Part 1: Debating Primary Therapy for Transplant-Eligible Multiple Myeloma

Douglas Sborov, MD, MS​ (Moderator)

Director – Multiple Myeloma Program​

Huntsman Cancer Institute

University of Utah

Salt Lake City, UT

CASE SUMMARY:

A 51-year-old man presented with pallor and worsening fatigue on exertion. Laboratory results showed that his hemoglobin was 9.2 g/dL, blood urea nitrogen/creatinine and calcium was within normal limits, and lactate dehydrogenase was within normal limits. Serum β2-microglobulin was 4.1 mg/L, serum albumin: 3.2 mg/dL, serum M-protein was 1.5 g/dL, and λ free light chains was 110 mg/dL.

A bone marrow biopsy showed 66% plasma cells. Fluorescence in situ hybridization showed a deletion 13q mutation. Urine protein electrophoresis showed a M-spike of 400 mg of λ free light chains in 24 hours. PET/CT scans showed lytic lesions in the ribs and L3 lymph node, and there was no increased standard uptake. Immunoglobulin G was positive in urine and serum free light chains.

The patient had adequate liver and heart function and was rated at an ECOG performance status of 1. He was diagnosed with stage II (International Staging System [ISS] and Revised ISS) multiple myeloma at standard risk.

DOUGLAS SBOROV, MD, MS: The question was “What primary therapy are you most likely to recommend for this patient eligible for transplant?” VRd [bortezomib (Velcade), lenalidomide (Revlimid), dexamethasone]; CyBorD [cyclophosphamide, bortezomib, dexamethasone]; KRd [carfilzomib (Kyprolis), lenalidomide, and dexamethasone], Dara-Rd [daratumumab (Darzalex), lenalidomide, and dexamethasone]; Dara-VRd [daratumumab, bortezomib, lenalidomide, and dexamethasone]; or other. So VRd was selected by 80% and Dara-VRd was 20%.

Some of you are convinced by the GRIFFIN [NCT02874742] data; others I suspect are waiting, understanding that GRIFFIN was a randomized phase 2 trial, and the primary end point was rates of stringent complete response [sCR] and the end of consolidation.¹ So, I think that this is in line with what we’re seeing across the board, across the country. The triplet regimen remains king, but we’re starting to move towards the quadruplet regimen. And as the data mature, I think that we’ll all be considering going towards that direction.

DISCUSSION QUESTIONS:

• What is the best approach (doublet, triplet, quadruplet) toward primary therapy? ​
• What aspects of a therapy are most important to you in treatment of newly diagnosed transplant eligible patients with multiple myeloma?​

SBOROV: Does anybody consider doublet for any patients? And if so, in what setting?

CHRISTOPHER CHEN, MD: [For] a non-transplant patient, somebody who has poor performance status, [and if] they’re admitted with acute renal failure. Sometimes, I will just give them bortezomib/dexamethasone in the hospital to get them out. I think that’s usually 1 of the occasions. Or sometimes, if they have neuropathy, I would use lenalidomide and dexamethasone.

SBOROV: So if they have significant neuropathy, you wouldn’t necessarily move to KRd versus VRd, you’d probably just stick with the doublet?

CHEN: Yes, generally speaking, I would probably go with that route. Because, if I can get a pretty good response, [and] if they have neuropathy to the point where I’m that worried, they’re probably not a patient I would want to push that hard anyway.

SBOROV: You said that if you have somebody with renal failure, their kidneys are bad, or an acute presentation at the hospital, you start them on bortezomib/dexamethasone. Or you start them on CyBorD as an inpatient, because we can get it pretty easily. Is that a patient that you would continue the CyBorD or the bortezomib/dexamethasone, or would you start moving patients towards the VRd triplet, more of an IMiD-[immunomodulatory drug] based regimen?

CHEN: If the patient recovers well, then I would probably go to the triplet. It’s just a rescue measure to get them out.

SBOROV: I agree. Would anybody else just continue CyBorD in somebody like that?

SURABHI AMAR, MD: I’ve had a bunch of patients who end up in the hospital with renal failure as presentation, and then I do the same thing with bortezomib/dexamethasone. Then, in outpatient, I generally shift them to VRd if they’ve recovered renal function. The only place I use doublets is if the patient is very frail, elderly, not a transplant candidate, and won’t be able to tolerate much. I’ve used lenalidomide/dexamethasone, and some of them do great even on that, but only in those situations.

SBOROV: Yes, I think that a lot of us are hesitant to bring in lenalidomide in patients with renal insufficiency, and certainly patients who are dialysis dependent. I think that we push lenalidomide pretty hard. You need significant dose reductions if you’re going to do that in patients with renal insufficiency, but it’s still doable, and can be a well-tolerated approach as you’re trying to get relatively quick disease control, especially in somebody who has light-chain disease and it’s hammering on the nephrons. Trying to get aggressive at the beginning can be beneficial for patients.

We have this 51-year-old patient who is [healthy but] fatigued, and he has newly diagnosed disease; do you want a fast, deep response? Are we more concerned about tolerability in those first couple of cycles? What things come into play in your decision-making?

ROBERT GALAMAGA, MD: I would say that we try to get the most mileage out of the induction regimen. I lean towards the GRIFFIN data, and looking at the rates of sCR that were achieved there, and MRD [minimal residual disease] negativity for those patients.1 So, if that’s going to help the patient do better in the long run as we move towards transplant, I think that’s important. I refer my patients [for stem cell transplant] pretty early. I know chemotherapy responsiveness defines the disease, but I think referring them early gets you on the same page with the transplanter, gets the patient more comfortable in the setting of a transplant, and makes it less anxiety provoking.

SBOROV: I agree. Being on the transplant side, having that extra time to get to know somebody can be helpful. Now, you said getting the most mileage. How do you define that?

GALAMAGA: Mileage in terms of how can I allow for this patient to achieve the longest road trip as it relates to the disease. And if that means getting them into an sCR or achieving an equivalent of MRD negativity, I think we extrapolate that to mean longevity and quality of life thereafter.

SBOROV: Dr Grover, what’s your approach?

RAJINDER GROVER, MD: I think for those patients, if they have otherwise good performance status and they’re considered transplant-eligible, I would probably give them either triplet therapy or quadruplet therapy if I can, if the insurance approves. Usually, my approach is to start them on the treatment, and then refer them to the transplant center quickly, but sometimes it takes a month or 2 months for them to get an appointment or get approval from their insurance. So, I don’t wait for them to [see a transplanter], but I would probably start them. And then, once they have a good response, and once they have seen the transplant team, then we make a plan on when to transition them to collection and transplant.

Because of COVID-19, we had some situations, but it wasn’t a big problem. I’m seeing more patients dying once they get the COVID, and that’s where I’ve lost most of my patients who had a stable disease.

_Reference:

_{1. Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136(8):936-945. doi:10.1182/blood.2020005288}