The treatment of patients with newly diagnosed multiple myeloma continues to evolve. The use of melphalan and prednisone in the early 1960s provided the first boost in survival for patients with this disease. The application of high-dose therapy in the 1990s further improved the outcome, and the last decade has brought forth new classes of drugs, like the proteosome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide, which have added to our therapeutic armamentarium and boosted survival further.
The availability of these drugs has reopened debate on the optimal frontline treatment of patients with multiple myeloma. There is great variability in practice across medical centers. In this article, I will review my approach to the treatment of patients with multiple myeloma who are not eligible for clinical trials. I will also try to provide the rationale for my approach.
The majority of patients referred to my clinical practice are under 70 years of age. These patients are usually eligible for high-dose chemotherapy.
Medicare will pay for a single autologous stem cell transplant until patients reach the age of 78. We certainly perform autologous stem cell transplants for a number of patients in their late 60s and early 70s. However, I take very few patients in their mid-70s to autologous stem cell transplantation. The major determinant of eligibility for stem cell transplantation is the patient's performance status. There is very little data available on the effect of comorbidities and proper geriatric assessment on outcomes of patients with multiple myeloma treated with either a high-dose therapy or conventional treatment approach.
Stem cell transplantation was shown in randomized clinical trials to offer superior progression-free and overall survival when compared with conventional therapy in trials done in the 1990s. The few trials that failed to show a survival advantage used very intensive chemotherapy regimens employing multiple alkylator and anthracycline-based treatments for an extended period, which is not routine clinical practice.
Also, these trials were handicapped by a high rate of crossover with patients on the conventional therapy arm crossing over to stem cell transplantation at the time of progression.
The subsequent advent of immunomodulatory drugs and bortezomib have improved outcomes in our patients. However, with nearly a decade of experience with these drugs, we know that nearly all patients ultimately progress. Most of these patients are healthy enough to seek alternative treatments thereafter. Therefore continuing to sequence both conventional and high-dose therapy options seems to be a rationale approach.
To remove high-dose therapy from the treatment algorithm, one would need to do a randomized trial to demonstrate that patients assigned to treatment with novel agents have comparable or superior outcomes to those treated with high-dose chemotherapy.
Unfortunately, today such trials are difficult to undertake, with resistance even from patient advocates who feel that denying a proven modality of therapy like autologous stem cell transplantation to patients on a clinical trial would be unethical. Certainly, there is currently an ongoing clinical trial being performed by the group at Dana Farber, together with the French Francophone Myeloma Intergroup (IFM), which randomizes patients to therapy with bortezomib, lenalidomide, and dexamethasone, or high-dose chemotherapy.
On this trial, even patients initially assigned to the nontransplant therapeutic option do have their stem cells harvested and stored for future use. Almost certainly, a lot of these patients will ultimately undergo stem cell transplantation after progression on bortezomib, lenalidomide, and dexamethasone. This will probably turn out to be an early- versus late-transplant trial, and not answer the question of whether stem cell transplantation is no longer necessary.
Timing of Autologous Stem Cell Transplantation
I continue to be a proponent of transplant early in the course of a disease as part of initial therapy. I delay stem cell transplantation until the time of first progression in patients whose performance status is limited after their initial three to six cycles of induction chemotherapy. I also delay stem cell transplantation until first progression if a patient prefers to do so for any reason.
A randomized prospective clinical trial done by the French group Myelome Autogreffe, and reported in the 1990s, showed that delaying transplant until first progression offered the same overall survival as transplant employed as part of initial therapy. However, delaying transplant to first progression did reduce event-free survival, resulted in patients requiring treatment for longer periods of time, and adversely impacted quality of life.
Though no prospective data is available in the era of immunomodulatory drugs and bortezomib, analysis of registry data suggests that delaying transplant until first progression is probably still acceptable.
Some have taken this data to support delaying transplant until beyond first progression. I think that this is not an appropriate strategy, and I usually dissuade patients who are referred to me for stem cell transplantation after failure of multiple lines of therapy.
As with the situation for any therapy employed later in the course of the disease, progression-free survival continues to decrease as transplant is pushed to much later lines of therapy. It is conceivable that at some point if delayed too long, the benefit in terms of progression-free survival after stem cell transplantation may be limited to just a few months, of which several weeks may be spent recuperating from the adverse effects of high-dose therapy. In such a scenario, patients may feel cheated that they went through a somewhat harsh treatment for little benefit.
I have adopted three-drug induction therapy as standard for my transplant-eligible patients. This is based on early data from clinical trials suggesting higher rates of complete remission both pre- and post-transplant, and superior progression-free survival when three drugs are used in the induction regimen, as compared with two.
The data from these trials are not mature enough at this time to show a survival advantage. However, since most clinical trials have shown that complete remissions to frontline therapy in patients with multiple myeloma is a surrogate for long-term overall survival, my adoption of three-drug regimens is based on the hope that with longer follow-up, these patients would live longer as well.
My most common induction regimen is three to four cycles of treatment with a combination therapy of bortezomib, lenalidomide, and dexamethasone. This is based on the high overall response rate and complete response rates observed with this regimen in frontline clinical trials. In those patients who present with renal insufficiency, I substitute Cytoxan for the Revlimid in this three-drug regimen, given the higher hematological toxicity and need for dose reductions with lenalidomide in this patient population.
For patients who cannot afford co-pays for lenalidomide, I use bortezomib with dexamethasone as a two-drug combination. Alternatively, for those who wish to have the convenience of an all-oral regimen, and avoid visits to the physician's office on a frequent basis, I may go with lenalidomide and dexamethasone. For patients who get a two-drug induction regimen, I generally wait four to six cycles before moving on to autologous stem cell transplantation.
Stem Cell Transplantation
I move on to high-dose therapy with melphalan after a finite period of induction therapy, as discussed above. This approach is based on the fact that in randomized clinical trials, patients assigned to autologous stem cell transplantation underwent high-dose therapy after a fixed number of cycles, as long as they did not have disease progression.
In fact, Phase II clinical trials have shown that even patients with disease progression on induction regimens seem to benefit from a high-dose chemotherapy approach. The use of prolonged induction regimens to attain greater depth of response before moving on to high-dose therapy is not supported by data. It is instructive in this regard that a randomized trial employing CD34 selection as a purging strategy failed to show any benefit either. Also, on the contrary, some take the stance that those patients who have achieved a deep response may not benefit by an immediate stem cell transplant, and that it may be best to delay stem cell transplantation in these patients. This too is not supported by any prospective data.
Tandem Autologous Stem Cell Transplantation
I utilize a tandem transplant approach only in patients who have less than a very good partial response after their first transplant, and whose insurance will cover this as an approved benefit. However, many individuals undergoing stem cell transplantation are over 65 years of age and are enrolled on the Medicare program, which does not pay for tandem stem cell transplantation. It is, however, unclear whether a tandem transplant is required in an era of increased use of maintenance therapy.
Since the presentation of the CALGB 100104 data showing a survival advantage in patients receiving maintenance therapy with lenalidomide post autologous transplant at the International Myeloma Workshop meeting in Paris in May 2011, I have adopted a policy of lenalidomide maintenance for patients post-transplant.
However, a French study (IFM-2005-02) looking at lenalidomide maintenance post autologous transplant has yet to show a survival advantage, though progression-free survival was superior in those patients who received lenalidomide maintenance as compared with no maintenance.
It is unclear why the French trial has failed to show a survival advantage. This may possibly be related to the fact that patients on the French study, in contrast to the patients enrolled on the CALGB trial, were treated more intensively up front. Half these patients received an anthracycline-based induction, half the patients received DCEP as part of induction therapy, approximately 20% underwent tandem stem cell transplantation, and all patients received two cycles of consolidation therapy with Revlimid and dexamethasone given at a dose of 25 mg post autologous transplant before being randomized to lenalidomide maintenance versus observation.
I have tried to reconcile these two conflicting trials by adopting a policy of using lenalidomide maintenance for a fixed period of two years. My decision to use a finite period of maintenance therapy is further supported by the fact that current ongoing clinical trials employing lenalidomide maintenance do use it for a finite period of time. Also, I have a somewhat low threshold to stop lenalidomide maintenance therapy in patients who experience side effects such as GI disturbance, fatigue, and cytopenias.
For patients with high-risk cytogenetics — deletion 13 on cytogenetics, t(4;14), t(14;16), t(14;20) and 17p deletion—and patients who have renal insufficiency at the time of diagnosis, I add bortezomib at a dose of 1.3 mg/m2, dosed every two weeks for a total of two years of therapy, in addition to the lenalidomide, as maintenance.
This practice is based on the fact that patients who have adverse-risk cytogenetics have shorter progression-free survival after autologous stem cell transplantation, and bortezomib overcomes the adverse impact of deletion 13 and translocation 4;14. Also, in a randomized trial done by the HOVON Cooperative Group, patients who were randomized to bortezomib-based induction, followed by autologous transplant and bortezomib maintenance 1.3 mg/m2 given every two weeks for a total period of two years, compared with patients receiving VAD for induction chemotherapy pretransplant, and then thalidomide as maintenance therapy post-transplant.
In this trial, the bortezomib induction, followed by the bortezomib maintenance arm, had a survival advantage. The survival advantage was especially marked in patients with adverse-risk cytogenetics, including deletion 13, t(4;14) and also patients with deletion 17p, seem to do much better as well. Also, patients who had renal insufficiency at the time of diagnosis had far better outcomes as compared with the control group.
Patients with Renal Insufficiency
In patients with renal insufficiency at diagnosis, I think it is especially important to be aggressive with a three-drug regimen to achieve rapid cytoreduction in an attempt to salvage renal function. It has been shown that patients who reverse renal failure within two months of diagnosis have survival nearly akin to those who present with renal dysfunction. Failure to reverse the renal dysfunction in a timely manner, on the other hand, confers an inferior survival.
In patients with renal insufficiency, it has been shown that the use of bortezomib-based regimens leads to a greater rate of salvage of renal function. As noted above, the combination of bortezomib, Cytoxan, and dexamethasone is my preferred regimen for these patients.
In patients with a good performance status who fail to reverse their renal failure, I still proceed on to stem cell transplantation, as long as the patients have a good performance status. For patients who remain on dialysis at the time of stem cell transplantation, I reduce the dose of melphalan from 200 mg/m2 to 140 mg/m2.
Certainly, patients with renal dysfunction have a 5% to 10% rate of mortality with high-dose therapy, as compared with the usual 1% to 2% mortality rate in patients with normal renal function. However, several series of patients with dialysis-dependent renal failure seem to report benefit for this patient cohort with the use of high-dose therapy.
In patients who are not eligible for autologous stem cell transplantation, my practice is usually to use a two-drug combination. For convenience, the most common two-drug combination that I employ is lenalidomide and dexamethasone, given the convenience of this all-oral regimen. For patients who have high-risk cytogenetics, or renal insufficiency, I will use bortezomib and dexamethasone.
Although the three-drug combination of bortezomib, melphalan, and prednisone, and some of the trials looking at three-drug combinations of melphalan, prednisone, and thalidomide have shown a survival advantage to patients treated with melphalan and thalidomide, alone, this may not be an adequate clinical comparator, and modern two-drug combinations may be as good.
Also, although these three-drug regimens have been studied in patients over age 65, several of these patients are transplant-eligible in this age group. The true elderly who are not transplant candidates are often not very tolerant of these three-drug combinations either. The use of the three-drug combination of melphalan, prednisone, and lenalidomide has been associated with high rates of neutropenia requiring growth factors, which is not optimal in this elderly population that has other alternatives. Also, this three-drug regimen is still to show a survival advantage as compared with use of melphalan and prednisone alone.
Outside the context of a clinical trial, I rarely take recourse to upfront allogeneic transplantation. However, I may discuss this as a therapeutic option in the few young patients under the age of 40 that I see.
In this scenario, I have a detailed discussion with the patients regarding the data on efficacy and the morbidity and mortality, including, but not limited to, acute and chronic graft-versus-host disease, opportunistic infections, and other transplant-related toxicities.
To date, two randomized clinical trials done in Europe (Bruno et al: NEJM 2007, Bjorkstrand et al: JCO 2011) have shown a survival advantage to the use of a tandem autologous, reduced intensity allogeneic transplant strategy compared with tandem autologous stem cell transplantation. However, another trial in high-risk patients done by the French (Moreau et al: Blood 2006) did not show any survival advantage.
Two additional trials (HOVON 24 and CTN 0102) are also apparently not showing a survival advantage. However, the HOVON 24 data seem to suggest that a survival advantage in favor of the allogeneic transplant arm may emerge with longer follow-up. Also, in the CTN 0102 trial, it is felt that a survival advantage may emerge on longer follow-up for the high-risk subset.
The use of bisphosphonates for reduction of skeletal-related events is something that I practice for those patients who have evidence of skeletal involvement on routine skeletal survey. For those patients who have a normal skeletal survey, I lately have started performing MRI scans of the spine and pelvis, and if bony lesions are detected, then I am inclined to put these patients on a bisphosphonate as well.
Although the randomized clinical trials that established the benefit of bisphosphonates allowed only patients who had evidence of bony destruction visible on plain radiographs, it seems logical that even patients with only MRI-detectable skeletal abnormalities would benefit, given that bisphosphonates have also been shown to be effective, even in patients with smoldering myeloma.
The optimal duration of bisphosphonate use is still debated. Currently ASCO guidelines suggest that these drugs be given for two years post-diagnosis, and be stopped thereafter if the disease is inactive.
I, for the most part, follow these guidelines. However, the recent MRC IX trial showed a survival advantage with the use of zoledronic acid as compared with patients receiving clodronate, independent of its effect on skeletal-related events. Although on this trial bisphosphonates were given long-term for the duration of the follow-up, it is unclear whether a more abbreviated course of bisphosphonates may confer the same survival advantage. Since the results of this trial have become available, I have adopted the practice of reducing the bisphosphonate use to every two to three months after the initial two years, rather than stopping it at that time.
For patients who receive bortezomib, it is important that prophylaxis against herpes zoster be instituted. For patients receiving lenalidomide, an anticoagulant needs to be on board if combined with dexamethasone. I use 81 mg of aspirin for the vast majority of my patients. However, for those with more high-risk disease, as evidenced by a previous history of deep venous thromboses, immobility, known coagulopathies, etc., I use full anticoagulation with warfarin or low molecular weight heparin.
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