Ide-cel Shows Efficacy Earlier in R/R Multiple Myeloma Despite Crossover

Surbhi Sidana, MD

Assistant Professor of Medicine

Blood and Marrow Transplantation and Cellular Therapy

Stanford Health Care

Palo Alto, CA

CASE SUMMARY

• A 60-year-old woman was diagnosed with Revised International Staging System (R-ISS) stage II/R2-ISS stage III IgGκ multiple myeloma​.
• Medical history: acute onset of renal insufficiency and hypercalcemia ​
• Cytogenetics: 1q21+ amplification; t(14:16); high risk​
• ECOG performance status: 0​
• Patient declined autologous stem cell transplant.​
• She received daratumumab (Darzalex), bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone, followed by lenalidomide maintenance.​
• Best response: ​very good partial response (VGPR)

Two Years Later

The patient experienced her first relapse​.

• She continued lenalidomide maintenance therapy​.
• On routine follow-up, she reported having mild fatigue but continued to work full-time​.
  • Bone marrow plasma cells, light chains, and M protein levels rising​
  • Kidney function worsening; estimated glomerular filtration rate: 22​
  • Now stage IV chronic kidney disease​
• Following second relapse, the patient was initiated on daratumumab, carfilzomib (Kyprolis), and dexamethasone with a best response of VGPR.

Six Months Later

After 2 prior lines of therapy​, the patient presented to her oncologist with complaints of increased fatigue and persistent bone pain in her lower back exacerbated by minimal movement​.

• She expressed interest in chimeric antigen receptor (CAR) T-cell therapy with her clinical team.​
• She also stated that she wants to travel out of the country for her daughter’s wedding in 3 months.

Targeted Oncology: Could you explain the design of the phase 3 KarMMa-3 trial (NCT03651128) and its significance in patients with relapsed/refractory multiple myeloma?

SURBHI SIDANA, MD: KarMMa-3, the trial of ide-cel [idecabtagene vicleucel; Abecma], enrolled patients who have had 2 to 4 prior lines of therapy, so [it did not include] the very early relapses with 1 prior line. They had to be refractory to the last regimen. It was a 2:1 randomization to ide-cel vs standard of care [SOC], and there were 5 different options. Very importantly, it was a crossover design. If you were randomly assigned to SOC, you could then cross over and get CAR T-cell therapy. This will become important because of the overall survival [OS] data [where] the curves don't separate out, probably because of crossover.

Bridging therapy was optional; if I was the one designing the trial, I wouldn't design it like this. It was optional and [must be] 1 cycle or less with a minimum 14 -day washout. [A total of 225 of 254 patients in the experimental arm] received CAR T-cell therapy with 150 to 450 million cells in the CAR T-cell arm. The patients in the comparator arm received standard regimens until progression. Over 200 patients received CAR T-cell therapy, and 126 patients received SOC. The primary end point was progression-free survival [PFS] and secondary end points were overall response rate [ORR], OS, etc.

The big picture is that the characteristics were well balanced [between the arms].¹ Over 90% of these patients were daratumumab refractory, 95% and 93% [in the experimental and SOC arms, respectively], which tells you this is a very heavily treated population. The median number of prior lines of therapy for this trial was 3, so even though it's an earlier trial [than the prior KarMMa trial (NCT03361748)], it's not an early-line trial. The median number of lines of therapy for the initial approval was 5 and this is 3, so most patients had exhausted conventional options by this time point. it's important to keep this in mind because the results do look different between the 2 trials.

What were the key efficacy outcomes in this trial?

This trial was positive, meeting its primary end point for PFS.² The median PFS for the CAR T-cell therapy arm was almost 14 months, and the median PFS for the SOC arm was 4 months. So SOC did just as I would have expect it to do [in patients with] 3 prior lines of therapy. The CAR T-cell therapy arm did better than what ide-cel results showed in the fifth-line setting, which was a median of 9 months of PFS.

The ORR was also better in the ide-cel arm, 71% vs 42%. The control arm did just as I would have expected; we expect an ORR of 30% to 40% at this stage. This is almost 2 times [better], which is great. The complete response rate was 44% with ide-cel vs 5% in SOC. When patients get a response, many of them get a deep response with CAR T-cell therapy. Even the PFS2, which is the PFS with the next line of therapy, was 23.5 months and with the SOC regimens was 16 months. These patients did better [with ide-cel than SOC] combined with the next line of therapy even though crossover was possible.

REFERENCES:

1. Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al. Ide-cel or standard regimens in relapsed and refractory multiple myeloma. N Engl J Med. 2023;388(11):1002-1014. doi:10.1056/NEJMoa2213614

2. Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al. Idecabtagene vicleucel (ide-cel) versus standard (std) regimens in patients (pts) with triple-class–exposed (TCE) relapsed and refractory multiple myeloma (RRMM): updated analysis from KarMMa-3. Blood. 2023;142(suppl 1):1028. doi:10.1182/blood-2023-178933