Lisocabtagene Maraleucel Versus Standard of Care for Second-Line Relapsed/Refractory Large B-Cell Lymphoma: 3-Year Follow-Up From the Randomized, Phase III TRANSFORM Study

Author(s): Manali Kamdar, MD, MBBS X [email protected]¹; Scott R. Solomon, MD²; Jon Arnason, MD³; Patrick B. Johnston, MD, PhD⁴; Bertram Glass, MD X⁵; Veronika Bachanova, MD, PhD⁶; Sami Ibrahimi, MD X⁷; Stephan Mielke, MD⁸; Pim Mutsaers, MD⁹; Francisco Hernandez-Ilizaliturri, MD¹⁰; Koji Izutsu, MD, PhD¹¹; Franck Morschhauser, MD, PhD¹²; Matthew Lunning, DO¹³; Victor A. Chow, MD¹⁴; Sandrine Montheard, MS¹⁵; Josu Santamaria, MSc¹⁵; Silvia Colicino, PhD¹⁵; Ken Ogasawara, PhD, MPH¹⁶; Lara Stepan, BS¹⁴; Fei Fei Liu, GDCE, MBA¹⁶; Jeremy S. Abramson, MD, MMSc¹⁷;

Source: https://doi.org/10.1200/JCO-25-00399

Dr. Maen Hussein's Thoughts

CAR-T therapy outperformed standard of care (SOC) as a second-line treatment, with progression-free survival (PFS) not reached in the CAR-T group compared to 6.2 months in the SOC group. Despite two-thirds of patients crossing over, CAR-T still demonstrated a three-year overall survival rate of 63%, versus 52% with SOC. These are impressive and durable results. The SOC regimen consisted of three cycles of chemoimmunotherapy followed by high-dose chemotherapy and autologous stem cell transplant. This positions CAR-T as a viable second-line option for eligible patients.

PURPOSE

To report the results of the multicenter, open-label IRAKLIA trial (ClinicalTrials.gov identifier: NCT05405166) of isatuximab subcutaneous (SC) versus intravenous (IV), plus pomalidomide and dexamethasone, in relapsed/refractory multiple myeloma (MM), to our knowledge, the first phase III MM trial using an on-body injector (OBI).

METHODS

Patients with ≥1 prior line of therapy were randomly assigned 1:1 to Isa OBI (1,400 mg) or IV (10 mg/kg) once weekly in cycle (C)1 and then every 2 weeks, plus pomalidomide (4 mg once daily, day [D]1-21) and dexamethasone (40 mg once weekly [age ≥75: 20 mg]) and treated until progression, unacceptable toxicity, or patient request. Coprimary end points were overall response rate (ORR; noninferiority margin, 0.839) and Isa Ctrough (C6D1 predose; noninferiority margin, 0.8). Noninferiority of OBI versus IV was demonstrated if both coprimary end points achieved noninferiority.

RESULTS

IRAKLIA randomly assigned 531 patients (OBI, n=263; IV, n=268). After 12-month median follow-up, the ORR was 71.1% (OBI) and 70.5% (IV; relative risk, 1.008 [95% CI, 0.903 to 1.126]; lower CI exceeded noninferiority margin). The mean (standard deviation) C6D1 Ctrough was 499 (259) μg/mL (OBI) and 340 (169) μg/mL (IV). The Ctrough geometric mean ratio (90% CI) was 1.532 (1.316 to 1.784); lower CI exceeded noninferiority margin. Grade ≥3 treatment-emergent adverse event incidences were 81.7% (OBI) and 76.1% (IV); infusion reaction incidences were 1.5% and 25.0%. Injection site reactions occurred in 0.4% of OBI injections (all grade 1-2); 99.9% of injections completed without interruption.

CONCLUSION

IRAKLIA demonstrated efficacy and pharmacokinetic noninferiority between Isa OBI and IV. No unexpected safety signal was observed, with excellent local tolerability of Isa OBI. Efficacy and safety were comparable with Isa IV in ICARIA-MM, except the lower OBI infusion reaction rate. These results support potential use of the OBI, designed to improve practice efficiency.

Author Affiliations

¹University of Colorado Cancer Center, Aurora, CO; ²Northside Hospital Cancer Institute, Atlanta, GA; ³Beth Israel Deaconess Medical Center, Boston, MA; ⁴Mayo Clinic, Rochester, MN; ⁵Helios Klinikum Berlin-Buch, Berlin, Germany; ⁶University of Minnesota, Minneapolis, MN; ⁷University of Oklahoma Stephenson Cancer Center, Oklahoma City, OK; ⁸Karolinska Institutet and University Hospital, Karolinska Comprehensive Cancer Center, Karolinska ATMP Center, Stockholm, Sweden; ⁹Erasmus University Medical Center, Rotterdam, the Netherlands; ¹⁰Roswell Park Comprehensive Cancer Center, Buffalo, NY; ¹¹National Cancer Center Hospital, Tokyo, Japan; ¹²Centre Hospitalier Universitaire de Lille, Groupe de Recherche sur les formes Injectables et les Technologies Associées, Lille, France; ¹³University of Nebraska Medical Center, Omaha, NE; ¹⁴Bristol Myers Squibb, Seattle, WA; ¹⁵Bristol Myers Squibb, Boudry, Switzerland; ¹⁶Bristol Myers Squibb, Princeton, NJ; ¹⁷Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA

Teclistamab plus Daratumumab in Relapsed or Refractory Multiple Myeloma

Dual Targeting of Extramedullary Myeloma with Talquetamab and Teclistamab

This is a very impressive signal in a notoriously difficult population—seeing a 79% response rate and median progression-free survival (PFS) of 15.4 months in true extramedullary, triple-class–exposed myeloma is better than expected. Toxicity is real and management-intensive, but the depth and durability of response make this dual-bispecific approach feel like a meaningful advance.

Isatuximab Subcutaneous by On-Body Injector Versus Isatuximab Intravenous Plus Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Phase III IRAKLIA Study

Guess who’s coming as an option beyond AI (OBI)? Yes—this study showed no safety concerns and demonstrated comparable efficacy.

Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma

The AQUILA trial compared daratumumab to active monitoring in high-risk smoldering multiple myeloma, demonstrating a significant improvement in progression-free survival (PFS) (84% vs 54% at 48 months) and a trend toward better overall survival (OS) (94% vs 86% at 48 months). Dara also achieved a higher rate of deep responses, with 60% of patients reaching minimal residual disease (MRD) negativity compared to none in the monitoring arm. This looks like a game-changer to delay progression, but we’ll need to weigh the toxicity profile carefully in practice and wait for survival data.

Salvage autologous transplant in relapsed multiple myeloma: long-term follow-up of the phase 3 GMMG ReLApsE trial

Is the need to transplant declining? Salvage autologous transplant vs lenalidomide/dexamethasone offers no significant survival benefit in RRMM. Patients who relapsed were treated with high-dose chemotherapy followed by maintenance lenalidomide vs dexamethasone and lenalidomide and progression-free survival (PFS) was 20 vs 19 months.