With powerful new drugs capable of achieving sustained and deep remissions in multiple myeloma, the role of upfront stem cell transplantation is being questioned by experts, who debated the pros and cons at the National Comprehensive Cancer Network (NCCN) 9th Annual Congress on Hematologic Malignancies, held recently in New York.1
In Defense of Upfront Transplant
Taking the pro position, Sergio A. Giralt, MD, Chief of the Adult Bone Marrow Transplant Service and Melvin Berlin Family Chair in Multiple Myeloma at Memorial Sloan Kettering Cancer Center in New York, maintained, “The preponderance of evidence supports the use of high-dose melphalan and autologous stem cell transplant as upfront consolidation therapy for myeloma. Until the results of randomized trials come out, high-dose melphalan consolidation should be considered the standard of care for all transplant-eligible patients with myeloma.”
It is agreed that complete remission is an important surrogate for long-term disease control and survival in myeloma, Dr. Giralt continued. “Patients who do achieve a [complete remission] to induction therapy represent a particular group. But even in those patients, high-dose therapy seems to be associated with high rates of prolonged disease control,” he added.
Patients can be stratified for risk, Dr. Giralt continued. A recent multivariate analysis identified the following prognostic factors for progression-free survival in multiple myeloma: less than a complete remission at induction, del(17p) and/or translocation (4:14), International Staging System score > 2.2
A landmark analysis of the nonrandomized E4A03 study found that upfront transplant improved progression-free and overall survival in patients under age 65 as well as in those between age 65 and 70.3 “Going to transplant upfront reduced the burden of disease,” Dr. Giralt said.
Adding newer drugs to the transplant regimen can improve outcomes. Pooled data from four randomized trials found that the addition of bortezomib (Velcade) to transplant improved both progression-free and overall survival, but the overall survival benefit was not observed in the individual trials, only in the pooled data, he said.
“We believe that bortezomib should be part of induction for transplant-eligible patients,” he told listeners.
The rationale for upfront transplant rests on the idea that the more intense the treatment, the better the outcome, he continued. Data suggest that double transplant is better for patients with poor-risk cytogenetics, but the results of the STaMINA trial will provide definitive results, Dr. Giralt said.
Until that time, the current expectation comes from the results of the Cancer and Leukemia Group B (CALGB) 100104 study, which demonstrated a median time to progression of 4.5 years in patients who received lenalidomide maintenance. Finally, Dr. Giralt noted that Raghavendra et al reported at the American Society of Hematology (ASH) meeting that significantly more patients were alive at 10 years if they had initial transplant compared with those who did not.4
An ongoing study initiated in 2009 is using newer drugs as induction therapy (the VRD triplet [bortezomib, lenalidomide (Revlimid), dexamethasone]) and should shed light on the issue of early vs late stem cell transplant in newly diagnosed multiple myeloma transplant-eligible patients. This study, known as IFM/DFCI 2009, is being led by Paul G. Richardson, MD, at Dana-Farber Cancer Institute, Boston.
A separate study is comparing early vs late stem cell transplant in 402 patients younger than age 65, but it is too early to see an advantage in overall survival.5
Risk stratification is an important factor. New surrogate markers of myeloma activity, such as minimal residual disease by flow cytometry or polymerase chain reaction may be helpful in this regard, Dr. Giralt said.
Not All Patients Need Upfront Transplant
Taking the antagonist role, Kenneth C. Anderson, MD, Kraft Family Professor of Medicine at Harvard Medical School and Director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at Dana-Farber Cancer Institute, noted that in the pre–novel therapy era, transplant achieved limited improvement in survival compared with no transplant in newly diagnosed multiple myeloma patients.
“We have shown that we can do better with novel therapies. In the past 15 years, a number of novel agents have become available and these have been integrated in to the treatment paradigm. Now we are at the point where we can ask the question, ‘Do we really need transplant?’” he told listeners.
In the current era using triplet combinations, patients almost universally respond, including some molecular complete remission. “This is an unprecedented time in myeloma, and I believe it is getting even better,” he said.
A recent study with carfilzomib (Kyprolis)/lenalidomide/dexamethasone as first-line therapy in newly diagnosed patients found that all patients achieved at least a very good partial response, and 85% achieved a near-complete or complete response.6
It is possible to achieve minimal residual disease status with novel therapies, he continued. In the past, minimal residual disease could only be achieved with transplant.
“It is a new day in myeloma. We are catching up with chronic myelocytic leukemia [CML]. Now we are worried about one myeloma cell in 1 million cells. In a separate study of carfilzomib/lenalidomide/dexamethasone followed by lenalidomide extended dosing,7 among 27 patients who achieved complete remission, 100% were minimal residual disease–negative by flow cytometery. This is an unprecedented response without transplant,” he stated.
The investigational agent ixazomib, an oral “son of bortezomib,” may represent an advance over bortezomib. In a study of weekly ixazomib plus lenalidomide and dexamethasone, 48% of patients achieved 100% reduction in M protein, and these reductions were seen at multiple dose levels.8 Of nine patients with minimal residual disease samples collected in this trial, 88% were minimal residual disease–negative.
“This is very early data, but there have been few relapses,” Dr. Anderson continued.
A separate study of this triplet combination showed that the depth of response increased over the course of treatment.9 Of patients who achieved stringent or standard complete remission, 82% of 12 patients who provided samples were minimal residual disease–negative.
“The extent of response is quite high,” Dr. Anderson said.
The burning question is whether early or delayed transplant is preferred in the era of novel agents. Thus far, studies suggest that there is little difference in progression-free survival with early vs late transplant in patients who are treated with novel therapies upfront.
Cytogenetics matter, Dr. Anderson continued. Patients with high-risk genetics do slightly worse, but when bortezomib or lenalidomide are used together as maintenance, high-risk patients do better, he explained.
“At our center, we use lenalidomide/dexamethasone or lenalidomide/bortezomib/dexamethasone. We can tell you what we think, but does that really matter? We need data to inform NCCN guidelines,” Dr. Anderson continued.
Two ongoing trials are looking at early vs late transplant in patients treated with novel agents: the European Intergroup Trial and a study at Dana-Farber called DETERMINATION.
“In today’s world, we have a new era of novel agents that achieve unprecedented responses. They can achieve [minimal residual disease] whether or not transplant is included. Again, maintenance therapy with novel drugs can prolong progression-free and overall survival. In the past and today, early vs late transplant appear similar with novel therapies. Ongoing trials will establish the added value of early vs late transplant. My conclusion is that not all newly diagnosed patients need early transplant therapy,” Dr. Anderson stated. ■
Disclosure: Drs. Giralt and Anderson reported no potential conflicts of interest.
References
1. Giralt S, Anderson K: Debate: Is there a role for upfront transplant in the current management of symptomatic multiple myeloma? NCCN 9th Annual Congress on Hematologic Malignancies. Presented September 20, 2014.
2. Cavo M, Salwender H, Rosiñol L, et al: Double vs single autologous stem cell transplantation after bortezomib-based induction regimens for multiple myeloma: An integrated analysis of patient-level data from phase III European studies. American Society of Hematology Annual Meeting. Abstract 767. Presented December 9, 2013.
3. Siegel DS, Jacobus S, Rajkumar SV, et al: Outcome with lenalidomide plus dexamethasone followed by early autologous stem cell transplantation in the ECOG E4A03 randomized clinical trial. American Society of Hematology Annual Meeting. Abstract 38. Presented December 5, 2010.
4. Raghavendra M, Al-Hamadani M, Go RS: Long-term (10 years or more) survivors of multiple myeloma: A population-based analysis of the US National Cancer Data Base. American Society of Hematology Annual Meeting. Abstract 760. Presented December 9, 2013.
5. Gay F, Cavallo F, Caravita T, et al: Maintenance therapy with lenalidomide significantly improved survival of young newly diagnosed multiple myeloma patients. American Society of Hematology Annual Meeting. Abstract 2089. Presented December 7, 2013.
6. Jakubowiak AJ, Dytfeld D, Griffith KA, et al: A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood 120:1801-1809, 2012.
7. Korde N, Zingone A, Kwok ML, et al: Phase II clinical and correlative study of carfilzomib, lenalidomide, and dexamethasone followed by lenalidomide extended dosing (CRD-R) induces high rates of MRD negativity in newly diagnosed multiple myeloma (MM) patients. American Society of Hematology Annual Meeting. Abstract 538. Presented December 9, 2013.
8. Kumar SK, Berdeja JG, Niesvizky R, et al: A phase 1/2 study of weekly MLN9708, an investigational oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma (MM). American Society of Hematology Annual Meeting. Abstract 332. Presented December 10, 2012.
9. Richardson PG, Hofmeister CC, Rosenbaum CA, et al: Twice-weekly oral MLN9708 (ixazomib citrate), an investigational proteasome inhibitor, in combination with lenalidomide (Len) and dexamethasone (Dex) in patients (Pts) with newly diagnosed multiple myeloma (MM): Final phase 1 results and phase 2 data. American Society of Hematology Annual Meeting. Abstract 653. Presented December 9, 2013.
