Upfront Transplant Prevails Again in Newly Diagnosed Myeloma

An immunomodulatory-free carfilzomib (Kyprolis)-based triplet regimen failed to prove non-inferior to autologous hematopoietic stem-cell transplantation (HSCT) for the upfront treatment of newly diagnosed multiple myeloma, a randomized trial from the U.K. found.

The open-label phase II CARDAMON study included nearly 300 patients, with 57.7% achieving at least a very good partial response (VGPR) with the induction regimen of carfilzomib, cyclophosphamide, and dexamethasone (KCd) — meeting one of the study’s co-primary endpoints, reported Kwee Yong, PhD, of the UCL Cancer Institute at University College London, and colleagues.

But at 2 years, the progression-free survival (PFS) rate was 68% in patients randomized to further cycles of KCd consolidation as compared with 75% for those assigned to standard high-dose melphalan and autologous HSCT, a 7.2% difference (70% CI -11.1 to -2.8) that exceeded the prespecified non-inferiority margin, according to findings published in The Lancet Haematology.

Yet there was no evidence of benefit with HSCT in the 23% of patients who attained minimal residual disease (MRD)-negative status after induction. Transplant consolidation did prove superior for patients who were MRD-positive following induction, however, with a 7.3-month difference in restricted mean survival time over 60 months (P=0.045).

Together, the findings suggest that “patients who are MRD positive after induction could benefit more from autologous HSCT than from consolidation chemotherapy,” wrote Yong and colleagues. “Conversely, individuals who are MRD negative should be investigated on a deferred autologous HSCT pathway in a larger prospective randomised trial.”

Yong’s group explained that multiple prior randomized trials comparing upfront autologous HSCT versus non-transplantation consolidation — including the IFM 2009 Study, HOVON-65/GMMG-HD4 trial, EMN02/HO95 trial, and DETERMINATION most recently — have all shown a clear PFS advantage with upfront transplant, yet “an overall survival advantage has not yet emerged, which prompts the question of whether patients are harmed by not receiving upfront autologous HSCT.”

Results of the current study again support the role of upfront autologous transplant in newly diagnosed multiple myeloma, but “they also highlight the need to evaluate a targeted selection of patients for autologous HSCT based on MRD status after induction,” noted Meral Beksac, MD, of Ankara University in Turkey, and Patrick Hayden, MD, of Trinity College Dublin, in an accompanying comment.

“In the absence of further evidence on how best to modify treatment pathways based on post-induction MRD, there is a general consensus that a delayed autologous HSCT approach is reasonable in patients at standard risk,” wrote Beksac and Hayden. “However, for patients who present with high-risk multiple myeloma, upfront autologous HSCT remains the preferred option.”

Study Details

From 2015 to 2019, CARDAMON enrolled 281 adults with newly diagnosed transplant-eligible multiple myeloma across 19 centers in England and Wales. Median age of the participants was 59 years, a majority were men, 71% were white, 17% were Black, and 8% were Asian. Most (80%) had standard-risk genetics, and 61% were stage II on the Revised International Staging System.

Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, though those with ECOG status greater than 2 were allowed to enroll if their complications were myeloma related.

Primary endpoints were at least a VGPR after induction and difference in PFS rates at 2 years, with a non-inferiority margin of 10% in the intent-to-treat population. Median time from induction to consolidation was 5.6 months, and median follow-up from randomization was 40 months.

All patients received induction therapy, consisting of four 28-day cycles of KCd (intravenous carfilzomib 56 mg/m² on days 1, 2, 8, 9, 15, and 16; oral cyclophosphamide 500 mg on days 1, 8, and 15; and oral dexamethasone 40 mg on days 1, 8, 15, and 22) followed by peripheral blood stem cell mobilization. Study authors noted that the dose of carfilzomib used is higher than that of other carfilzomib-based triplets using twice-weekly dosing.

Following induction, 49% had a VGPR, 28% achieved a partial response, 5% had a stringent complete response (CR), and 3% a CR.

Ultimately, 218 patients had at least a partial response and were randomized to four more cycles of KCd consolidation (n=109) or high-dose melphalan and autologous HSCT (n=104). Patients in both arms then received 18 cycles of carfilzomib maintenance (56 mg/m² on days 1, 8, and 15).

Response rates increased with consolidation, with at least a VGPR in 77% of patients in the HSCT group and 78% of those in the KCd group.

Following consolidation, a higher rate of MRD negativity was seen in the HSCT group (48% vs 30% in the KCd group, P=0.0083), a difference that was largely maintained 6 months into maintenance therapy (46% vs 31%, P=0.026).

At 2 years, overall survival was not significantly different between arms, at 94.4% and 90.8%, respectively.

Common grade 3/4 adverse events (AEs) with KCd included lymphocytopenia (26% of induction patients and 14% of consolidation patients) and infection (18% and 14%, respectively). During maintenance, the most common grade 3/4 AEs among the HSCT group and KCd consolidation group included hypertension (23% and 21%, respectively) and infection (25% and 16%).

Serious AEs related to treatment occurred in 39% of patients during induction, most commonly infections (29%). There were five deaths during induction — infections in three patients, a cardiac event in one patient, and renal failure in another patient. One patient in the autologous HSCT group died from esophageal cancer during the maintenance part of the trial.

The study authors noted that carfilzomib dose modifications were allowed for certain AEs: grade 3/4 non-hematological AEs deemed related to the proteasome inhibitor, grade 3 thrombocytopenia with active bleeding, and grade 4 thrombocytopenia or neutropenia.