Carfilzomib-Based Induction in Untreated Myeloma with Carfilzomib Post-Transplant Consolidation (KIWI): An Investigator-Initiated Phase II Trial

Introduction

Bortezomib-containing triplet regimens are well-established induction therapies for transplant-eligible patients with newly diagnosed multiple myeloma (MM). There is still scope for improving triplet regimens, particularly where anti-CD38 monoclonal antibody containing quadruplet regimens remain inaccessible. We aimed to evaluate the efficacy and safety of carfilzomib, cyclophosphamide and dexamethasone (KCd) induction and carfilzomib, thalidomide and dexamethasone (KTd) consolidation in transplant eligible patients with multiple myeloma.

Method

This is an investigator-initiated, single arm, open-label phase II study conducted at two sites in New Zealand. We enrolled transplant-eligible patients with untreated multiple myeloma, aged ³ 18 years and ECOG performance status 0-2.

Induction was 5x 28-day cycles of Carfilzomib 20/56 mg/m² (capped at 120 mg) D1, 2, 8, 9, 15, 16; Cyclophosphamide 300 mg/m² PO D1, 8, 15; Dexamethasone 20 mg D1, 2, 8, 9, 15, 16. This was followed by autologous stem cell transplant and 3 months post-transplant, consolidation with 4x 28-day cycles of carfilzomib 56 mg/m² (capped at 120 mg) D1, 2, 8, 9, 15, 16; Thalidomide 100 mg daily (continuously); Dexamethasone 20 mg D1, 2, 8, 9, 15, 16.

The primary objective was to assess overall response rate (ORR) following induction, transplant and consolidation. Secondary objectives include measurable residual disease (MRD) at the corresponding time points via EuroFlow standards (sensitivity 10^-5), median overall survival (mOS), median progression free survival (mPFS), median time to next treatment (mTTNT) and safety. Study recruitment is complete and all patients are under long term follow up.

Registration: Australian New Zealand Clinical Trials Registry (ANZCTR),ACTRN12615000188538.

Results

Between 11^th May 2017 and 15^th October 2020, 50 patients were enrolled into the study. Median age was 59 years old (range 37 – 69), 50% were female, 72% were European, whilst 16% were Maori or Pacific Islander. Baseline disease characteristics: high risk cytogenetics (t(4;14), t(14;16), del (17p) or TP53 mutation) in 20% and ISS stage III disease in 20%. Induction therapy was completed in 45 (90%) patients, 41 (82%) received transplant, and 39 (78%) completed transplant and consolidation.

Responses deepened with time. The ORR of evaluable patients after induction therapy was 48/50 [96%] (≥VGPR: 34 [68%]; PR: 14 [28%]), 40/41 [98%] after transplant (≥VGPR: 35 [85%]; PR: 5 [12%]), and 39/39 [100%] (≥VGPR: 39 [100%]) after completion of consolidation. 9 patients withdrew from study pre-transplant, 5 of which were due to treatment intolerance and 2 did not proceed with transplant.

Of all enrolled patients, MRD negativity was achieved in 16 (32%) patients after induction, 26 (52%) after transplant, and 34 (68%) at the completion of consolidation.

At data cut off 2^nd July 2024, mPFS was 6.00 years (95% CI 4.66 – NR). mOS was 6.01 years (95% CI 5.76 – NR). mTTNT was not reached, though TTNT at 6 years was 54% (95% CI 28.9% - 73.6%).

Haematologic toxicity of any grade was the most common AE and occurred in 31 (62%) patients, of which grade ≥ 3 neutropenia, thrombocytopenia and anaemia occurred in 15 (30%), 11 (22%) and 6 (12%) respectively. Most common non-haematologic AEs were dyspnoea (60%), nausea (52%), and fatigue (42%), almost none were grade ≥3. Pneumonia or lower respiratory tract infection occurred in 15 (30%) of participants, and 8 (16%) were grade 3, none were grade 4. Cardiac AEs were seen in 15 (30%), of which 7 (14%) were grade ≥ 3. There were no grade 5 treatment related adverse events.

Conclusion

The KIWI trial regimen with KCd induction, followed by transplant and KTd consolidation showed high response rates with a manageable safety profile. This regimen achieved high rates of disease response and MRD negativity and responses increased with each step of treatment. The efficacy of this carfilzomib-based regimen for newly-diagnosed transplant eligible patients is in line with published literature. Where anti-CD38 containing quadruplet regimens are not available, carfilzomib containing induction and consolidation approach is an effective alternative. Our study adds to the existing literature that this higher carfilzomib dose regimen and post-transplant consolidation is feasible and efficacious.