed on multiple classes of approved therapies, when should we recommend a CAR T-cell therapy trial to these patients?
I recommend CAR T-cell trials when my patient has progressed after treatment with multiple PIs, IMiDs, and monoclonal antibodies yet has maintained a good performance status and meets the eligibility criteria for a CAR T-cell trial. I would also recommend appropriate trials (eg, the currently accruing KaRMMA-2) to patients with high-risk disease who relapsed within a year of transplant; these patients have poor outcomes historically, and should be considered for CAR T-cell therapy earlier than patients with lower risk. As described earlier in the eligibility criteria for the KarMMa-3 trial, treatment with a BCMA‑directed strategy may disqualify a patient from a trial testing another BCMA‑directed strategy. An ongoing challenge is that current CAR T-cell trials are fairly small with limited enrollment goals, so many patients must seek alternatives. At my site, we prioritize enrolling the sickest patients. Fortunately for those with rapidly progressing disease, we can administer bridging therapy while their CAR T-cell therapy is being manufactured.
We can now safely say that cellular therapies are efficacious and can certainly be used in RRMM. It is incumbent upon us to determine the best strategy for these therapies, and I think we have only just begun to scratch the surface. My ultimate hope is that we can leverage these strategies to cure a subset of our patients.