Lenalidomide Maintenance in Elderly Patients?

Alway lenalidomide maintenance therayp is not approved, but researchers now have the final results of the melphalan, prednisone, and lenalidomide followed by lenalidomide maintenance study.

According to their study, this will probably translate into routine practice in the next year because it is probable that this therapy will be approved by the European Medicines Agency.

This regimen will be approved only in patients aged 65-75 years, on the basis of the results of that particular study.

Adding Bortezomib: The VISTA Trial

In a large randomized trial, melphalan/prednisone (MP) regimen was compared with the regimen bortezomib plus melphalan/prednisone (VPM). With a median follow-up of 5 years (4.5 years from the last patient enrolled), there was a significant overall survival benefit of more than 1 year (13.3 months) in favor of the experimental arm (VMP group). This benefit was observed across group analyses.

In addition, this study has shown something that is very important about the paradigm of using a more conventional approach (MP up front) and reserving the other drugs until the time of relapse. This study has clearly shown that it is better to use an optimized treatment up front.

The third message of the study was that for the first time, in the analysis of risk for second primary malignancies with the use of bortezomib (in this case, in combination with MP), it showed that the incidence is the same as in the control arm.

The study was not sufficiently powered to analyze the role of cytogenetics because the number of patients with high-risk cytogenetics was very small (22 patients in 1 group and 24 in the other). Initially, we saw an advantage for the experimental arm vs the MP group, but now with longer follow-up, the incidence of second primary malignancies was exactly the same. One could argue that at the time of relapse, fewer patients were receiving bortezomib, but this is not the right answer. The right answer is that no difference in risk for second primary malignancies was seen in this study.

In the VISTA study, we used biweekly dose of bortezomib. Now we have the once-a-week regimen of bortezomib. We had an update of the weekly administration of bortezomib.[3] This clearly indicated (especially in older patients) that not only is weekly bortezomib associated with better tolerance, but at the end of the day, the cumulative dose of bortezomib is higher. The complete response (CR) rate is the same, and there might even be a trend toward a better CR rate, especially with a maintenance phase in these trials. So, clearly, weekly administration of bortezomib is the way to go in older patients, and discussions are occurring about treating even older and frailer patients with weekly doses of bortezomib.

 Early vs Late Autologous Stem Cell Transplant

In younger patients who are eligible for high-dose therapy and autologous stem cell transplantation. A prospective comparison of melphalan/prednisone/lenalidomide vs melphalan (200 mg/mgMEL200 ) in tandem with autologous stem cell transplantation following an induction phase with lenalidomide-dexamethasone (len-dex) was also reported.

Today, early transplant should be considered the standard because the study that compared the conventional approach (a novel agent vs an autologous transplant approach including a novel agent) clearly showed that the use of the autologous transplant significantly improves progression-free survival (PFS). We do not yet have data in terms of overall survival, but there is a clear advantage in terms of PFS. For the younger patient, a strategy including a novel agent as induction, consolidation with high-dose melphalan in tandem with stem cell support, and maintenance should be introduced as quickly as possible.

High-Risk Smoldering Myeloma

A study compared no treatment with a len-dex combination in patients with high-risk smoldering multiple myeloma. There was a survival advantage in favor of len-dex in the trial group.

Basically, the study was len-dex with some kind of maintenance vs observation, and patients who received len-dex had a PFS advantage and a survival benefit. We still have some discussion about whether the survival benefit is meaningful, and so forth, but on the other hand, the difference in terms of delaying progression is very important. Some patients in the control group who progressed had renal insufficiency and bone disease — events that are really not good for patients.

Novel Agents and Combinations

There are three new types of agents that are used to treat multiple myeloma. They are proteasome inhibitors, immunomodulatory drugs, histone deacetylase (HDAC) inhibitors.

Significant data indicate that carfilzomib, a novel proteasome inhibitor, will have a role in myeloma.[6] The study that compared carfilzomib with len-dex vs len-dex in relapsed, refractory myeloma has completed accrual.

Pomalidomide is another interesting agent that may induce responses in 25%-30% of patients with myeloma who are refractory to both bortezomib and lenalidomide.[7] We are very eager to see the data from the randomized trial, which compares high-dose dexamethasone vs pomalidomide and low-dose dexamethasone.

The third agent of interest is elotuzumab, and based on the update that we heard at ASH[8] on len-dex with elotuzumab, ongoing trials are assessing this combination, in both the relapsed, refractory setting and in the front-line setting.

Also there is a new class of drug called MLN. It is a novel proteasome inhibitor, which will be useful for patients, especially (but not only) elderly patients.[9] The drug is effective as a single agent. The combination of lenalidomide, low-dose dexamethasone, and MLN is also promising, so the drug may be combined with MP, lenalidomide, or low-dose dexamethasone.[10] We will have a phase 3 trials for potential approval of MLN in the next few months and years.

It is very good. As a general comment, we will have a more complex treatment approach in the near future because we will have, basically, 3 proteasome inhibitors — bortezomib, carfilzomib, and MLN — with different profiles, so we should use them accordingly in different ways. We already have 3 immunomodulatory drugs: thalidomide, lenalidomide, and pomalidomide. So, in the immunomodulatory setting, we will have to make the appropriate choice of drug according to the patient’s condition. We will have elotuzumab, which is a completely new class of drug, but also the histone deacetylase (HDAC) inhibitors. We will have at least 2 HDAC inhibitors, vorinostat and panobinostat, and probably more are coming.