If you define ‘cure’ as living long enough to die of something else, then I think we are curing patients—just not enough of them. The road to cure goes through complete remission, so we need to work to get them there.
—Sergio A. Giralt, MD
The field of multiple myeloma is rapidly changing, and the shifts that are occurring impact the management of these patients, from initial diagnosis through multiple relapses. At the 9th Annual New Orleans Summer Cancer Meeting, Sergio A. Giralt, MD, Chief of the Adult Bone Marrow Transplant Service at Memorial Sloan Kettering Cancer Center and Professor of Medicine at Weill Cornell Medical College, New York, shared his approach to various patient subgroups.1 The ASCO Post captured his presentation.
How Far We’ve Come
In 2001, we had little to offer upfront to a newly diagnosed patient: thalidomide (Thalomid) plus dexamethasone or VAD (vincristine, doxorubicin, and dexamethasone), or pulse dexamethasone. But 4 out of 10 patients receiving these treatments would not respond, and 20% would progress on treatment, which meant a significant proportion did not even get to transplant. For the 60% who responded, the discussion was whether to give high-dose melphalan for consolidation. Post-melphalan, there was no well-established maintenance treatment, except for bisphosphonates.
Remember, at that time, the only randomized trial looking at optimal induction was one comparing thalidomide/dexamethasone to VAD. Thalidomide/dexamethasone was associated with improved response rates prior to transplant, but after transplant, the results were similar.2 The question was whether there was an optimal induction regimen for patients undergoing transplant, and the answer was “anything but melphalan,” because melphalan negatively affected stem cell collection
In the early 2000s, multiple randomized trials showed the benefit of autologous stem cell transplant, particularly for progression-free survival, and four trials found an overall survival benefit. The problem in using those data now is that they come from old studies, and we no longer use thalidomide/dexamethasone or VAD for induction.
Choice of Induction Regimen
The question is whether patients with high-risk vs low-risk features should receive the same induction regimen. The randomized trial by Cavo et al back in 2008 was the first to show that triple therapy is better than double therapy.3 The addition of bortezomib (Velcade) to thalidomide/dexamethasone not only improved response rates after induction, but this translated into improvements in progression-free survival (though no overall survival benefit). The progression-free survival benefit was seen in all risk categories—high-risk and low-risk alike.
More recently, at last year’s American Society of Hematology (ASH) Annual Meeting, Cavo et al reported a meta-analysis of the four trials of bortezomib-based induction.4 These were the IFM 2005-1, HOVON-6.5/GMMG-HD4, GIMEMA MM-BO2005, and PETHEMA GEM05MENOS65. In the combined analysis of about 1,000 patients, both progression-free survival (P = .0001) and overall survival (P = .0402) were significantly improved, vs non–bortezomib-based induction before transplant.
With these emerging data, one has to be convinced that the optimal induction regimen for transplant-eligible patients includes bortezomib. I am the first to recognize that this has not been compared to lenalidomide (Revlimid)/dexamethasone, which we commonly use in the United States. But the preponderance of data suggests that the standard treatment should include bortezomib, and that is what I do in my practice.
Patients Ineligible for Transplant
We do not consider patients with poor performance status. This can include the elderly, frail patient, the patient who cannot perform activities of daily living, and the patient with decompensated comorbidities.
Other important barriers to transplantation are socioeconomic: lack of a caregiver, distance from the hospital, inability to comply with post-transplant care, and so forth. Age by itself is not a contraindication. Patients with very low-risk disease also may not need to go to transplant.
Optimal Drug Combinations
For improving the induction response prior to transplant, VRD (bortezomib, lenalidomide, and dexamethasone) is commonly used in the United States, partly because this is the only country where lenalidomide has an upfront indication for transplant-eligible patients. I use VRD or CyBorD (cyclophosphamide, bortezomib, and dexamethasone), interchangeably. These regimens have been compared head-to-head in small phase II studies, and the results are equivalent.
Questions About Consolidation
Should we use the same consolidation regimen for the patient who obtains a stringent complete remission after four cycles of VTD (bortezomib, thalidomide, and dexamethasone), vs the same patient who has persistent disease after this regimen? And who should receive high-dose melphalan and autologous transplant: the patient who achieves a complete remission, the one who does not, both, or neither? This last question is difficult, and can require an hour of consultation with the patient.
Fifteen years ago, the conversation about transplant was relatively straightforward. We said, “We gave you the best treatment, and you still have residual disease. Achieving a complete remission makes a difference. We will, therefore, give you high-dose melphalan, which converts residual disease to a complete remission 30% of the time.” You can’t have this conversation with the patient who is already in complete remission, and with modern induction regimens, 20% are in complete remission.
In E4A03, patients received lenalidomide/dexamethasone for four cycles, then either stopped treatment and went to transplant or not, or continued primary lenalidomide therapy beyond four cycles.5 The important finding was this: four cycles, then stopping is not sufficient. The overall survival rate for this group was 55% at 3 years, compared to 80% for patients who continued on lenalidomide and 92% for those who went to transplant (who were also younger).
We really need a randomized controlled trial comparing early high-dose therapy and autologous stem cell transplant as consolidation for all patients vs late, ie, high-dose therapy and autotransplant only for patients who relapse after primary therapy. Palumbo et al evaluated MPR (melphalan, prednisone, and lenalidomide) vs high-dose melphalan and tandem transplant as consolidation after lenalidomide induction.6 The response rates were 92% and 97%, respectively, and progression-free survival at 12 months was 91%. So we have at least one trial showing the benefit of high-dose melphalan. The problem is that these patients never got bortezomib, and that makes a difference.
Currently, there are two national trials—one in the United States and one in Europe—looking at the optimal induction regimen of VRD, then randomly assigning patients to early vs late transplant followed by maintenance lenalidomide. This should answer the question of whether early transplant is important, or whether we can collect stem cells and hold them until relapse.
With regard to the patient who obtains a complete remission after induction, vs the one with residual disease, I think both should go to transplant. The preponderance of the data, at least until the randomized trials are reported, still suggests a benefit for transplant.
Prognostic Factors Can Guide Treatment
At last year’s ASH Annual Meeting, Cavo et al presented a multivariate analysis that identified three important prognostic factors: inability to achieve a complete remission with induction, the presence of poor-risk cytogenetics at baseline, and disease stage > 2 by International Staging System (ISS > 2).4 These factors worsen progression-free survival outcomes by 80%, 56%, and 57%, respectively.
This information allows us to risk-stratify patients into those with no high-risk features (13%), one adverse feature (61%), two adverse features (23%), or all three adverse features (3%). Their respective median progression-free survival times are 61 months, 56 months, 36 months, and 26 months.
In the context of bortezomib induction, you can tell the patients who lack any high-risk features that they have less than a 50% risk of having to re-treat their disease in the next 5 years. On the other hand, the patient with all three poor-risk factors should consider transplant right away.
Maintenance for (Almost) All
Let’s suppose the patient with low-risk disease has an autotransplant and remains in complete remission, but the patient with high-risk disease still has residual disease after transplant. Should they both get maintenance therapy? This is another difficult discussion.
In 2014, while it is still somewhat controversial, the evidence suggests there is a benefit to maintenance lenalidomide. This was shown in the IFM 2005-02 trial, where even patients who achieved a complete remission prior to transplant had prolonged progression-free survival, and many patients with persistent disease converted to complete remission.7
Similar results were reported in the CALGB 100104 trial, where median progression-free survival was 24 months without maintenance vs 40 months in the maintenance arm.8 CALGB 100104 also showed an overall survival benefit, whereas the French study did not. The potential downside to maintenance is a threefold risk for second malignancies (an increase from 1% to 3%), but this did not affect the survival benefit of these patients.
So I think it is reasonable to offer almost all patients maintenance lenalidomide. The one exception is the patient with low-risk disease who is in complete remission prior to transplant. His or her progression-free survival is about 5 years, and it is reasonable to monitor this patient and initiate lenalidomide upon signs of progression.
Putting all these approaches together, we await the results of the STaMINA trial, which is evaluating the role of consolidation in the context of high-dose melphalan and lenalidomide maintenance. Patients were randomly assigned to a second autotransplant, vs four cycles of consolidation, then maintenance. We will have the results in 2 years.
Possibly, a Cure?
The surrogate marker for long-term survival is complete remission—this is what gives the survival advantage. The importance of achieving a complete remission is the same for transplant-eligible and transplant-ineligible patients. It makes a big difference in both groups. High-dose melphalan has a role in transplant-eligible patients and in my opinion continues to be the standard of care, because it’s the single most effective way of getting a complete remission.
Can we cure myeloma? My answer is that 30% of patients who achieve a complete remission remain in remission 10 years down the line, according to data on the Total Therapy protocol from the University of Arkansas for Medical Sciences, Little Rock. If you define “cure” as living long enough to die of something else, then I think we are curing patients—just not enough of them. The road to cure goes through complete remission, so we need to work to get them there. ■
Disclosure: Dr. Giralt reported no potential conflicts of interest.
1. Giralt S: Multiple myeloma: How to integrate novel agents with stem cell transplantation in the era of targeted therapy. 9th Annual New Orleans Summer Cancer Meeting. Presented July 20, 2014.
2. Macro M, Divine M, Uzunhan Y, et al: Dexamethasone + thalidomide compared to VAD as a pre-transplant treatment in newly diagnosed multiple myeloma: A randomized trial. Blood (ASH Annual Meeting Abstracts) 108:Abstract 57, 2006.
3. Cavo M, Tacchetti P, Patriarca F, et al: A phase III study of double autotransplantation incorporating bortezomib-thalidomide-dexamethasone (VTD) or thalidomide-dexamethasone (TD) for multiple myeloma: Superior clinical outcomes with VTD compared to TD. Blood (ASH Annual Meeting Abstracts) 114:Abstract 351, 2009.
4. Cavo M, Salwender H, Rosinol 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. Blood (ASH Annual Meeting Abstracts) 122:Abstract 767, 2013.
5. Rajkumar SV, Jacobus S, Callander NS, et al: Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: An open-label randomized controlled trial. Lancet Oncol 11:29-37, 2010.
6. Palumbo A, Cavallo F, Ben Yehuda D, et al: A prospective, randomized study of melphalan, prednisone, lenalidomide versus melphalan (200 mg/m2) and autologous transplantation (Mel200) in newly diagnosed myeloma patients: An interim analysis. Blood (ASH Annual Meeting Abstracts) 114:Abstract 350, 2009.
7. Attal M, Christini C, Marit G, et al: Lenalidomide maintenance after transplantation for myeloma. J Clin Oncol 28(suppl):Abstract 8018, 2010.
8. McCarthy P, Owzar K, Hofmeister CC, et al: Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 366:1770-1781, 2012.