Maintenance Therapy and Follow-Up in Multiple Myeloma

Paul G. Richardson, MD:As we think of how we use maintenance therapy in patients, I think it’s important to recognize that the recent meta-analysis has really helped us understand the full clinical benefit of a maintenance approach. Maintenance therapy has been shown to be beneficial in older patients with the success of the FIRST trial, and also, most importantly, it’s clearly become a standard of care, in my opinion, for patients who have undergone autologous stem cell transplantation. And why? Well, because we now have meta-analysis looking at a multitude of trials done both in the United States and in Europe in which we’ve been able to show a survival benefit. Now, that survival benefit is not small. The median survival gain from lenalidomide maintenance post autologous stem cell transplant is at the order of two-and-a-half years. That is very substantial, and it reflects the enormous number of patients and an enormous body of work to illustrate that point. And so, when you have a meta-analysis plus a series of randomized trials that show such benefit to maintenance, it’s important to really consider that as an appropriate choice in patients.

And for which patient? Well, it would seem from the meta-analyses that all categories of patient benefit. Not just those who have not achieved the best response, but even those patients who have achieved a complete response derive clinical benefit from maintenance, which intuitively makes sense. Maintenance is essentially an immunomodulatory strategy with lenalidomide, and in fact, what we’re realizing in the field is that it may be important to even add to that and that there is a clear role for the addition of proteasome inhibition to that platform, as well as other newer strategies that are in development to augment the ability of maintenance to control disease.

So, currently, there is a large body of evidence from phase II studies primarily showing that the addition of a proteasome inhibitor to the IMiD backbone may be very important in high-risk patients. So, patients who have high-risk cytogenetics, who have not had an optimal response to therapy, may benefit, in fact, not only from lenalidomide maintenance, but the addition of proteasome inhibition. And that may take the form of bortezomib, for example, every 2 weeks. There’s even now, studies looking at carfilzomib in this setting. And most importantly, with the recent approval of ixazomib, there’s the ability to think about an oral proteasome inhibitor in this setting, as well. I should emphasize that there are current trials exploring ixazomib plus lenalidomide, and initial studies of ixazomib and lenalidomide have been really quite favorable in this regard.

When you think of following patients, like this lady, after transplant on maintenance, one of the advantages of a maintenance strategy is that you see the patient on a regular basis: monthly for the administration of lenalidomide and a minimum of every 3 months for an MD visit, I would suggest, in order to evaluate the patient to see how blood counts are performing, see how the patient is doing overall. But to some providers, be it nurse practitioner, or physician, or physician extender in the office, it’s very appropriate to assess these patients monthly. In our own practice, that’s what we do. We prescribe lenalidomide according to the guidelines, and at the same time, we use bisphosphonate therapy also. Someone like her, who achieved a sustained remission over time, could reasonably be on bisphosphonate therapy monthly for up to 2 years and then after 2 years move to a three-monthly schedule. The lenalidomide runs in partnership with that.

One of the interesting questions about lenalidomide maintenance is whether or not it needs to be continuous. The dose range is typically 10 to 15 mg daily. In our own group, we tend to use the 3 weeks on, 1 week off schedule because we find a week break quite helpful from the point of view of side effect management. This is particularly important in patients post-transplant. The same paradigm may not be needed for non-transplant patients because we’ve found in our experience, the non-transplanted patients tend to be able to tolerate maintenance in some ways somewhat better, and that’s certainly true in the older population, as well. But regardless, the 3 weeks on, 1 week off schedule of lenalidomide can be very helpful in this setting. So, careful monitoring, assessing at least every month, periodic blood count checks, at least monthly, and then the initial start of treatment. Sometimes, it’s worth doing them once every 2 weeks to see how a patient is doing.

The options for treatment of a patient who is largely asymptomatic, with good performance status and developing biochemical relapse on lenalidomide maintenance alone, are actually quite interesting at this time. In the same context of no obvious progression, clinically, there are even some studies and some lines of thought that suggest some of the antibodies to that platform can be useful. For example, the introduction of elotuzumab as an adjunct to lenalidomide has been of considerable interest. I have to say, my own practice is that if a patient, like our lady, for example, had been on treatment with lenalidomide for 5 years and progressed on this, I might think of a switch to a different IMiD. Now, obviously, the next best IMiD after lenalidomide is pomalidomide. This is a more potent IMiD than lenalidomide; it’s much more potent than thalidomide. It’s almost a synthesis of two of the best aspects of the two molecules. It’s very well tolerated, and we’ve clearly demonstrated that it’s active after lenalidomide failure. So, the use of pomalidomide after lenalidomide has run out of steam, is well accepted as an appropriate strategy.

I have to say, though, in my own practice, I tend to move away from the prior, give it a rest, use a drug like pomalidomide. I would also consider adding an additional agent to that platform. Now, we have a variety of choices. And in that context, we have the choice of a proteasome inhibitor. Could be oral; for example, ixazomib. It could be bortezomib, recognizing that that’s obviously very much a standard of care. And similarly, of course, we could think about more aggressive approaches with a proteasome inhibitor, such as carfilzomib. But in the case of a patient with just biochemical progression, that probably isn’t necessary. What one could reasonably do is switch to another IMiD and, at the same time, thinking about an adjunct that one might reasonably add.

Now, the advent of the antibodies is particularly interesting, though, and we do have preliminary data combining pomalidomide with elotuzumab that is equally impressive and encouraging, although it remains early and the studies have yet to be fully completed, published, and then presented. But certainly, our preliminary evidence is that the combination of pomalidomide and elotuzumab is particularly active, actually, and very well tolerated.

So, in that context, I think clinicians are left with choices. But I think, in the community setting, with someone like this who is active, working full time and so forth, if she has only biochemical progression, I think it’s very reasonable to think about a switch in oral therapy from lenalidomide to pomalidomide, with the appropriate use of a low dose of steroid as a very reasonable strategy. And if, for any reason, that proved suboptimal—in other words, she didn’t respond optimally to that—then one could then add a proteasome inhibitor. And classically, we think in terms of bortezomib in this setting because it’s obviously established, from a variety of studies, that the combination of pomalidomide and bortezomib is very well tolerated and very active. I have to say, we also have initial data now on pomalidomide and ixazomib, which is also very encouraging, showing excellent tolerability and efficacy.

Case Scenario 1:

July 2011

• The patient is a 61-year-old Caucasian female who was diagnosed with stage II MM. Genetic testing showed her to have t(4:16). At the time she was treated with lenalidomide, bortezomib, and dexamethasone (RVD) induction therapy followed by autologous stem cell transplantation.
• She achieved a partial response with RVD and remained in remission. Based on her high-risk cytogenetics, the patient was placed on lenalidomide maintenance therapy.

August 2016

• Routine follow up shows that her M-protein levels have now risen to 1.4 g/dL and her light chain levels continue to rise.
• Although she has developed mild anemia and her creatinine level is slightly elevated to 1.3 mg/dL, she continues to work full-time, has no bone pain, and a has a normal calcium level.