High-Dose Chemotherapy and ASCT Reign Supreme in Frontline Myeloma

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."

Zonder briefly touched on maintenance therapy, noting the CALGB 100104 study, which established the role of lenalidomide as maintenance for patients with myeloma following autologous hematopoietic stem cell transplant. Findings from this study contributed to the February 2017 FDA approval of the agent for this indication. In CALGB 100104, median PFS with lenalidomide maintenance was 5.7 years (95% CI, 4.4-not estimable) versus 1.9 years (95% CI, 1.6-2.5) with no maintenance.⁵

There a few trials coming down the pike that may impact practice for newly diagnosed patients, said Zonder. This includes the E1A11, DFCI 2009, and the GRIFFIN trials.

The E1A11 trial (NCT01863550) is comparing carfilzomib (Kyprolis), lenalidomide, and dexamethasone to RVd as induction, with a second randomization evaluating optimal duration of maintenance therapy. Zonder said this is an important nontransplant study that will help the field learn about the 2 ends of the treatment paradigm.

The DFCI 2009 trial (NCT01191060) is the American counterpart to the French IFM 2009 study. It is an important study, Zonder explained, because it includes indefinite lenalidomide maintenance, which will allow for the comparison of the effect of maintenance duration between the 2 studies. When the data sets are subsequently combined, investigators can then look at things like high-risk cytogenetics, Zonder added.

The GRIFFIN trial (NCT02874742) is comparing RVd to RVd with daratumumab (Darzalex) in patients with newly diagnosed myeloma. Daratumumab was approved by the FDA in May 2018 for use in combination with VMP as a treatment for patients with newly diagnosed myeloma who are ineligible for ASCT.

This approval was based on findings from the ALCYONE study, in which daratumumab plus VMP demonstrated a 50% reduction in the risk of progression or death compared with VMP alone (HR, 0.50; 95% CI, 0.38-0.65; P <.001). In the daratumumab arm, median PFS had not been yet reached compared with an 18.1-month PFS in the VMP arm.^6,7

"Even in the era of modern therapy and modern triplets with high response rates, we see that the response rate can improve further, and the quality of responses can improve quite dramatically with the addition of high-dose chemotherapy," concluded Zonder. "Maintenance therapy also extends the duration of response and depth of response, no matter how you get there."

Zonder acknowledged that the introduction of precision medicine, such as chimeric antigen receptor T cells, into cancer care may shake up this current treatment paradigm for newly diagnosed multiple myeloma.

References

1. Palumbo A, Cavallo F, Gay F, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371(10):895-905. doi: 10.1056/NEJMoa1402888.
2. Mina, R, Petrucci MT, Corradini P, et al. Treatment intensification with autologous stem cell transplantation and lenalidomide maintenance improves survival outcomes of patients with newly diagnosed multiple myeloma in complete response. Clin Lymphoma Myeloma Leuk. 2018;18(8):533-540. doi: 10.1016/j.clml.2018.05.019.
3. Cavo, M Palumbo A, Zweegman S, et al. Upfront autologous stem cell transplantation (ASCT) versus novel agent-based therapy for multiple myeloma (MM): a randomized phase 3 study of the European Myeloma Network (EMN02/HO95 MM trial). J Clin Oncol. 2016 (suppl; abstr 8000).
4. Attal M, Palumbo A, Holstein SA, et al. Lenalidomide (LEN) maintenance (MNTC) after high-dose melphalan and autologous stem cell transplant (ASCT) in multiple myeloma (MM): a meta-analysis (MA) of overall survival (OS). J Clin Oncol. 2016;34(suppl; abstr 8001).
5. Mateos M-V, DA Meletios, Cavo M, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018;378(6):518-528. doi: 10.1056/NEJMoa1714678.
6. Mateos M-V, DA Meletios, Cavo M, et al. Phase 3 randomized study of daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) in newly diagnosed multiple myeloma (NDMM) patients (pts) ineligible for transplant (ALCYONE). In: Proceedings from the 2018 ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, Georgia. Abstract LBA-4.