Trials Investigate Novel Agents, Autologous Stem Cell Transplantation in Newly Diagnosed Multiple Myeloma

Trials Investigate Novel Agents, Autologous Stem Cell Transplantation in Newly Diagnosed Multiple Myeloma

Results of research on first-line therapy options for patients with newly diagnosed multiple myeloma were presented at the Oral Abstract Session “Hematologic Malignancies—Plasma Cell Dyscrasia,” held Friday, June 3.

Michele Cavo, MD, of Bologna University School of Medicine, Italy, presented results of the EMN02/H095 MM trial (Abstract 8000). Dr. Cavo said that the interim analysis of the trial indicates that up-front autologous stem cell transplantation (ASCT) should remain the preferred treatment for younger patients who are newly diagnosed with multiple myeloma.

Dr. Michele Cavo

“[ASCT] was associated with significant improvement in progression-free survival (PFS) when compared with bortezomib, melphalan, and prednisone (VMP) in the overall patient population in the trial,” Dr. Cavo said.

The role of ASCT has been questioned in the “novel agent era,” Dr. Cavo said. Previously, the role of ACST had been accepted based on randomized clinical trials that compared transplant or no transplant with conventional chemotherapy. Those previous trials had, however, been conducted without use of bortezomib as part of induction therapy before ASCT. Use of bortezomib-based therapy is now “the gold standard for all transplant-eligible patients with myeloma,” he said.

All 1,266 patients in the EMN02/H095 MM trial received three to four cycles of induction therapy with a combination of bortezomib, cyclophosphamide, and dexamethasone, followed by cyclophosphamide at a dose between 2 and 4 g/m2, in addition to granulocyte colony-stimulating factor to mobilize peripheral blood stem cells. The threshold for optimal stem cell collection was fixed at 2 x 106 of CD44-positive cells.

For the first randomization of the trial, patients who reached the threshold level of the CD44 cells received high-dose melphalan (200 mg/m2) and underwent single or double ASCT (in centers with a double intensification policy, patients were randomly assigned to receive high-dose melphalan or VMP), or they received four cycles of VMP, which was the standard of care in Europe when the study was designed, Dr. Cavo said.

For the second randomization, patients in both arms received either consolidation therapy with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD), or no consolidation therapy. Patients in both arms received maintenance therapy with 10 mg daily of lenalidomide until relapse or progression.

The first prespecified interim analysis of 1,192 patients was performed in early 2016 after 33% of required events with regard to PFS from the first randomization had been observed. Patients with an upper age limit of 63 were included, with the median follow-up of 26 months. PFS at 36 months was superior among patients treated with ACST compared with those treated with VMP (hazard ratio [HR] 0.73, 95% CI [0.59, 0.90]; p = 0.001). That advantage was retained across some prespecified subgroups of patients at low and high risk. The PFS benefit with ASCT in the overall patient population was retained in a multivariate analysis of patients with standard risk cytogenetics and an International Staging System score of I, Dr. Cavo said, and “the superiority of ASCT over standard VMP was further supported by the significant improvement in the rate of at least a very good partial response.”

Results of this analysis, he said, support the conclusion that up-front ASCT “continues to be the reference treatment of choice for fit patients with newly diagnosed multiple myeloma, even in the novel agent era and even in the prospective comparison with a standard-dose regimen including bortezomib.”

ASCT Maintenance Therapy

Phillip McCarthy, MD, of Roswell Park Cancer Institute, presented a meta-analysis that evaluated the use of lenalidomide maintenance therapy after high-dose melphalan and ASCT in multiple myeloma (Abstract 8001). The meta-analysis demonstrated that lenalidomide maintenance therapy after high-dose melphalan and ASCT significantly prolonged overall survival (OS) compared with no maintenance therapy among patients with previously untreated multiple myeloma (HR 0.74, 95% CI [0.62, 0.89]; p = 0.001).

The meta-analysis included patient data from three randomized controlled trials: CALGB 100104, IFM 2005-02, and GIMEMA (RV-MM-PI-209). The trials, which collectively included about 1,200 patients, each intended that lenalidomide maintenance would be given until progression. However, a second primary malignancy signal was detected at the end of 2010 in the IFM and CALGB studies. The National Cancer Institute supported the decision by the CALGB investigators to continue lenalidomide maintenance until progression in CALGB 100104; IFM elected to discontinue lenalidomide maintenance; and GIMEMA elected to continue lenalidomide maintenance until progression.

At a median follow-up of 80 months, there was a 26% reduction in risk of death, which represented an estimated 2.5-year increase in median survival, Dr. McCarthy said.

“Lenalidomide maintenance is feasible for long-term disease control after transplant, and the OS benefit of lenalidomide maintenance outweighs the risk of developing a second primary malignancy,” Dr. McCarthy said. “Lenalidomide maintenance after ASCT can be considered a standard of care for patients with newly diagnosed myeloma.”

Understanding the role of minimal residual disease detection and immune reconstitution after ASCT “should allow us to further improve on OS. And, critically, we need to develop early endpoints as surrogates for long-term outcome and OS, as this is critically important for the future. Otherwise, trials may need to continue for 10 years or longer,” Dr. McCarthy said.

Phase I/II Ixazomib Trial

Martha Lacy, MD, of the Mayo Clinic, presented results of a phase I/II trial that evaluated ixazomib, cyclophosphamide, and dexamethasone for patients with untreated symptomatic multiple myeloma (Abstract 8002). Ixazomib is an investigational, reversible 20S proteasome inhibitor and the first oral proteasome inhibitor in trials. Preclinical studies of the agent have demonstrated antitumor activity in multiple myeloma cell lines and in animal models, Dr. Lacy said.

The combination of ixazomib, lenalidomide, and dexamethasone has been approved for treatment of relapsed myeloma in patients who have been previously treated with one to three therapies. Researchers hypothesized that combining ixazomib with cyclophosphamide and dexamethasone could potentially provide an effective, all-oral regimen for previously untreated multiple myeloma that would be less costly than current therapies. 

The primary objective of the phase I trial was to determine the maximum tolerated dose of cyclophosphamide that can be combined with ixazomib and dexamethasone. For the phase II trial, the primary objective was to determine the very good partial response or better rate of the combination. The trial’s secondary objectives included assessment of PFS and OS and the toxicities associated with the combination therapy.

Patients enrolled in the trial (median age 64) had Eastern Cooperative Oncology Group Performance Status of 0 to 2 and adequate hematologic, hepatic, and renal function. The patients received 4 mg of ixazomib on days 1, 8, and 15; 40 mg of dexamethasone on days 1, 8, 15, and 22; and 300 or 400 mg/m2 of cyclophosphamide on days 1, 8, 15, and 22. The cycles were 28 days.

Median follow-up was 8.7 months for all 48 patients and 7.6 months for the 45 patients in the phase II part of the trial. The overall response rate was 77% for all patients (95% CI [63, 88]) and 78% (95% CI [63, 89]) for the phase II group. OS at 12 months was 100% for all patients and 100% for patients in the phase II group. PFS at 12 months was 91% (95% CI [80, 100]) for all patients and 90% (95% CI [78, 100]) for patients in the phase II group.

The combination of ixazomib, cyclophosphamide, and dexamethasone—an active, all-oral proteasome inhibitor-based treatment combination for frontline treatment of myeloma—was well tolerated, Dr. Lacy said. Two percent of patients needed a dose reduction of ixazomib. Toxicities were fairly manageable and similar to previous ixazomib studies, and neurotoxicity was “mild and does not appear to be cumulative,” she said.

Choosing Frontline Therapy

During his presentation, William Bensinger, MD, of the Fred Hutchinson Cancer Research Center, said that important questions remain regarding treatment of newly diagnosed multiple myeloma.

The initial treatment approach for patients who have symptomatic multiple myeloma includes induction therapy or initial therapy. Transplant-eligible patients receive consolidation usually with ASCT, as well as additional consolidation, and then they go on to maintenance. Patients who are not eligible for transplant receive their initial therapy and either stay on continuous therapy or go on maintenance or continued therapy, he said.

Questions remain, however, about the treatment, including “whether ASCT is a useful consolidation in the era of novel drugs with such high response rates; what, in fact, is the best induction regimen for patients either having a transplant or not; and should everyone receive maintenance therapy after transplant,” Dr. Bensinger said.

Dr. Bensinger reviewed the results of several early drug trials that compared triplet with doublet therapies or ones that compared novel drug regimens with standard therapy at that time. The response rates were typically higher for the triplets than for the doublets because of the use of ASCT. The percentage of patients who achieved a near complete response or better was improved with ASCT, he said.

Multiple trials have shown that getting a complete response is a surrogate for prolonged survival. “The greater percentage of patients that can achieve a complete response, the better their outcome is likely to be,” Dr. Bensinger said.

He summarized the results of four prospective randomized trials that compared novel induction with novel drug with transplant. Patients received one or more of the new drugs for their initial therapy, and then the comparator was either ASCT given as one or two transplants or a novel drug regimen or standard therapy.

“It is safe to say that ASCT improves the depth of response, regardless of which induction therapy is used,” he said. “The four trials that compared differing induction and conventional chemotherapy consolidation versus one or more transplants all showed improved PFS. Two of the trials with more than 36 months of follow-up showed improved OS. It is safe to say that ASCT remains an important consolidation therapy even after novel drug induction and, in my opinion, should be the standard of care for eligible patients.”

As for which therapies are better for induction, several trials have indicated that triplets in general are better than doublets, Dr. Bensinger said. One of his concerns with the oral therapy is “whether we are sacrificing efficacy for convenience.”

“Novel drug combinations have become the standard of care for patients with newly diagnosed multiple myeloma, but high-dose melphalan and ASCT improves the depth of remission regardless of the induction regimen, translating into better PFS and OS,” he said. “I think triplets of VRD or bortezomib, thalidomide, and dexamethasone are the best induction regimens. Maintenance therapy with lenalidomide improves PFS and OS and should be considered for the majority of patients with myeloma.”

Future directions for research and therapy, Dr. Bensinger said, may include incorporation of immunotherapies into frontline therapy, with the use of either daratumumab or elotuzumab. He predicted that there will be increased reliance on minimal residual disease testing to guide therapy and that combinations for maintenance therapies will be one of the next steps to be studied.

“Ultimately, I think we are going to select therapies based on genetic risk factors by looking at the myeloma cells,” he said. 

-Kathy Holliman, MEd