Here is the body of the article about multiple myeloma related research studies I started to post yesterday, Is It Time to Abandon Up-Front Transplantation in Multiple Myeloma?
Elsevier Global Medical News, written by P. Wendling on the medical professionals only site, Oncology STAT:
He (Dr. Jean-Luc Harousseau) cited data from several trials, including the pivotal phase III VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma) trial, in which the addition of the novel agent bortezomib to standard melphalan and prednisone chemotherapy boosted the complete response rate – even among newly diagnosed elderly patients who were ineligible for aggressive treatment – to 30%, a rate comparable to that delivered by ASCT (N. Engl. J. Med. 2008;359:906-17).
MPR Comparable to ASCT
The current phase III trial involved 402 patients who were younger than 65 years, had newly diagnosed multiple myeloma, and were given lenalidomide plus low-dose dexamethasone induction therapy before randomization to six courses of melphalan/prednisone/lenalidomide (MPR) or two courses of autologous transplantation using high-dose melphalan 200 mg/m2 (MEL200), followed by a second randomization to no maintenance or lenalidomide maintenance therapy until relapse.
There were no significant differences in complete response rates, progression-free survival, or overall survival between the MRP and MEL200 arms, said the lead author, Dr. Antonio Palumbo of the University of Turin (Italy).
The complete response rate was 13% in 117 patients after at least three cycles of MPR vs. 16% in 122 patients after at least one cycle of MEL200 (P = .82). The response rates are somewhat lower than expected, but the data may be underreported because of the lack of bone marrow evaluation after treatment in some patients, he said. The very good partial response (VGPR) rate was 42% with MPR and 37% with MEL200; partial responses occurred in 36% and 38%, respectively.
After a median follow-up of 14.07 months, median progression-free survival at 12 months was projected at 91% for both arms (P = .77), with median overall survival at 97% for MPR and 98% for MEL200 (P = .27). Subset analyses suggest that patients with an ISS (International Staging System) stage of II-III do worse than those with an ISS stage I, as do those with deletion 17 or translocation 4:14 or 4:16, Dr. Palumbo said.
“Longer follow-up is needed to finally assess the role [of novel agents], but the impression is that despite the short follow-up, the combination including a new agent is certainly decreasing the difference between standard treatment vs. autologous transplant,” Dr. Palumbo said.
Dr. Harousseau, director of the Centre René Gauducheau in Nantes, France, agreed that the follow-up is too short to detect differences in overall survival and even in progression-free survival, because it is known that lenalidomide maintenance prolongs the latter after transplant and after nonintensive therapy.
The question of whether up-front ASCT is still needed should be addressed in a randomized trial to avoid selection bias when the patients or doctors choose ASCT, he said. “Is it really time to abandon autologous transplantation up front? Maybe, but not yet.”
Dr. Harousseau suggested that the current study may be underpowered to detect a difference between MPR and high-dose melphalan, and that it may be impossible to compare the two strategies in some prognostic subgroups.
“I think that the most important point is that up-front autologous transplantation might be useful only in subgroups [of patients], so we need large numbers of patients to assess differences across prognostic subgroups,” Dr. Harousseau said.
Significantly more neutropenia, thrombocytopenia, systemic events, infections, and GI events occurred with MEL200 (all P less than .001, compared with MPR).
The trial also evaluated the safety and efficacy of four 28-day courses of induction therapy with lenalidomide 25 mg/day and dexamethasone 40 mg/day. The best response among 370 evaluable patients was complete response in 6%, VGPR in 31%, and partial response in 49%. Again the complete response rate was not high, but the safety profile is one of the best you can find, said Dr. Palumbo, noting that less than 10% of patients experienced neutropenia.
Finally, asking whether the study compared the best available treatments, Dr. Harousseau highlighted the strong phase I/II results presented by Dr. Paul R. Richardson.
100% Response to RVD
The three-drug combination of lenalidomide, bortezomib, and dexamethasone (RVD) is the first regimen in previously untreated multiple myeloma to result in a 100% response rate without ASCT, Dr. Richardson said at the meeting.
The best response to RVD, by modified EBMT (European Group for Blood and Marrow Transplantation) criteria, was a partial response or better in 100% of all 66 patients in the phase I/II study, including 35 patients only in the phase II portion. (See box.)
Responses improved with continued therapy, as 75% of 56 patients who stayed from cycle 4 to cycle 8 saw an improvement, and 53% of 38 saw improvement beyond cycle 8, said Dr. Richardson of the Dana-Farber Cancer Institute in Boston.
With a median follow-up of 27.3 months, 44 patients are without disease progression. Median duration of response, median progression-free survival, and median overall survival have not been reached. The estimated 2-year progression-free survival rate is 68%, and the estimated 2-year overall survival rate is an encouraging 95%, he said.
Sensory peripheral neuropathy occurred in 82% of patients. Dr. Richardson acknowledged that this is an important challenge going forward, but added that the vast majority of events were grade 1, which are reversible in almost all patients and manageable with dose reductions or schedule changes.
Grade 3/4 adverse events included lymphopenia (14%), neutropenia (14%), thrombocytopenia (6%), and hypophosphatemia (5%) associated with high-dose steroids. Thromboembolic events were uncommon at 6%, and there were no treatment-related deaths.
A post hoc landmark analysis of progression-free survival by transplant status in 53 patients who had not progressed at 1 year follow-up detected no difference by whether patients received ASCT or not (log rank P value = .84). Although this finding is encouraging, Dr. Richardson again cautioned that follow-up remains short.
Dr. Palumbo and coauthors disclosed a consultant/advisory role with and honoraria and research funding from Celgene Corp. Dr. Richardson and coauthors reported relationships with more than 10 companies. Dr. Harousseau disclosed a consultant/advisory role with Celgene and Janssen-Cilag, and honoraria from Amgen Inc., Celgene, Janssen-Cilag, and Novartis.
Lots and lots of excellent information! But I feel the article’s title, Is It Time to Abandon Up-Front Transplantation in Multiple Myeloma? is a bit controversial and misleading. No matter how successful novel therapy agent therapy becomes, I find it hard to believe myeloma docs will “abandon” up-front SCT’s anytime soon. They may be used less. They may be postponed until later in the treatment process. But not abandoned. And who is to say the performance of SCT’s can’t also be improved through better induction drug combinations and just the right maintenance therapy.
I believe a more accurate title might have been: Is It Time to Re-evaluate the Role of Up-Front Transplantation in Multiple Myeloma? Maybe it is time to start considering SCT’s are best saved for, say, the first time a patient’s myeloma returns following an initially successful induction and maintenance therapy regimen.
Much to ponder–and still not enough data or consensus among researchers to really know when the optimum time is to go to SCT.
Feel good and keep smiling! Pat