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Thursday, March 7, 2013

ONLINE FIRST: Myeloma: The Pros and Cons of Transplantation




NEW YORK -- To transplant or not to transplant, that is the question for multiple myeloma patients, a question tackled here at the 17th Annual International Congress on Hematological Malignancies. While multiple myeloma remains incurable in more than 95 percent of cases, both overall and progression-free survival have increased substantially in recent years, particularly with the advent of immunomodulatory drugs (IMiDs) and proteasome inhibitors.


These advances raise the question of whether autologous stem cell transplants still have a role in treatment of the disease. In the debate here,


Nikhil Munshi, MD, said yes; and

James Berenson, MD, said no (with exceptions).


Why Delay?

Munshi, Associate Professor of Medicine at Harvard Medical School, turned the question of transplant into “why delay?”


“At an earlier time point patients are healthier, induction cytoreduction is optimal or maximal, and there is less cumulative toxicity,” he said. “There is also emerging data showing that earlier intervention provides better outcome than delayed.”


In the three trials Munshi cited -- IFM90 (Attal et al: NEJM 1996;335:91-97), the Medical Research Council (MRC) VII  (Child et al: NEJM 2003;348:1875-1883) and IMMSG (Palumbo et al: Blood 2004;104:3052-3057) -- the improvement in both overall and progression-free survival for autologous stem cell transplant compared with conventional chemotherapy was approximately 12 months for each trial.


Similarly for the complete response rates, which were approximately four times higher for transplant compared with chemotherapy in each of those three trials. And, transplant patients had a lower risk of progression even compared with a chemotherapy regimen containing a novel agent, he noted.


Munshi also cited a GIMEMA trial from the randomized Phase III Italian Multiple Myeloma Network (Palumbo et al: JCO 2010;28:15(suppl; abstr 8015) in which melphalan-prednisone-lenalidomide (MPR) was compared with high-dose melphalan and autologous transplantation (MEL200) in 402 patients newly diagnosed with multiple myeloma under age 65.


The transplant patients had a 49 percent reduction in the risk of progression at two years (74% for MEL200 vs. 54% for MPR), although overall survival at that time was similar -- 90 vs. 87 percent, respectively.


He said transplant should definitely be performed early in patients with bone disease; who are between 65 and 70 years old; who have renal dysfunction; or who have aggressive disease.


Munshi said this debate question should be definitively answered by the ongoing Phase III IFM/DFCI 2009 trial, in which both lenalidomide and bortezomib are being tested against melphalan plus transplantation. The randomized, prospective trial includes newly diagnosed patients who are transplant candidates.


In that trial, after randomization, induction with lenalidomide (Revlimid)-bortezomib (Velcade)-dexamethasone (RVD), and stem cell collection for all patients, consolidation is done with either melphalan at 200 mg/m2 plus autologous stem cell transplant for the transplant arm, or additional RVD for the chemotherapy arm. Transplant is followed by additional RVD and then lenalidomide maintenance; the chemotherapy arm continues with lenalidomide, with transplant for patients who relapse.


“But until that trial is over, we should stick with transplant,” Munshi concluded.


Role of Transplant Changed in Era of New Drugs

Berenson, President and Chief Medical Officer of the Institute for Myeloma and Bone Cancer Research in West Hollywood, Calif., noted that survival for the disease has greatly improved in recent years -- more than doubling since 2000 to now more than seven years, and in some cases to 11 years.


“Myeloma is not a ‘100-yard dash disease’ anymore -- it’s a marathon,” he said. “It’s better to run 10-minute miles and run all 26 miles in the marathon than four-minute miles and last only five miles.”


With combinations involving already approved drugs and clinical trials of drugs recently and not yet approved, it’s clear that patients have many more options today, he said. And patients need to be able to avail themselves of the opportunity to receive different therapies, and reducing that ability with too much prior therapy is detrimental.


“Patients want the longest possible life with therapy and a disease that has the least impact on their life, and that does not necessarily mean they want the regimen with the highest percentage of CRs,” he said.


Complete responses in multiple myeloma are based on the level of paraprotein and are not really molecular CRs, Berenson said. “There’s very little difference in tumor burden between stable disease and ‘CR.’”


Berenson agreed with Munshi that transplantation is associated with the highest CR rates, which in turn are associated with delay in time to disease progression and prolonged progression-free survival.


But, citing a paper from last year’s ASH Annual Meeting, Berenson said that with front-line carfilzomib-lenalidomide-dexamethasone, the highest CR rates can be without the use of high-dose chemotherapy (Jakubowiak et al: Blood 2012;120:1801-1809).


Another argument in favor of transplant, he said, is that older trials show an advantage in time to progression and progression-free survival, and in some cases, overall survival. But there was no consistent advantage to overall survival from randomized Phase III trials, even prior to the availability of IMiDs and protease inhibitors.


He cited a 2012 study of lenalidomide-dexamethasone (LD) that showed no difference in either progression-free survival or overall survival in patients undergoing transplantation within 12 months of diagnosis or after 12 months (Kumar et al: Cancer 2012;118:1585-1592).


Those authors concluded that “an excellent four-year survival rate of more than 80 percent was observed among transplantation-eligible patients who received initial therapy with LD regardless of the timing of transplantation.”


Berenson also cited the same GIMEMA trial that Munshi did (Palumbo et al), but noted that while there was a significant reduction in the risk of disease progression, the overall survival rates at two years were essentially the same – 90 percent for the transplant arm vs. 87 percent for chemotherapy alone.


And one final point in support of transplant -- that no additional therapy is required afterward -- is moot now that all patients receive ongoing therapy, he said.


Treatment options are rapidly increasing, and “compromising a patient’s ability to receive these options because of toxicity from high-dose therapy is important to consider.”


Berenson also cautioned about interpreting the results, especially for overall survival, from trials in which treatment options are limited. “As multiple myeloma patients are living longer, optimizing quality of life becomes of increasing importance,” Berenson concluded, calling for more specific tumor treatments tailored to each patient’s disease, comorbid conditions, and lifestyle.


Still, in a panel discussion after the debate, Berenson allowed that there are a small number of patients who do require a transplant upfront.