CHICAGO—Two recent studies challenge the use of autologous stem cell transplantation (ASCT) as front-line therapy for younger patients with multiple myeloma.
A Phase III trial tested a regimen of melphalan-prednisone-lenalidomide (also known as MPR, for melphalan-prednisone-Revlimid) against high-dose melphalan at 200 mg/m2 plus autologous transplantation (MEL200) in newly diagnosed myeloma patients. At 12 months, the response rates for both study arms were very similar, and the progression-free survival rate was 91% for both study arms, either with or without ASCT.
In addition, a Phase I/II study showed a 100% response rate for a combination regimen of lenalidomide-bortezomib-dexamethasone (RVD) in patients with newly diagnosed, previously untreated, symptomatic multiple myeloma.
Both studies were reported here at this year's ASCO Annual Meeting.
The lead author of the Phase III study (Abstract 8015), Antonio Palumbo, MD, Chief of the Myeloma Unit of the University of Torino in Italy, said it was the first randomized study to address the question of systemic therapy versus high-dose chemotherapy with ASCT. Preliminary results were presented last December at the American Society of Hematology Annual Meeting, and these updated results confirm the initial findings, he said.
All trial participants first received lenalidomide and low-dose dexamethasone as induction, and had stem cells collected. Patients (median age of 58) were then randomly selected to receive two courses of MEL200 (200 patients), or six 28-day courses of MPR (202 patients).
Dr. Palumbo, who is a member of the Italian GIMEMA group (Gruppo Italiano Malattie Ematologiche Ddell'Adulto), reported that induction therapy resulted in 6% of patients achieving a complete response, 31% a very good partial response, 49% a partial response, 13% stable disease, and 2% had disease progression.
The induction safety profile was very good, he said, with Grade 3/4 adverse events including neutropenia in 9% of patients, cutaneous toxicity in 5%, infections also in 5%, and thrombocytopenia in 3%.
Responses, Survival Rates Similar
The response rates for the 117 patients who completed three courses of MPR and the 122 completing one course of the ASCT-containing MEL200 regimen, respectively, were: complete response 13% vs 16%; very good partial response 42% vs 37%; partial response 36% vs 38%; stable disease 7% vs 5%; and disease progression 1% vs none.
Dr. Palumbo said the complete response rates were lower than expected, but that that was probably due to the lack of bone marrow evaluation after treatment.
At 12 months, progression-free survival rates were the same, at 91% for each group. Overall survival at 12 months is again the same, a projected 97% for each group.
Dr. Palumbo acknowledged that longer follow-up is needed to finally assess these comparisons, but, he said, “the impression is that despite the shorter follow-up, certainly the combination including new agents is reducing the difference between standard treatment versus autologous transplant.”
After chemotherapy or chemotherapy with ASCT, patients were again randomly selected to receive maintenance with a 28-day course of lenalidomide, or no maintenance.
It was too early to have any data on maintenance, but toxicities for the consolidation phase were much higher among the 122 MEL200 patients, compared with the 117 MPR patients respectively: 85% neutropenia for MEL200 vs 48% for MPR; thrombocytopenia 85% vs 7%, respectively; and gastrointestinal 22% vs none for MPR. But dropouts due to adverse events were slightly higher for MPR, 5% vs 3% for MEL200.
‘Unprecedented’ 100% Response Rate
In the other study (Abstract 8016), there was a 100% response rate for a lenalidomide-bortezomib-dexamethasone combination regimen (RVD) in patients with newly diagnosed, symptomatic multiple myeloma. Paul G. Richardson, MD, Clinical Director of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, who reported the data, said that this was the updated, final analysis of the prospective, randomized trial, initial results of which were e-published in Blood in April 12, ahead of print. The final data reported at the ASCO meeting were from a longer follow-up, with a median of 27 months.
The paper's first author is Kenneth C. Anderson, MD, Professor of Medicine at Harvard Medical School and Program Director and Chief of the Division of Hematologic Neoplasias at the Jerome Lipper Multiple Myeloma Center.
Dr. Richardson said that although Phase III studies have shown that both lenalidomide and bortezomib are highly active in reducing tumor burden in relapsed/refractory myeloma, the 100% response rate in a Phase II population and a 57% near complete response rate was unprecedented in this setting.
“Most important, in patients who went on to transplant versus those who did not, early follow-up showed there was no difference in progression-free survival between the groups. Also, the combination was able to override adverse cytogenetics, and there was no difference in quality of response or in progression-free survival.”
The objective of the study's Phase I part was to establish the maximally tolerated dose of RVD, which Dr. Richardson said is critical in upfront trials since the dosing may be quite different from treatment in relapsed/refractory disease. The Phase II objective was to determine the response rate and toxicity signals to inform Phase II trials.
In the trial, bortezomib was given on Days 1, 4, 8, and 11 of a 21-day cycle; dexamethasone on Days 1, 2, 4, 5, 8, 9, 11, and 12; and lenalidomide daily on Days 1-14.
Patients received up to eight cycles of RVD. Those who achieved a partial response or better could proceed to ASCT after receiving four or more cycles. After eight cycles, patients could also receive RVD as maintenance therapy.
Best Responses to RVD
For all 66 patients, the combined near-complete response and complete response rate was 40% at a median of 27 months, and the combined very good partial response and partial response rate was 60%, for an overall response rate of 100%, all without ASCT.
The two-year estimated overall survival rate was 95%, with or without ASCT. And the estimated two-year progression-free survival rate was 68%, again with or without ASCT.
Recognizing that these encouraging results are still early, Dr. Richardson said, they have nonetheless provided a platform for a new trial at Dana-Farber of RVD with transplant versus without transplant.
Role of Transplantation in Era of Novel Agents
The Discussant for both studies, Jean-Luc Harousseau, MD, Professor and Head of the Department of Clinical Hematology, University Hospital Hôtel-Dieu, in Nantes, France, and a member of the Intergroupe Francophone du Mye'lome (IFM), said the two trials clearly addressed the question of best front-line therapy in younger patients in the era of novel agents.
Until now, he said, ASCT has been superior to conventional chemotherapy, and he cited several historical trials showing complete response rates of 15% to 25% for autologous stem cell transplant versus less than 10% for standard chemotherapy.
And median overall survival has been 50 to 60 months for ASCT, versus 42 to 60 months for chemotherapy.
Nowadays, he said, referring to novel agents given prior to ASCT, all novel-agent combinations are superior to the classic VAD regimen. Dr. Harousseau cited very recent data from the Arkansas group's TT3 trial (Long-Term Follow-Up of Autotransplantation Trials for Multiple Myeloma: Update of Protocols Conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences: Barlogie B et al: JCO 2010;28:1209-1214—for which Dr. Harousseau was a coauthor), showing that novel agents improve the outcome in the ASCT paradigm, with an unprecedented five-year event-free survival rate of 71% and overall survival rate of 78%.
That led Dr. Harousseau to pose the question: Do we still need upfront high-dose melphalan with ASCT in the era of novel agents?
“Is it time to abandon ASCT upfront?” Dr. Harousseau said, referring to the outcomes of these and other trials. “My answer is maybe, but not yet, because we still have questions presented by this study.”
First, he said, “in the statistical hypothesis and design, Dr. Palumbo did not show a primary endpoint or a statistical hypothesis, and it may be that the study was underpowered to detect a difference between MPR and HDM [high-dose melphalan] due to improved progression-free survival in both arms.”
Dr. Harousseau's other concerns were that the study addressed two separate questions—MPR vs MEL200, and maintenance vs no maintenance.
“With only 402 patients it might be difficult to show a benefit to high-dose melphalan, and it may be impossible to compare MPR and HDM in some prognostic subgroups, although he showed very interesting data on subgroups,” Dr. Harousseau said.
Second, and maybe more important, is the median follow-up of only 14 months—”It is obviously too early [to assess] overall survival because of the salvage treatments we have available.”
And it is even too early for definitive data on progression-free survival, Dr. Harousseau said, “since we know that lenalidomide maintenance prolongs progression-free survival, both after ASCT and after non-intensive chemotherapy.”
He noted that Dr. Palumbo himself at the most recent ASH Annual Meeting reported a 47% reduced risk in progression-free survival in an update of the MM-015 trial comparing MPR-R (Revlimid) with MPR (Abstract 613).
Response Most Important
Dr. Harousseau said that in his opinion, the most important information in Dr. Palumbo's report at the ASCO meeting was the response rate, showing almost no difference between MPR and MEL200 in complete response plus very good partial response (55% vs 53%) at a median of 14 months.
“But an intent-to-treat analysis is still needed,” since relative response was evaluated as per-protocol in only 239 of 402 patients in the randomized trial.
Moving on to Dr. Richardson's presentation, Dr. Harousseau agreed that the 100% overall response rate among the 66 patients was unprecedented, and that the two-year overall survival rate of 95% was very encouraging.
Also very encouraging was the two-year progression-free survival rate of 68%, not different from that for the 41 patients with ASCT.
In the final analysis of novel agents with or without ASCT in recent clinical trials, Dr. Harousseau said that the progression-free survival rate with RVD in Dr. Richardson's trial appears to be the best, at about 67% at 27 months.
But Dr. Harousseau was not finished with the subject, and he presented yet another wrinkle in the question of where ASCT is heading.
He showed data from a trial with 474 patients by the Italian GIMEMA group presented by Michele Cavo, MD, at the 2009 ASH Annual Meeting (Abstract 351).
Progression-free survival of 85% was achieved after both induction and consolidation with bortezomib-thalidomide-dexamethasone (VTD) and double ASCT. “This might be the difference between the best non-intensive and the best intensive treatment,” Dr. Harousseau, comparing data from the reports by Drs. Richardson and Cavo, respectively.
Dr. Harousseau concluded that “initial results of the MPR-versus-HDM trial do not show any difference between the two, in response rate, progression-free survival and overall survival,” and he agreed with Dr. Palumbo that a longer follow-up is needed before drawing a definite conclusion.
“But the most important point” of the two studies, Dr. Harousseau reiterated, was that “upfront ASCT might be useful only in certain subgroups of patients, so we need a large number of patients to assess different across prognostic subgroups.”
One such large, randomized trial is the new IFM/DFCI (Dana Farber Cancer Institute) Phase III trial comparing VRD for induction and consolidation versus RVD followed by MEL200 and ASCT followed by RVD consolidation. All patients will receive the combination chemotherapy and will have stem cells harvested. Half will then receive ASCT while the others will receive only consolidation with RVD. All patients will receive lenalidomide for maintenance.
The primary endpoint is progression-free survival, Dr. Harousseau said, and with 1,000 patients the question will be whether ASCT is necessary for all or just a prognostic subgroup of patients.
In an interview after the presentations, a coauthor on the trial Dr. Richardson presented commented on that and Dr. Palumbo's trial.
Noopur S. Raje, MD, Director of the Multiple Myeloma Program at Massachusetts General Hospital, noted that Dr. Palumbo's Phase III randomized trial was the first to examine the role of autologous transplantation in a randomized fashion in the context of new drugs.
“The preliminary data suggest that there was really no difference between MPR and Mel-200—the intensive arm versus the less intensive arm—in terms of progression-free survival, in terms of overall survival, and even response rates,” Dr. Raje said. “This is actually very striking.”
She said there was one caveat, that Dr. Palumbo used RD as an induction regimen.
“Most of us have moved beyond RD towards combination treatments. RD gives you a complete remission rate of anywhere between 14% and 18%, and we can do much better than that.”
Dr. Raje, a coauthor with Dr. Richardson on the trial that combined lenalidomide and dexamethasone and then added bortezomib, commented on that report as well. She called the 100% overall response rate in this patient population, with VGPR or better at 74%, “absolutely remarkable.”
“Now, this was a Phase II study, so there was no randomization to transplant versus no transplant in this study. But retrospectively, a preliminary look showed no difference between patients who got transplanted versus no transplant.”
Dr. Raje said she appreciated Dr. Harousseau's comment that there may be a point when transplant may not be needed for all patients—“Coming from a transplanter, that is actually huge,” she said.