Isatuximab Provides Longer Survival in Early Relpase Multiple Myeloma

Joshua Richter, MD

Associate Professor of Medicine

Tisch Cancer Institute

Icahn School of Medicine at Mount Sinai

Director of Multiple Myeloma

Blavatnik Family Chelsea Medical Center at Mount Sinai

New York, NY

CASE SUMMARY

A 60-year-old White woman was diagnosed with stage III multiple myeloma.​

• Medical history: heavy smoker​
• ECOG performance status: 0​
• Three years ago, the patient developed an acute onset of renal insufficiency and hypercalcemia​.

Laboratory values:​

• Estimated glomerular filtration rate (eGFR): 44 mL/min/1.73 m^2​
• Serum creatinine: 2.9 mg/dL​
• Serum β₂-microglobulin: 5.9 mg/L​
• Lactate dehydrogenase: 283 U/L​
• Cytogenetics: amplification 1q; translocation 14:16 – high risk​

Treatment​

• At the time, she was treated with VRd (bortezomib [Velcade], lenalidomide [Revlimid], and dexamethasone) induction therapy, followed by autologous stem cell transplantation.
• She achieved complete remission with VRd and transplant and was negative for minimal residual disease (MRD). ​
• The patient was placed on lenalidomide maintenance therapy​.

Two years on lenalidomide maintenance​

• On follow-up, the patient reported having severe fatigue and pain in her back and legs that disrupted her ability to continue full-time work​.
• M-protein: 1.98 g/dL (rapid increase from prior bloodwork)​
• λ Free light chain: increased from 47.5 mg/dL to 136.7 mg/dL ​
• Hemoglobin: 9.8 g/dL​
• White blood cell count and platelets: within normal limits
• Creatinine: 1.4 mg/dL (H; range: 0.59-1.04 mg/dL)​
• eGFR:45 mL/min/1.73 m^2​
• Creatinine clearance: 40 mL/min​
• PET scan shows new vertebral fracture at L1 and new lesions in both femurs​.
• ECOG performance status: 1

The patient was then started on isatuximab (Sarclisa), carfilzomib (Kyprolis), and dexamethasone (Isa-Kd) and achieved a very good partial response (VGPR).

Targeted Oncology: Based on the results of the IKEMA trial (NCT03275285), how does Isa-Kd compare with other therapies being investigated?

JOSHUA RICHTER, MD: When you look at time to next treatment [and all the other efficacy] metrics, Isa-Kd is going to outperform [previous regimens]. We see that median time to next treatment with Isa-Kd...which is the time from when the patient starts therapy to when you're going to change [their therapy again], is 44.9 months [95% CI, 31.6–not changed (NC)].¹ Regardless of anything else, that's just an impressive number in the early relapse [setting]; it's hard to beat. Maybe the CARTITUDE-4 [NCT04181827] results will beat that, but the CARTITUDE-4 regimen is not approved and even when it's approved, it will be for a subset of patients.² However, in trials [for CAR (chimeric antigen receptor) T-cell therapy]...they'll show you the [very high] response rates, but [not everyone on the trial] got the CAR T-cell therapy...for reasons including disease progression. So, they couldn't control the disease [long enough] and the patient died waiting for CAR T-cell therapy. Or they got immune suppression and an infection, and then they died.

I had a patient...who had 3 attempts at CAR T-cell collection, and they couldn't manufacture [the CAR T]. We have manufacture failures with this therapy still. So, CAR T-cell therapies are a great technology for a subset of patients, but it doesn't work for everyone. I'm all about utility. I'm all about [focusing on] the patient that you see in the clinic tomorrow, that walks in with their laboratory results now showing their creatin is rising. This is someone where we can't wait. So, an anti-CD38 monoclonal antibody plus carfilzomib is our go to, but I would argue that Isa-Kd has the best outcomes [for these patients] so far.

What were the long-term results for patients with 1q21 in their disease?

To me, the...[main efficacy marker to look at in this subgroup] is median progression-free survival [PFS], because you need to be able to tell your patient if it's going to work or not. For the most part, with either regimen the response rates are all high, so it's got to work, but the question I always think about in the back of my head is, but for how long [will it work]? For that reason, PFS is the efficacy result we focus on. In patients with standard risk [on the IKEMA study], the median PFS was 20.3 months [range, 15.2-28.2] with Kd vs 42.4 months [range, 26.3-NC] with Isa-Kd.³ So even for the patients with standard risk, it improves their survival. It's not just for those [with a higher risk or abnormality].

In patients with a 1q21 addition, the median PFS was 16.2 months [range, 10.2-24.8] in the Kd arm vs 25.8 months [range, 17.1-38.2] in the Isa-Kd arm. For patients with isolated 1q21, it was 16.2 months [range, 10.2-25.1] in the Kd arm vs 38.2 months [range, 18.8-NC] in the Isa-Kd arm. [For those patients who gained] 1q21, the median PFS was 18 months [range, 10.2-25.0] with Kd alone vs 30.2 months [range, 20.8-NC] with Isa-Kd. The result that...[I think] shows how bad amplification of 1q21 is…that the median PFS is 14.5 months [range, 2.8-NC] with Kd vs 18.4 months [range, 13.1-NC] with Isa-Kd. That to me is a huge difference [from the other 1q21 groups]. If the patient had 3 copies and I put them on Isa-KD, they’re in remission for an average of 30 months, but if they had 1 extra copy of 1q21 you almost half that [PFS] to 18 months.

_References:

• _{Martin T, Dimopoulos MA, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in patients with relapsed multiple myeloma: updated results from IKEMA, a randomized Phase 3 study. Blood Cancer J. 2023;13(1):72. doi:10.1038/s41408-023-00797-8}
• _{San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med. 2023;398:335-347. doi:10.1056/NEJMoa2303379}
• _{Facon T, Moreau P, Špicka I, et al. P916: Long-term outcomes with isatuximab-carfilzomib-dexamethasone (Isa-Kd) In relapsed multiple myeloma patients with 1q21+ status: updated results from the phase 3 IKEMA study. Hemasphere. 2023;7(suppl):e7523284. doi:10.1097/01.HS9.0000970568.75232.84}