Part 2: Recommending Triplet and Quadruplet Therapies for Multiple Myeloma

Muhamed Baljevic, MD (Moderator)

Assistant Professor, Internal Medicine

Fred & Pamela Buffett Cancer Center

University of Nebraska Medical Center

Omaha, Nebraska

DISCUSSION QUESTIONS

• What are the options for primary therapy? What is the best approach (doublet, triplet, quadruplet) to primary therapy?
• What proportion of patients with newly diagnosed multiple myeloma (NDMM) are young, fit, and autologous stem cell transplant eligible?
• What aspects of a therapy are most important to you in treating patients who have received a new diagnosis of NDMM and are transplant eligible?

MUHAMED BALJEVIC, MD: What is the rationale for choosing triplet or quadruplet therapy?

BASSAM MATTAR, MD: I’m in Wichita, Kansas, and I do transplants, too. I voted for VRd [bortezomib (Velcade), lenalidomide (Revlimid), dexamethasone], but I have used daratumumab [Darzalex] plus VRd [D-VRd] in preparation for transplant. I had a 27-year-old [transplant] patient and I used D-VRd for him. There was an issue with insurance, but I was able to get some samples for him. So for the average 50-year-old patient as in this case, I would use VRd, but for very unusual cases in younger patients who I know have high-risk cytogenetics, I am inclined to use D-VRd.

BALJEVIC: Those are very interesting comments. So you would be more inclined [to use D-VRd] with the high-risk patients, perhaps those who are younger, considering the length of time that we would have to deal with their disease, not for just a few years, but hopefully decades.

MATTAR: It is like trying to debulk them….I don’t know if we want to use the word debulk in multiple myeloma as in solid tumor disease, but I try to reduce the tumor burden as much as I can so I can get better minimal residual disease [MRD] before the transplant. That’s my reasoning for that. For the average 51-year-old patient, I think we’re still going to get a good response with VRd, and I have not felt that D-VRd [is necessary]. The problem with D-VRd is what to maintain them on in that setting. So that’s another part when you do transplant that will become challenging.

BALJEVIC: Correct. That raises another question of single vs tandem transplants. Most of the centers, by my understanding, are performing single transplant, but some centers across the nation are considering dual transplants, particularly in the high-risk patients where data exist, and that’s interesting. Probably any time that discussion is held, it’s a very lively discussion because [clinicians] are very passionate about choosing one way or another. At this point, it seems clear that nobody’s really considering doublets, which I’m glad to see because we know that the triplets beat doublets at any point, and we’re slowly coming to a point where some of these quadruplets will also be labeled for frontline use. In fact, we already have 2 quadruplet regimens, which are D-VTd [daratumumab, bortezomib, thalidomide (Thalomid), dexamethasone] for transplant-eligible patients and D-VMP [daratumumab, bortezomib, melphalan (Alkeran), prednisone] for transplant-ineligible patients.

VICKI MORRISON, MD: I’m at the University of Minnesota and Hennepin County Medical Center in Minneapolis. I think others have made the comment that we should not save the good agents but [instead] use them up front as a rule, and I think that’s true. We’re fortunate that there’s such a multiplicity of agents now in multiple myeloma, and even if [patients] progress beyond 1 line of therapy there [are] lots of other agents to offer them.

BALJEVIC: I certainly agree with that line of thinking as well. There is something to be said about putting your best foot forward at the beginning while the disease is still, relatively speaking, untreated and resistance hasn’t been bred through selective pressures delivered through various classes of agents.

We are hopeful that when patients are more fit, their organ functions potentially more preserved, and bone marrow less [affected by] long-term toxicities, this type of approach might result in long-term impressive outcomes and data points for our patients. Median survivals are approaching 10-plus years at this point, and with the early introduction of newer classes of agents, our sequencing has become complicated as well.

SOMASEKHARA R. BANDI, MD: I am from St. Louis, Missouri, but I’m not a transplanter; I’m a general medical oncologist in a community setting. Would transplant still be an absolute necessity after 4-drug combinations and with the excellent or improving response rates?

BALJEVIC: That’s a fantastic question. I’m hopeful that in the coming years many of our trials will be conducted in such a way that the decision-forward points for patients, including whether to transplant immediately or wait until a patient relapses, will use an MRD-based assessment to try to make that decision.

Patients who reach deep responses, including MRD negativity by NGS [next-generation sequencing], for example, which goes to 10-6, might be slated for collection and storing and the continuation of consolidation, maintenance therapy, etc. Some of these studies will even consider discontinuing maintenance treatments at certain MRD-defined points. We have a lot of questions such as, do we really have to transplant an MRD-negative patient immediately or can you transplant them later? Hopefully we will have data [to answer] that.

I think there’s a tremendous difference between [sustained MRD negativity] and MRD negativity at 1 point. We know that in many meta-analyses, MRD negativity in multiple myeloma has been identified as a feasible and valid end point, and it’s been appropriated in some trials as a primary end point.

I would argue that sustained MRD negativity is more relevant and important and that those types of situations are probably arguing for places where you can think about collecting and storing stem cells and [continue] with the decision to either consolidate or do maintenance. At some point, some of the trials will explore the question of even pausing the maintenance and following the patients long term.

The current version of the NCCN [National Comprehensive Cancer Network] guidelines states that transplant-eligible patients should receive VRd as a category 1 recommendation. It is the only preferred regimen that is category 1. Other recommended regimens are D-VRd, KRd [carfilzomib (Kyprolis), lenalidomide, dexamethasone] and even in some cases NRd [ixazomib (Ninlaro), lenalidomide, dexamethasone], though it is a [category 2B recommendation].¹ I think sometimes [it] is a choice for the frailer patients who may not necessarily be transplant eligible and when you’re looking for easier oral therapies that can be convenient for patients with a questionable [adherence], for example.

We must mention CyBorD [cyclophosphamide (Cytoxan), bortezomib, dexamethasone] that is often used as frontline agent in patients who present with renal failure. VTd [bortezomib, thalidomide, dexamethasone] is still a category 1 recommendation,¹ but I would argue it is used more in European practice patterns, given that thalidomide is more common on that side of the pond.

_REFERENCE

_{1. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 1.2022. August 16, 2021. Accessed January 7, 2022. https://bit.ly/3q557m0}