Why Triplet Regimens Show Deeper Responses in RRMM

Commentary
Article

During a Case-Based Roundtable® event, Ariel Grajales-Cruz, MD, discussed how the use of the isatuximab, carfilzomib, and dexamethasone triplet regimen led to deeper responses in patients with relapsed/refractory multiple myeloma.

CASE SUMMARY

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 has sustained MRD negativity impacted outcomes in patients with relapsed/refractory multiple myeloma?

ARIEL F. GRAJALES-CRUZ, MD: There is evidence that has shown sustained MRD leads to longer progression-free survival [PFS] and overall survival [OS].1 One MRD negativity result is not necessarily as meaningful for some, but 2 sustained MRD-negative results has an impact on the course of treatment.

Ariel Grajales-Cruz, MD

Assistant Member, Department of Malignant Hematology

Multiple Myeloma Section

Moffitt Cancer Center

Tampa, Florida

Ariel Grajales-Cruz, MD

Assistant Member, Department of Malignant Hematology

Multiple Myeloma Section

Moffitt Cancer Center

Tampa, Florida

Please describe the bassline characteristics and makeup of the IKEMA trial (NCT03275285).

The randomization [in this trial] was 3 to 2 [with Isa-Kd or Kd, respectively].2 A senior patient population was enrolled, and it was very balanced in terms of demographics, but in terms of higher staging, older age, and worse renal function, those patients were more…on the Isa-Kd arm. That led to a subgroup analysis that suggested patients with more significant renal dysfunction possibly benefited more from the triplet therapy.3 But that's a subgroup analysis and that's not the intention of a trial, so we always have to take that with a grain of salt. They included patients with high-risk cytogenetics, especially patients with high-risk disease with gain(1q21) and…about 40% of the patients will have gain(1q21) [in their disease].2 But [in this study], the primary end point was PFS, and patients were treated until disease progression or [intolerable] toxicities. Carfilzomib in this trial was also given at 56 mg/m2 on days 8 and 9, but we would never [give carfilzomib at 56 mg/m2 twice weekly] in the real-world setting, but in a clinical practice we will do it weekly. Isatuximab is given weekly for the first cycle and then every other week had a dose of 10 mg/kg, and it doesn't go below that frequency of dosing.2

How does the identification of 1q21 impact these patients?

Now, gain(1q21) is not the same abnormality as just being positive for 1q21, because if they have gain(1q21) they have one extra piece of 1q21 [compared with just] an amplification of it, and the more copies of 1q21 the patient has the worse it is. If you look at our data the patients that do the worst [on these combination treatments will have a gain(1q21)].4 Those [patients with] double- or triple-hit myeloma will relapse in no time no matter what we do, in terms of traditional therapies, and when we say traditional therapies I’m also including the CD38 monoclonal antibodies.

What responses were observed on the IKEMA trial?

With the overall response rates, [they favored the] the triplet therapy of Isa-Kd [at 86.6% compared with 83.7% in the doublet arm (Odds ratio, 2.09; 95% CI, 1.26-3.48)], but it was not statistically significant.5 And as a result, the difference between the VGPR and complete response [CR] rates were not destined for significance either. Where you can see a clear difference is in the MRD negativity rates, especially in those patients that were MRD negative and had achieved a CR [with the triplet compared with the doublet at 26.3% vs 12.2%, respectively (Odds ratio 2.57; 95% CI, 1.35-4.88)].5 To me, these are the true MRD-negative patients altogether, because [if the patient has a] VGPR and MRD negativity that's not truly a MRD negative result in my book.

References

1. Landgren O, Kazandjian D. Modern myeloma therapy + sustained minimal residual disease-negative = (functional) cure! J Clin Oncol. 2022;40(25):2863-2866. doi:10.1200/JCO.22.00622

2. Moreau P, Dimopoulos MA, Mikhael J, et al; IKEMA study group. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021;397(10292):2361-2371. doi:10.1016/S0140-6736(21)00592-4

3. Capra M, Martin T, Moreau P, et al. Isatuximab plus carfilzomib and dexamethasone versus carfilzomib and dexamethasone in relapsed multiple myeloma patients with renal impairment: IKEMA subgroup analysis. Haematologica. 2022;107(6):1397-1409. doi:10.3324/haematol.2021.279229

4. 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

5. 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

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