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High-Dose Chemotherapy and ASCT Reign Supreme in Frontline Myeloma

Angelica Welch
Published: Monday, Oct 08, 2018

Jeffrey Zonder, MD

Jeffrey Zonder, MD

Among new advances in multiple myeloma, high-dose chemotherapy and autologous stem cell transplant (ASCT) remain the go-to frontline treatment for patients with newly diagnosed multiple myeloma, according to Jeffrey A. Zonder, MD.

In a presentation during the 2018 OncLive® State of the Science Summit™ on Hematologic Malignancies, Zonder, an associate professor of Clinical Hematology-Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, discussed initial therapy for patients with myeloma.

Currently, lenalidomide (Revlimid) with bortezomib (Velcade) and dexamethasone (RVd) is the most widely used induction regimen, said Zonder, cemented by the results of the SWOG S0777 trial, which compared this triplet to the doublet of lenalidomide plus dexamethasone.

In 2014, one of the earliest studies examining the role of high-dose chemotherapy following induction utilized some of the current standard drugs compared 200 mg/m2 of melphalan plus ASCT with melphalan-prednisone-lenalidomide (MPR).1 There was then a second randomization, where patients either received maintenance lenalidomide or no maintenance treatment. The primary endpoint was progression-free survival (PFS).

Focusing on the arms that included maintenance therapy, Zonder said that PFS was almost doubled with the addition of ASCT, and the 5-year overall survival (OS) favored transplant but was not statistically significant. At a median follow-up of 51.2 months, PFS in the ASCT arm was 43 months versus 22.4 months in the MPR arm (P <.001). The 4-year OS was 81.6% versus 65.3%, respectively (P = .02).

In 2018, a larger study randomized 791 patients to chemotherapy or ASCT, and subsequently randomized patients to maintenance or no maintenance. This study looked at patients who achieved complete remission (CR) following ASCT versus patients who achieved a CR without ASCT, explained Zonder. A larger number of patients had a complete remission with ASCT (n = 95) compared with those who had chemotherapy alone (n = 71).2 Patients in CR who received high-dose therapy with ASCT had an improved PFS (HR, 0.55; P = .01) PFS2 (HR, 0.46; P = .02), and OS (HR, 0.42; P = .03) versus those who were randomized to lenalidomide with an alkylator regimen.

"What this suggests is that it is not just [having] a higher chance of getting to remission, but there is something qualitatively different about the remissions," said Zonder. "This starts to get at what many of us have heard about recently, which is the importance of minimal residual disease (MRD)."

One of the more well-known trials of the addition of ASCT in myeloma is the Intergroupe Francophone du Myélome (IFM) 2009 study. This was a 700-patient study of RVd induction and then a randomization to ASCT plus consolidation versus additional RVd and finally lenalidomide maintenance, said Zonder. Findings from the study showed that when used in conjunction with ASCT, consolation therapy with RVd extended PFS compared with RVd alone.3

Median time to progression was 50 months for patients who received ASCT, which is compared with only 36 months for those who only received RVd. Although PFS was extended with ASCT, the 4-year OS in both arms was around 81%, noted Zonder.

Notably, MRD was not detected in 65% of patients in the RVd-only group compared with 79% of the patients in the ASCT group (P <.001). Patients who were MRD-negative had superior PFS (HR, 0.30) and OS (HR, 0.34) compared with patients who had detectable MRD, investigators noted. Findings from this trial are of particular use for American physicians because unlike previous European studies, IFM 2009 reflects how myeloma is treated in the United States, Zonder said.

There have been several studies aiming to determine the importance of high-dose chemotherapy in the treatment of high-risk patients with myeloma.

The phase III EMN02/HO95 MM trial randomized 1266 patients to bortezomib/melphalan/prednisone (VMP), or single or double ASCT after induction with bortezomib/cyclophosphamide/dexamethasone with or without consolidation and indefinite lenalidomide maintenance.4 PFS for the entire group favored ASCT, and it even more strongly favored the high-dose chemotherapy for the high-risk group, according to Zonder. Investigators reported that PFS was significantly improved in patients who received high-dose chemotherapy, (HR, 0.76; 95% CI, 0.61-0.94; P = .010).

"It is consistent with what we know from other studies, which is that deep suppression without residual detectable disease in these high-risk aggressive clones is particularly important," said Zonder. "This study provides strong data supporting the use of high-dose chemotherapy, even in high-risk groups."


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