Triplet therapy is very valuable for nontransplant patients with multiple myeloma. We have long-term data with RVd from the SWOG S0777 trial, as well as more recent data from the MAIA trial, and both trials show the significant benefits of triplet therapy over doublet therapy. Even patients over the age of 75 years can benefit from a triplet. We have learned to decrease the dosing in frail patients, and we call this RVd-lite (attenuated doses of lenalidomide, bortezomib, and dexamethasone). In general, you should be able to deliver either RVd-lite or DRd (daratumumab, lenalidomide, and dexamethasone) in most patients. Available data show that patients do better with these regimens than with doublet therapy. 

More recently, we have seen that there may be a small subset of patients who cannot even travel, and that such patients could use an all-oral regimen and still derive the triplet benefits, as shown in the TOURMALINE-MM2 study. Sometimes we think that combining 3 drugs is riskier than using only 2, and many patients are worried about it. I have found that another advantage of using a triplet is that you can often decrease the dose of the drugs more effectively without the loss of disease control as compared with relying on a doublet. Whereas you might give 25 mg of lenalidomide in a standard RVd regimen, you may be able to get away with 15 mg of lenalidomide in the RVd-lite regimen, and the patient may also experience quality-of-life benefits.

The same is generally true in the relapsed/refractory setting. That is, results from almost all trials have shown that triplets give a more sustained progression-free survival and, in many cases, overall survival over doublets. It is more difficult to control a disease that is relapsing when you have just 1 new drug, because when you are referring to “a doublet,” you are really talking about 1 drug plus dexamethasone. 

For the frail patient, the data on the DRd triplet from the MAIA study are very compelling, showing a median progression-free survival of somewhere between 4 and 5 years. Generally, it is easily taken overall, even considering some of the challenges of chronic lenalidomide administration. In my view, that is the standard for the older frail patient. The exception may be for patients who have high-risk disease, where, based on the available data, using a proteasome inhibitor seems to be the better way to go.

So, I agree about the value of triplets. The patients we see are not always reflective of the patients being seen in the community. It is therefore difficult for us to say, “You should always use a triplet,” because there are frail 95-year-old patients for whom more treatment might not be helpful. My personal philosophy about the intensity of induction therapy has changed with the truly older frail patient. In a younger patient, you can hit them as hard as you can, knowing that you can always back off, but at least you have gotten the disease under control. With the older, particularly frail individual, you cannot do the same because it might mean that they will not come back to see you again. Therefore, I think that you have to temper that approach a bit based on what you believe the patient can tolerate. For the majority of patients, a triplet is the preferred option for those who can get through it.

I agree with both of my colleagues. We do use doublets in the elderly population, but it is quite a small minority, and these decisions are based on frailty status rather than chronologic age. As mentioned, even older patients can benefit from the attenuated triplet RVd-lite. 

In the MAIA trial, we have seen that the incorporation of daratumumab up front not only confers value in the transplant-ineligible population but also in patients with high-risk multiple myeloma. Therefore, just because someone is elderly does not mean that we cannot give them triplet therapies; in fact, I would really encourage it. Each patient has individual needs. For example, some patients may want to have all-oral treatments because they live far away, for convenience, and to limit clinic visits in the era of COVID-19. The regimen of the oral proteasome inhibitor ixazomib, together with lenalidomide-dexamethasone, is good in that situation.

Finally, we give lenalidomide (an immunomodulatory drug that works by triggering the breakdown of proteins Ikaros 1 and 3 in multiple myeloma), the proteasome inhibitor bortezomib (which blocks the proteasomal degradation of protein), and dexamethasone, and that triplet works very well. And, for years, people have been asking us how this works. Triggering protein degradation with lenalidomide and blocking it with bortezomib seems like an oxymoron. However, there is a very interesting new concept that may underlie at least some of this benefit of the combination. When you induce death or apoptosis of a cancer cell, in our case myeloma with bortezomib, then the dying myeloma cells can, via a process called immunogenic cell death, trigger an antimyeloma immune response, which is then amplified by lenalidomide.