Sborov Reviews How Isatuximab Fits Into R/R Multiple Myeloma

CASE

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 acute onset of renal insufficiency and hypercalcemia​.

Laboratory values:​

• Estimated glomerular filtration rate (eGFR): 44 mL/min/1.73 m2​
• 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 a 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 m2​
• Creatinine clearance: 40 mL/min​
• PET scan showed 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: What were the toxicities seen with Isa-KD in patients with multiple myeloma?

DOUGLAS SBOROV, MD​: The important thing to highlight is that the majority of treatment-emergent adverse events [TEAEs] were driven by the Isa-KD arm, not so much isatuximab [by itself].¹ I think that isatuximab is well tolerated and is as well tolerated daratumumab [Darzalex], but [there is a] difference between infusion and injection [methods for these therapies]. Both drugs are associated with infusion reactions in weeks 1 and 2 of cycle 1, but once you get into those first couple weeks [of treatment], that goes away.¹

However, it is a big deal because daratumumab is given weekly for 2 months, then given every other week for 4 months thereafter, whereas isatuximab is given weekly for the first cycle [of therapy] then given every other week indefinitely. After that 6-month mark, patients are ultimately getting less [of the drug compared with] when they're getting the daratumumab. [The drug manufacturer] is working hard to try to figure out if there's a better dosing frequency [that can] match up better with the daratumumab, but that has not yet been reached.

Douglas Sborov, MD​Associate Professor

Division of Hematology and Hematologic Malignancies

Department of Internal Medicine

University of Utah, Huntsman Cancer Institute​

Salt Lake City, UT​

How does the addition of isatuximab compare with other therapy considerations at this point in treatment?

The addition of isatuximab did not increase the rate of cardiac events.¹ I think that's an important point to highlight, but in my opinion, we often don't see any significant toxicity with the CD30 antibodies other than infections, and sometimes some gastrointestinal TEAEs. I would argue that [when looking at both] the CANDOR [NCT03158688] and IKEMA [NCT03275285] studies...I would say that the majority of patients will not be continued on daratumumab until disease progression.

The majority of patients who are going through to first-line of therapy will probably be on immunomodulatory drugs indefinitely. They'll probably get daratumumab, but that will be a for time limited duration, maybe 1 to 3 years long. But the progression-free survival is so long right now,² that I don't think we need to be continuing these patients, unless they have extremely high-risk disease—then we need to be [moving faster]. I think that most of us are thinking about…[using it as much as we can], but let's not burn the patient out.

Are there any other advantages to this drug outside of efficacy data?

If you have home health [for a patient in a rural area] then you can send them a body device [to track their vitals] and if they have a home health nurse, they can then give the patient isatuximab at home.... All of a sudden, you have a regimen that you're doing at home [for the patient in the middle of a rural area].... There may be some interesting approaches [with isatuximab], and I think one of the things that I've talked to the [drug manufacturer] about is that [at our practice], we have this unique patient population out in the middle of nowhere, and [we need to ask]: how do we improve the delivery of care to those folks? This may be one of those ways, but [they still need time to develop].

^References:

^{1. 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}

^{2. Usmani SZ, Quach H, Mateos MV, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): updated outcomes from a randomised, multicentre, open-label, phase 3 study. Lancet Oncol. 2022;23(1):65-76. doi:10.1016/S1470-2045(21)00579-9}