University of Pennsylvania Experts Discuss Treatment Options in Transplant-Eligible and -Ineligible Newly Diagnosed Multiple Myeloma

Alfred L. Garfall, MD

Edward A. Stadtmauer, MD

Dan Vogl, MD, MSCE

Sandra P. Susanibar-Adaniya, MD

During an Around the Practice® program hosted by CancerNetwork®, experts from the University of Pennsylvania discussed multiple patient cases involving those with high-risk transplant-eligible newly diagnosed multiple myeloma and those who were transplant ineligible. The panel was led by Alfred L. Garfall, MD, director of autologous hematopoietic stem cell transplant and assistant professor of medicine at Penn Medicine.

Additional panelists included Edward A. Stadtmauer, MD, section chief of hematologic malignancies, and Roseman, Tarte, Harrow, and Shaffer Families’ President’s Distinguished Professor; Dan Vogl, MD, MSCE, director of the Abramson Cancer Center Clinical Research Unit, and associate professor of medicine; and Sandra P. Susanibar-Adaniya, MD, assistant professor of medicine at Penn Medicine.

The experts discussed treatment regimens best suited to each patient population, and considerations for clinicians who may need to stop therapy due to toxicity or potential toxicity.

Patient Case 1

Garfall: Can you discuss the treatment regimen decisions? (Patient Case 1)

Stadtmauer: The radiation and the plasmacytoma were appropriate. That was the symptomatic disease. When we started the RVd regimen, we had very good data for patients of this age compared with the Rd regimen with a high response rate and survival advantage. The current question that has been raised by the phase 3 MAIA study results [NCT02252172], which have been remarkable, is is the addition of daratumumab [Darzalex], a CD38-directed monoclonal antibody, useful and appropriate in all patients who [have transplant-eligible newly diagnosed multiple myeloma]?¹ This is something that is an important comparison to potentially be studied. The RVd regimen has been shown in this setting to be very effective and is certainly appropriate, and we have to compare that to the daratumumab, lenalidomide, and dexamethasone [DRd] regimen which also has high response rates and is appropriate for this group of patients.

Garfall: How can the MAIA regimen apply to this patient?

Susanibar-Adaniya: The MAIA study was a phase 3 randomized clinical trial that studied the addition of daratumumab to the standard of care [SOC] for [patients] who weren’t eligible for transplant. In addition to the backbone of lenalidomide/dexamethasone, daratumumab is added. The results have been very exciting. In close to 5 years of follow-up, the median progression-free survival [PFS] has not been reached for the subgroup of patients who received daratumumab vs 36 months [in the lenalidomide arm]. That’s very similar to what was shown in the small phase 2 VRd–lite study. For people who are borderline candidates for transplant, these data allow us to have a deep discussion—maybe not in 1 visit but in a couple of visits—about what the patients prefer. We have many options for these patients but starting with daratumumab, lenalidomide, and dexamethasone is an excellent option.

Garfall: When first beginning therapy, how important is it to have the ability to change regimens if it’s not working for your patient?

Susanibar-Adaniya: It will be nice if all the patients achieved the best response in the first month, but that’s not the case. What we need to assess is how the patient can tolerate this because several studies have shown that the responses continue to deepen across the spectrum of induction, consolidation with or without transplant, and even maintenance [therapy]. We have patients who continue to [experience] a deepening of response even in their third year of maintenance; that has been shown in the phase 2 GRIFFIN trial [NCT02874742].² I think what we need to be careful about is paying attention to the [adverse] effect profile, especially because in the myeloma field, we have been blessed with a variety of tools that we can use. As we are becoming more efficient at being able to assess which medication will be better for which patient, we also have become better at picking up and adjusting the medications in a way that the patient can continue to be on that and benefit from it.

Just to simplify this, if you compare the lenalidomide/dexamethasone arm in the MAIA trial to the historical trials before it, the benefit was longer; they have [better] PFS and longer overall survival. [This tells the myeloma] community as a whole that we have become better at providing supportive care to our patients.

Stadtmauer: I think this is so important because sometimes when you crack open the textbook, you’ll see doses of 25 mg of lenalidomide and twice weekly doses of bortezomib. So much of the success of these therapies is their long-term use. If you generate tons of toxicity at the beginning, you frequently will reduce the ability [to continue its use]. As patients become older and frail, it’s important to think at the beginning of doses and schedules that will be well tolerated, and then make adjustments to either increase or decrease doses and frequency. You can still have tremendously good outcomes.

Vogl: At the same time, if you start off with a regimen, especially a simpler regimen with triplet therapy instead of quadruplet, you may not see the kind of response over the first 2 cycles indicating that the patient is likely to achieve a deep response with induction therapy. Usually, I’m looking for at least a hint of response after 1 cycle and preferably clearly heading into at least a partial response after 2 cycles; if you’re not going to get that with your initial therapy regimen, it is easy to add in daratumumab, or—if you’ve left out bortezomib—to add in bortezomib. If the patient’s already starting to respond, you can also attenuate doses to make the drugs more tolerable and make sure that you can achieve that deep response with initial therapy, which probably is a good marker for better long-term outcomes.

Patient Case 2

Patient Case 2 (continued)

Garfall: Can you discuss how this patient was treated, and why you chose this regimen? (Patient Case 2)

Susanibar-Adaniya: When the patient initially came out to our center after the first cycle of the VRd, she was having trouble tolerating the medication. She was having a good response so more than 50% and her free κ light chain went down, but she was having severe shortness of breath. The pain was keeping her up. The decision was to change to a regimen that can be equally successful but can improve her quality of life. Fortunately, she did well after the change. The neuropathy improved, so now she says that she’s back to her baseline and is able to enjoy life.

We haven’t needed to reduce her lenalidomide or anything like that, so we continued her on daratumumab. Now, she’s receiving it monthly. She continues to be on lenalidomide, which was adjusted for her renal [impairment]; she’s getting 10 mg for 3 weeks on, and 1 week off.

The only thing that I changed that was different from what was written in the MAIA study is that I decreased the steroids when her response started to deepen, not only because she’s diabetic but because we know patients who suffered from the [adverse] effects of prolonged steroid use. That’s something that needs to be discussed more because we also have the data from the small phase 3 randomized [ELOQUENT-2; NCT01239797] trial that was done in Italy showing that after 9 cycles of lenalidomide and dexamethasone, a patient can safely receive just lenalidomide.3

Garfall: What are the differences between traditional VRd and VRd-lite?

Vogl: It’s interesting because our categorization of therapies according to transplant-eligible and transplant-ineligible patients dates to the time when the SOC for older patients with myeloma was an oral melphalan-based regimen, which would then make it hard to collect stem cells and go on to transplant. Since we showed that lenalidomide and dexamethasone were at least equivalent and probably superior to melphalan/prednisone/lenalidomide, and we’ve abandoned the oral melphalan, the distinction doesn’t matter as much. This is why we don’t necessarily have to label the patient as transplant eligible or transplant ineligible when we first see them.

For this patient, it was important to acknowledge that she had a lot of comorbidities at the time of presentation and a high risk of complications, not just from neuropathy but from fluid retention, especially from the steroids and the bortezomib. The idea of using a dose-attenuated regimen, making sure that the initial bortezomib dosing is weekly instead of twice weekly, lowering the lenalidomide dose, and being careful about steroid dosing, does make for a tolerable regimen for many patients.

It's true that the daratumumab/lenalidomide/dexamethasone regimen has less toxicity than the bortezomib combination because daratumumab is so well tolerated. For my especially frail patients, I will choose to leave out the bortezomib and include daratumumab instead. For patients who have a reasonable performance status at the time that you’re starting therapy, I don’t think it’s wrong to use the bortezomib-based regimen. Because as long as you’re observing carefully, to me, the key for this case was noticing after the first cycle that the patient was developing a painful peripheral neuropathy and changing therapy immediately. The worst thing you can do is to stick to the regimen despite emerging toxicity when there are good alternatives.

Garfall: Let’s review the risk-adapted approach and whether it’s applicable to use in patients who are of high-risk status or who have cytogenetic abnormalities. Is that really rooted in evidence or should we just think about comorbidities, [adverse] effect profiles, and tolerances of these medications in and of themselves?

Stadtmauer: The issue of bortezomib comes from one of the oldest studies, the phase 3 APEX study where we randomized patients to dexamethasone vs bortezomib and dexamethasone. [We] found that the patients who had 14th chromosome abnormalities did better, which was considered to be a high-risk feature. [Moreover], the addition of bortezomib seemed to alleviate the high-risk [nature] of that feature.4 The data aren’t very strong in terms of if you don’t give bortezomib in the current era to these groups of patients, those patients definitely do worse. I don’t think there are a lot of strong data that way, so that's not the way to make the decision. On the other hand, most patients with dose-adjusted bortezomib and frequency of dose [adjusted] bortezomib can tolerate that as long as they’re very sensitive to the development of neuropathy, and either reduce the dose or discontinue the medication when that starts happening.

Vogl: In some ways, it’s important to keep in mind that the decision of what to give first to a patient does not necessarily mean that that’s the only thing that they’re going to get. We have very little comparative information that would tell us the best combinations and sequences of therapy. Arguing about whether a patient needs to get bortezomib because of their cytogenetic risk as part of their initial therapy ignores the fact that if they're not going to get bortezomib as part of first-line therapy, there’s a very high chance that they’re going to get bortezomib as part of second-line therapy.

The same applies to daratumumab. If you’re not going to use it as part of first-line therapy, you’re very likely to use it as part of second-line therapy. The trickier question is when is the optimal time to use these agents for each individual patient? I don’t think we have clear clinical trial data to guide those decisions based on cytogenetic risk profile at the time of diagnosis. I think we can decide based on the patient’s clinical characteristics, their burden of disease, and their risk of getting particular [adverse] effects to individualize the therapy for the patients on that basis.

Stadtmauer: Toxicity or potential toxicity is probably higher on the list of how we should choose our regimens than biological characteristics. This patient had cardiac issues which is an interesting area because we know that the proteasome inhibitors as a class do have a little bit more issues with cardiac potential—both how to adjust the doses, as well as potential toxicities. Renal insufficiency is very key. Those 2 characteristics are key in our decision-making regarding regimens and doses for these patients.

Susanibar-Adaniya: What I wanted to point out is that in the studies when they do the post-hoc analysis and they separate between groups so you could see that standard-risk and high-risk patients, all responded. The problem comes with the follow-up. The high-risk patients tend to relapse quicker. That should also make us more vigilant when we’re observing our patients. In the follow-up when you see that a patient responds but then plateaus, maybe their myeloma markers start creeping back up. Then you must pay attention and not wait too long for another medication that will be safe and very well-tolerated.

Garfall: What is your approach for patients who are receiving daratumumab plus lenalidomide and are not planning to have a transplant?

Vogl: The first principle is to make sure that once you’ve achieved a good response, you then turn the treatment regimen to something that’s going to be reasonably convenient and well-tolerated for the patient—[for instance], lowering the dose of lenalidomide to a very tolerable dose and not necessarily continuing the same dose indefinitely. The daratumumab on the standard regimen shifts to monthly dosing, which then becomes very convenient for the patient. I’m a big believer in both reducing the frequency and the dose of the steroid component of the regimen and, in many patients, eliminating steroids completely, even as a pre-medication for daratumumab. I think both in clinical practice and even in some clinical trials, we’ve shown that we can do so completely safely so that the patient’s treatment—even getting no pre-medications for daratumumab—becomes a very quick monthly office visit, which can be combined with regular monitoring of their labs.

Lenalidomide continues at a low tolerable oral medication at home, which is a regimen that patients can envision staying on for a long time. My tendency in that situation then is if that regimen is, indeed, well-tolerated and it’s continuing to work, I don’t think we’ve shown any advantage from stopping a treatment that's working. If the patient’s having [adverse] effects, I very much believe in further lowering the dose of lenalidomide or stopping it completely. By the same token, I think we can correctly tell our patients that we don’t know for sure that continuing therapy will lead to better outcomes. [Therefore], if a patient has a strong preference to stop therapy, it may be just as good to stop. Patients who want to should be told that that’s an okay thing to do. Although our standard practice is in part based on the success of lenalidomide maintenance after autologous stem cell transplant and prolonging overall survival. We tend to apply that to other situations and think that ongoing continued therapy, especially with a lenalidomide-based regimen, is probably the right thing to do.

Stadtmauer: Most of the new medicines are from studies, and we’re usually studying it in a setting of patients who have relapsed and refractory disease. If we see someone who’s responding, we’re very hesitant to stop the medication. Most of our practice is to continue medicines. We’re victims of the past; in the past, we didn’t have such effective regimens and [the ability to treat continuously]. I think that the theme that we’re all [highlighting] is that our patients are going on and doing well, less is more, minimizing the toxicity, and giving back the quality of life. The whole reason we’re doing this is to give people long, happy lives, so no need to keep pounding them with toxicity.

References

1. Facon T, Kumar SK, Plesner T, et al. Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(11):1582-1596. doi:10.1016/S1470-2045(21)00466-6
2. Sborov DW, Laubach J, Kaufman JL, et al. Daratumumab (dara) + lenalidomide, bortezomib, and dexamethasone (RVd) in patients with transplant-eligible newly diagnosed multiple myeloma (NDMM): final analysis of GRIFFIN. Presented at: 19th International Myeloma Society Annual Meeting; August 25-27, 2022; Los Angeles, CA. Abstract OAB-057
3. Dimopoulos MA, Lonial S, White D, et al. Elotuzumab, lenalidomide, and dexamethasone in RRMM: final overall survival results from the phase 3 randomized ELOQUENT-2 study. Blood Cancer J. 2020;10(9):91. Published 2020 Sep 4. doi:10.1038/s41408-020-00357-4
4. Richardson PG, Sonneveld P, Schuster M, et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood. 2007;110(10):3557-3560. doi:10.1182/blood-2006-08-036947