Multiple Myeloma Goals and Risk Factors for Triplet Vs Quadruplet Therapy

Caitlin Costello, MD

Associate Professor of Medicine

Division of Blood and Marrow Transplantation

UC San Diego

CASE SUMMARY

A 54-year-old woman presented with Revised International Staging System stage II multiple myeloma, based on evaluations that showed a hemoglobin level of 7.0 g/dL, β2 microglobulin of 6 mg/dl, albumin 3.2 g/dL, calcium 11.3 mg/dL, lactate dehydrogenase of 200 U/L, and creatinine clearance of 45 mL/min. Bone marrow showed 22% clonal plasma cells. Serum kappa free light chains were 24 mg/dL. She had no cytogenetic abnormalities and an ECOG performance score of 1. A PET/CT scan showed multiple bone lesions in the vertebrae. She had no extramedullary disease. She was diagnosed with IgG-kappa myeloma and was considered transplant eligible.

DISCUSSION QUESTIONS​

• How do you decide between quadruplet and triplet regimens? ​
• What type of comorbidities would prevent you from using a triplet regimen? ​
• For a patient who is eligible for transplantation, do you initiate treatment with a quadruplet or triplet regimen?​
• How do responses compare between the 2 approaches, in your experience? ​

COSTELLO: What has anyone done when they’re trying to decide between a triplet and a quadruplet, or how have your experiences been thus far, in terms of choosing one over the other? Someone who chose a quadruplet, what makes you choose a quadruplet right now?

ALBERT DEKKER, MD: I choose the quadruplet, and to me, quadruplet is the default; triplet is for patients who for whatever reason are not candidates for a quadruplet: too old, too frail, too much neuropathy, too poor kidney function. So, [I use] quadruplet unless proven otherwise.

COSTELLO: Which quadruplet?

DEKKER: I chose dara-VRd [daratumumab (Darzalex), bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone], because for the majority of patients, bortezomib is much better tolerated. With carfilzomib [Kyprolis], it’s still the issue of who to pick because of cardiotoxicity.

COSTELLO: Would anyone else choose a triplet over a quadruplet, and why? [In the poll], 60% of you wanted to do a triplet.

PAMELA MIEL, MD: I would do the triplet. I know there’s been a lot of discussion with using daratumumab-based treatment moving forward, because there were studies that showed that the outcome is good; but recently I had a discussion with transplant doctor James K. Mangan, [MD, PhD], over at UC San Diego, and he said he still prefers VRd [bortezomib, lenalidomide, and dexamethasone] for induction therapy for transplant-eligible patients. He would add daratumumab if the patient has high-risk disease. This patient had normal cytogenetics, so I think I would go with VRd for this patient.

COSTELLO: Got it. So, I’ve heard some concerns about cardiotoxicity with carfilzomib, I’ve heard starting with a triplet and maybe add the CD38 monoclonal antibody for a patient with higher-risk disease. What other situations would make you choose a quadruplet, or make you choose a triplet?

DEKKER: It really comes down to this goal: is myeloma a potentially [curable] disease, or it is not a [curable] disease….In my opinion, we could potentially cure some patients if quadruplet is given up front. And yes, I would understand that transplant specialists are somewhat hesitant about quadruplet, including some who I refer to, because patients get deep responses that it becomes difficult to convince patients to get a transplant.

COSTELLO: That is a good problem, isn’t it?

[In your practice], what is an acceptable outcome? What are we aiming for? What are your end points?

DEKKER: MRD [minimal residual disease].

COSTELLO: Do you check MRD pretty regularly?

DEKKER: If I’m trying to decide if this transplant-eligible patient will need a transplant, I check MRD status, and if patient has [positive MRD status], I decide to hold off on transplant. If they don’t have [positive MRD status], I refer for transplant evaluation, though I heard recently that I should do it the other way around.

COSTELLO: It does get a little confusing, doesn’t it? I think you’re right—we’re all looking a common end point by which we can finally get rid of transplant. Every patient wants to do that…a good point to say is if we have good treatments that are getting to the same end points as transplant does, maybe not everyone needs a transplant.

Does anyone else treat to a specific target? If you have a patient like this, that you have started on VRd as an example, how many cycles would you do? Or, at what point would you say you’ve been successful?

SWARNA CHANDURI, MD: In most of these patients, if they are transplant eligible and not high risk, we see their M-protein come down over past 3 to 4 treatments and then we’ll send them usually ahead of time for transplant. They have been successfully transplanted, and I’m following a lot of them, and then they’re cured. So, I don’t think just because we have a new medication, daratumumab, that everybody should get all 4, because we have seen in the past with VRd and transplant, they are being followed, and they are cured.

I think there have to be criteria for who needs all these new drugs. The daratumumab is not easy to give in the beginning. They’ll have to come to the clinic often, and get intravenous infusions. If they can be given VRd as subcutaneous injection, and we can achieve the same thing, I would prefer that.

COSTELLO: Understood. I love hearing the word “cure.” That’s obviously the thing we’re all aspiring to. I guess that’s a question, are we curing patients? Are [you] seeing patients with very long durable responses with some of these new regimens?

PREETI CHAUDHARY, MD: I generally go with triplets because the aim of induction is to get them to a good place where they can benefit from consolidation, and then maintenance. Maintenance can be single-agent lenalidomide or doublet daratumumab. So, I think in our practice—Dr Chanduri and I are in the same practice—we have seen once we get our patients to consolidation with transplant, and then switch to a single agent or a doublet maintenance, we are seeing very durable responses lasting for years. I don’t think we have cured them, but I do feel [they have improved] quality of life and meaningful extension of their life.

COSTELLO: That’s great. I think you have all brought up excellent points: triplets may be just as good; quadruplets seem like they’re getting really good, deep responses; MRD could be a good end point to help define your treatment strategy. Maybe that means we don’t need transplant for some of these patients.