A Review of the Treatment for Multiple Myeloma - Episode 21
Ola Landgren, MD, PhD: I would like to spend a little bit of time talking about the nontransplant candidates, although I guess we talked about the transplant candidates and discussed how maybe they don’t need to be transplanted even if they could. That’s what we spent a little bit of time talking about, at least many of them. But then there are those patients for whom transplant is not even on the table, the so-called nontransplant eligible. There was the SWOG S0777 trial that was published in The Lancet about 2 years ago. It’s an old study that finally was published showing that the 3-drug combination was superior to the 2-drug combination of Velcade [bortezomib] and lenalidomide and dexamethasone or bortezomib-lenalidomide-dexamethasone was superior to lenalidomide-dexamethasone in the control arm. Not so surprising, as you said before, John.
On top of that, we have another new study that recently led to FDA approval in 2019, the so-called MAIA study using daratumumab with lenalidomide-dexamethasone versus lenalidomide-dexamethasone. This again showed that 3 drugs are better than 2 drugs. What do you think, Sundar? Is this going to be the new standard of care for the so-called nontransplant eligible, or do you think the Velcade is going to stay? What are your thoughts?
Sundar Jagannath, MD: I think it is good that you said that we have to talk about older patients—patients who are not eligible for stem cell transplantation. In this regard, these studies have shown incorporating the anti-CD38 monoclonal antibody, and right now it is daratumumab, either with lenalidomide-dexamethasone or with MPV [mean platelet volume], which was also a study published earlier in the New England Journal of Medicine. When you did that, the daratumumab again added to the depth of response. In terms of prolongation, there was also improved progression-free survival and ultimately it shows a signal on improvement in overall survival too.
Ola Landgren, MD, PhD: Right.
Sundar Jagannath, MD: In older patients, first of all, there is major progress when you look at the SEER [Surveillance, Epidemiology, and End Results] Program, and we talked about the European population-based data—the life expectancy of myeloma patients has gone up. The transplant only addresses people 65 years or younger. Usually in Europe, the age of 65 was the cutoff; in America, maybe 70 years consistently. I would say that the novel drugs really improved the majority because the median age is 70 years. The knowledge has really improved the life expectancy of all patients. These new studies make it even better because of the daratumumab monoclonal antibody with lenalidomide and dexamethasone; all of them are fairly well tolerated. The adverse events include less frequent hospitalizations and things like that.
In the older patient, particularly someone who is 80 to 82 years of age, you get 1 chance to do the best therapy. They are not good after they relapse once or twice because of their physical state. As they get older, they get even more debilitated, and the patients’ philosophy toward ongoing therapy also dramatically changes. They don’t want more incremental treatment with increased adverse events or toxicity. For many reasons, older patients need to be treated with the best treatment available. And in this regard, I find that the addition of daratumumab to LEN [lenalidomide] backbone or MPV [melphalan, prednisone, bortezomib] backbone in Europe is actually very welcome, because they use melphalan-prednisone, and I do use that.
Ola Landgren, MD, PhD: Do you think that’s going to become a popular regimen versus the so-called Vrd [bortezomib, lenalidomide, dexamethasone] regimen in the older population?
Sundar Jagannath, MD: Let me put it this way. There is also a GRIFFIN study. Maybe you’ll talk a little later.
Ola Landgren, MD, PhD: I would like to save that for a little while. We’re going to talk about that at the end of the conversation here.
Sundar Jagannath, MD: I would say Rd [lenalidomide, dexamethasone]—DARA [daratumumab] is excellent. Whether somebody will do Rd [lenalidomide, dexamethasone], VRd-light and DARA, that’s a different issue by itself. But Rd –DARA is well tolerated, and this study is excellent.
Ola Landgren, MD, PhD: But if we stick to 3 drugs for this discussion here…
Sundar Jagannath, MD: This is the best.
Ola Landgren, MD, PhD: DARA, REV [lenalidomide], DEX [dexamethasone] versus bortezomib, REV, DEX. You think that DARA, REV, DEX is an important step forward.
John Fox, MD, MHA: It’s fascinating because the NCCN [National Comprehensive Cancer Network Guidelines]—and I think you agree with this, for those nontransplant eligible patients, newly diagnosed—say triple therapy is the best. Yet in the MAIA study, we looked at a 2-drug combination, lenalidomide and dexamethasone, which would typically be indicated for those patients who were older and frail and aren’t going to tolerate triple therapy. What we showed is that in adding daratumumab to those patients, they do better—surprise. Again, this is the dilemma because today, at least as I read it, RVd [lenalidomide, bortezumab, dexamethasone] is the standard of care in that patient population. But we don’t know if daratumumab is better. You’re asking Sundar the question if this is going to become the standard of care. Based on what? It’s based on indirect comparisons. As a payer, I deal with that all the time, and you must too, to look at indirect comparisons and wonder whether these populations entered into the clinical trial are comparable enough that we can compare the results. Will this become the standard of care? Maybe, because it’s well tolerated.
Ola Landgren, MD, PhD: Here’s the question. The study you were asking for is VRd versus DRd [daratumumab, lenalidomide, dexamethasone]. That’s the study you would like to see.
John Fox, MD, MHA: Correct. Wouldn’t you?
Ola Landgren, MD, PhD: I guess we all want that, but this is not true only for this situation…
John Fox, MD, MHA: I agree.
Ola Landgren, MD, PhD: It’s with everything.
John Fox, MD, MHA: Yeah, but this is where society as a whole is failing because we’re asking and answering questions that are really less relevant than the ones that are most important to patients.
Ola Landgren, MD, PhD: But as practicing physicians, we still have to treat our patients. When I asked Sundar if he thinks this is standard care, I think that’s the question that he and I face every day.
John Fox, MD, MHA: And I do too.
Ola Landgren, MD, PhD: I was asking for his opinion.
John Fox, MD, MHA: I’m not criticizing his opinion. I’m simply saying that wouldn’t it be wonderful if we had evidence to support our opinions rather than just inferential data based on indirect comparisons of trials.
Ola Landgren, MD, PhD: We now know that daratumumab is very far along in its developmental subcutaneous administration. I do think with the subcutaneous administration, that’s going to make it highly competitive in combination with REV—DEX versus VRd. I think the extension of it is also that now we have a potential maintenance therapy with daratumumab that could be given.
John Fox, MD, MHA: Yeah. So, it is once a month subcutaneous infusion for daratumumab with an oral IMiD [immunomodulatory drug].
Ola Landgren, MD, PhD: What’s the payer perspective of that?
John Fox, MD, MHA: If the evidence supports it, we’ll pay for it. I don’t know, what’s the infusion now for IV [intravenous] daratumumab—3 or 4 hours compared with a few minutes of subcutaneous infusion?
Ola Landgren, MD, PhD: The infusion is 1½ hours for the third dose, in other words.
John Fox, MD, MHA: Clearly the subcutaneous will become favored if it’s equally efficacious, which I think the evidence supports.
Ola Landgren, MD, PhD: Right.
John Fox, MD, MHA: It’s more convenient for the patient, so why wouldn’t we want to do that?