18th International Myeloma Workshop
Idecabtagene vicleucel for relapsed and refractory multiple myeloma
Prof Larry Anderson - UT Southwestern Medical Center, Dallas, USA
This presentation at IMW 2021 is an update of the data from the KarMMa study showing longer term efficacy and safety results with a median of 24.8 months of follow-up in patients treated with Ide-Cel CAR T-cell therapy. This trial was done in triple class exposed relapsed and refractory multiple myeloma after a prior immunomodulatory drug, a proteasome inhibitor and CD38 antibody therapy, where outcomes following other approved therapies in this population has been poor.
This analysis not only gives longer term follow-up data but also breaks down outcomes by number of prior lines of therapy, three versus four or more, since the FDA label is requiring at least four prior lines of therapy and this study only required three.
As for the methodology used in this study, for Ide-Cel therapy autologous peripheral blood T-cells are taken from the patient by leukapheresis and modified with a viral vector to express a chimeric antigen receptor, or CAR, T-cell receptor recognising BCMA, or B-cell maturation antigen, which is a plasma cell surface antigen protein marker on myeloma cells and not expressed on other healthy normal tissues. In this phase II KarMMa trial 128 patients with relapsed/refractory myeloma were treated with Ide-Cel across a target dose range of 150-450 million CAR T-cells. Patients had received a median of six prior lines of therapy, ranging from three to sixteen.
Our results showed a median overall survival of 24.8 months in this triple class exposed relapsed/refractory multiple myeloma setting now at a median follow-up of 24.8 months. Overall survival was similar with three versus four or more prior lines of therapy. It was also over 20 months for those with extramedullary and triple class refractory as well. The overall response rates are 73% with a median progression free survival of 8.6 months as an average across all target doses of CAR T-cells. However, for the highest target dose of 450 million CAR T-cells the overall response rate was 81% with complete response rates of 39%, progression free survival of 12.2 months. Outcomes did not vary based on number of prior lines of therapy of three versus four or more. Responses to Ide-Cel were durable with a median duration of response of 10.9 months among all Ide-Cel treated patients and increased with depth of response to 21.5 months of remission for those achieving a complete response. Also for those achieving a CR, 41% were still in remission at two years.
As for toxicity, although 84% experienced cytokine release syndrome, or CRS, most was low grade with only 6% grade 3 or higher. Only 18% experienced any grade of neurotoxicity with only 4% grade 3 and no grade 4 or 5 neurotoxicity events. The safety profile of Ide-Cel was similar regardless of number of prior lines of therapy and remained consistent with longer follow-up with similar rates of infections and second primary malignancies and no unexpected gene therapy related toxicities observed.
As for how these results may impact future treatment of myeloma, based on the KarMMa trial Ide-Cel has now been approved by the US FDA in March 2021, by Health Canada in May 2021 and the EMA approval was just last month in August 2021 for relapsed/refractory multiple myeloma patients who have received at least four prior lines of therapy in the US and at least three prior lines of therapy in Canada and the EU.
This treatment is already rapidly becoming a standard of care option for our heavily refractory myeloma patients. We are still trying to figure out who is the most optimal candidate to increase the odds of achieving a complete response from Ide-Cel where the median duration of response, again, was 21.5 months and 41% stay in remission for at least two years. However, this data is giving hope for this group of patients that previously had little hope.
As for next steps, although the results of the study are impressive and many patients do well, many of these patients still relapse within two years. We postulate that by using Ide-Cel earlier in the course of the disease when T-cells may be more functional and less beaten up by many years of chemotherapy and steroids, that hopefully that will be very important. We now have studies ongoing that are giving Ide-Cel as third line therapy in the KarMMa-3 trial, as second line therapy in the KarMMa-2 trial and even first line therapy in the KarMMa-4 trial where we use CAR T-cells instead of front-line stem cell transplant in patients with high risk chromosomes.
For now the current treatment still adds significant value to these patients that may live less than a year on average with other approved therapies in this population, compared to 24.8 months of survival with a single infusion of Ide-Cel followed by no ongoing therapy required after that infusion. However, ongoing studies will hopefully help shed light on optimal timing.
This is an exciting era of novel immunotherapeutic options for our myeloma patients that can now give them hope that did not exist before. For those that relapse after BCMA directed therapies there are also many ongoing trials currently being done with other CAR T-cell products, bispecific antibodies targeting non-BCMA targets like GPRC5D and FcRH5 and others. In the future we’re going to see combinations of these immunotherapies and hopefully used earlier in the course of treatment which will hopefully lead to even better outcomes.
