expert roundtables

Effective Triplets for Nontransplant Patients With Multiple Myeloma

by Kenneth C. Anderson, MD; Sagar Lonial, MD, FACP; and S. Vincent Rajkumar, MD

Overview

RVd (lenalidomide, bortezomib, and dexamethasone) continues to represent the standard of care even for older patients, for whom other triplets are also now available. With options for attenuated dosing and with the introduction of newer agents, triplet therapy is possible in the vast majority of nontransplant patients.

Q:

What are the options for triplet therapy for nontransplant patients? Should triplets be recommended for all patients?

S. Vincent Rajkumar, MD

Edward W. and Betty Knight Scripps Professor of Medicine
Mayo Clinic
Rochester, MN

“Triplet therapy is very valuable for nontransplant patients with multiple myeloma.”

S. Vincent Rajkumar, MD

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. 

Sagar Lonial, MD, FACP

Chair and Professor
Department of Hematology and Medical Oncology
Anne and Bernard Gray Family Chair in Cancer
Chief Medical Officer
Winship Cancer Institute
Emory University School of Medicine
Atlanta, GA

“I agree about the value of triplets. 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.”

Sagar Lonial, MD, FACP

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.

Kenneth C. Anderson, MD

Kraft Family Professor of Medicine
Harvard Medical School
Director, LeBow Institute for Myeloma Therapeutics
Director, Jerome Lipper Multiple Myeloma Center
Dana-Farber Cancer Institute
Boston, MA

“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."

Kenneth C. Anderson, MD

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. 

References

Chari A, Suvannasankha A, Fay JW, et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017;130(8):974-981. doi:10.1182/blood-2017-05-785246

Dimopoulos MA, Lonial S, Betts KA, et al. Elotuzumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended 4-year follow-up and analysis of relative progression-free survival from the randomized ELOQUENT-2 trial. Cancer. 2018;124(20):4032-4043. doi:10.1002/cncr.31680

Durie BG, Hoering A, Sexton R, et al. Longer term follow-up of the randomized phase III trial SWOG S0777: bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone in patients (pts) with previously untreated multiple myeloma without an intent for immediate autologous stem transplant (ASCT). Blood Cancer J. 2020;10(5):53. doi:10.1038/s41408-020-0311-8

Durie BGM, Kumar SK, Usmani SZ, et al. Daratumumab-lenalidomide-dexamethasone vs standard-of-care regimens: efficacy in transplant-ineligible untreated myeloma. Am J Hematol. 2020;95(12):1486-1494. doi:10.1002/ajh.25963

Facon T, Kumar S, Plesner T, et al; MAIA Trial Investigators. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380(22):2104-2115. doi:10.1056/NEJMoa1817249

Facon T, Venner CP, Bahlis N, et al. The phase 3 TOURMALINE-MM2 trial: oral ixazomib, lenalidomide, and dexamethasone (IRd) vs placebo-Rd for transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM) [abstract 551]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.

Kumar SK, Facon T, Usmani SZ, et al. Updated analysis of daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM): the phase 3 MAIA study [abstract 2276]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.

Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol. 2020;95(5):548-567. doi:10.1002/ajh.25791

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