Assessing The Rationale Behind Triplet Regimens in RRMM

Commentary
Article

During a Case-Based Roundtable® event, Ariel Grajales-Cruz, MD, discussed the long-term results of the phase 3 IKEMA study that build the rationale for use of the triplet therapy isatuximab, carfilzomib, and dexamethasone, in patients with relapsed/refractory multiple myeloma in the second article of a 2-part series.

CASE STUDY

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

  • Medical historyheavy 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 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: How do you define minimal residual disease negativity for a patient that just has a very good partial response?

ARIEL GRAJALES-CRUZ, MD: You can have a VGPR with MRD-negativity, but that means you're not truly MRD negative. Those are the patients who don't have sustainable MRD negativity, because if [they just have a] VGPR and they’re MRD negative, they’re not considered MRD negative, because they’re just considered [to have a] VGPR.1

What were the efficacy results on the phase 3 IKEMA study (NCT03275285)?

The median progression-free survival [PFS] benefit [with Isa-Kd] was 35.7 months [95% CI, 25.8-44.0] in the intent-to-treat population...and [there was] a clear difference, in terms of the number of months with PFS, at 35.7 months vs 19.2 months [95% CI, 15.8-25.0], and that was for all comers [HR 0.58; 95.4% CI, 0.42-0.79].1 This extended to patients with a 1q21 gain, and that's what the data is revolving around, the gain 1q21 population.

Ariel Grajales-Cruz, MD

Ariel Grajales-Cruz, MD

Assistant Member, Department of Malignant Hematology

Multiple Myeloma Section

Moffitt Cancer Center

Tampa, FL

The time to next treatment was also much better for the patients who received 3 drugs vs 2 drugs, and so again, there is a benefit of the addition of that CD38 [monoclonal antibody] no matter how you look at it. [Looking at] the long-term updates of this study, in terms of the depth of response and PFS, we can see that there is still a benefit, whether the patient is at standard risk [HR 0.50; 95% CI, 0.29-0.84], if they have a gain 1q21 [HR 0.58; 95% CI, 0.37-0.92], [or] another high-risk cytogenetic [feature]. For patients with an amplification of 1q21, the difference was a little bit narrower, [at a median PFS of 18.4 months (95% CI, 13.1-not calculable [NC]) with isa-Kd vs 14.5 months (95% CI, 2.8-NC)], but we know that these patients still benefit [from the triplet therapy].2

What was the safety profile of this triplet regimen compared with the doublet?

We're all very familiar with the safety profile for both combinations altogether. We'll always have the incidents of heart failure, we'll always have the cytopenias, and myalgia and arthralgias [will be seen after] infusion, and that gastrointestinal toxicity is always there.1 What's interesting is that [looking at incidents of] cardiac toxicity, there was no difference between the Isa-Kd and Kd arms that was statistically meaningful. [Further], the treatment-related discontinuation rates were lower on the Isa-Kd arm compared with the Kd arm [at 12.4% vs 18.0%, respectively],1 so we didn't have that cumulative toxicity that would sway you to not use 3 drugs [vs 2].

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. Facon T, Moreau P, Spicka I, et al. 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. J Clin Oncol. 2023;41(16):8029. doi:10.1200/JCO.2023.41.16_suppl.8029
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