Part 2: Using Depth of Response and MRD as Goals for 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.

DISCUSSION QUESTIONS:

• What are the important goals of frontline therapy​ (for example, depth of response)?
• ​What is the typical follow-up for this type of patient?​

CHAD CHERINGTON, MD: I think most of the time I’m looking for depth of response. If they’re a more elderly patient, then I’m [considering how much] they can tolerate.

DOUGLAS SBOROV, MD, MS: It brings up an interesting point when we’re talking about just depth of response. One of the questions out there is, do we need to get patients into an MRD [minimal residual disease] state, or stringent complete response [sCR], before going to transplant? Or can we go with the historical standard of if you’re in a partial response [PR] or better, and have hit your plateau, then that would be the time to go to transplant? Have any of the participants had experience with that? Do you have that goal in mind? In a patient who's had a PR, a 65% reduction [in serum monoclonal protein], and they have a monoclonal protein [spike], is that somebody that you’re comfortable taking over to transplant, or referring to transplant?

WAQAS ARSLAN, MD: Every patient we get is referred to transplant, but I think there may be a role of MRD. We see in acute lymphoblastic leukemia, if the patient is MRD-positive we need to give them blinatumomab [Blincyto] and then send them for transplant.¹ For multiple myeloma, I don’t think that is a standard of care as of yet, but it may become [standard] later on when we have the clinical trials done for that.

SBOROV: Yes, I agree. My personal approach to this is that I know melphalan flufenamide [Melflufen], historically and presently, is one of our best multiple myeloma drugs. It’s not very well tolerated compared with daratumumab [Darzalex], or lenalidomide [Revlimid], but it’s a highly effective drug, and it can be a great way to consolidate response. So what I will sometimes do in those patients that have just a PR, or are approaching a very good partial response [VGPR], is I’ll take them to transplant and see how well it works. If they’re sensitive to melflufen, I can probably get away with just going to maintenance therapy after that. But, if I have somebody who is closer to a CR, or still in a VGPR, I can always give them a couple cycles of consolidation.

And that’s a question that we’re all facing in the field is, what is the role of consolidation? We look at CASSIOPEIA [NCT02541383], we look at GRIFFIN [NCT02874742], and there’s 2 cycles of consolidation in there.^2,3 The way I think about that is that we, historically, [use] 4 cycles of induction, then transplant. But we could do 4 to 6 cycles and still successfully collect [stem cells from] most of our patients, even with 6 cycles of that therapy. So, are you taking them deeper before, or are you going to wait until after [collection] to try to deepen the response a little bit?

The data from GRIFFIN would suggest that we can continue to get deepening of response over time. And so it may not be absolutely necessary to try to achieve that MRD-negative state before transplant, or even a complete response. But I think that it’s a great point. I think that these data are continuing to evolve, and we’ll hopefully have that answer in the not-so-distant future.

DISCUSSION QUESTIONS

• Are you using MRD assessment routinely in your practice? Why or why not? How do you define response? ​
• If this patient achieved a deep MRD-negative response to primary therapy, would you proceed to transplant or wait until disease progression? ​

SBOROV: I’m curious if anybody’s using MRD routinely.

JYOTHI DODLAPATI, MD: Not at this time.

SBOROV: Is there anybody who is using it, and who may be using it to make treatment decisions?

CHRISTOPHER CHEN, MD: My co-fellow, the transplanter, uses it. I personally don’t, but with the patients we share, I’ll follow that. But it doesn’t change my assessment of what I’m going to do, since the transplanter usually is the person taking the reins on those patients. Those are the only ones I check MRD on.

SBOROV: Do you have access to MRD flow [cytometry] through your groups, or if you’re looking at MRD, are you just sending off for [Adaptive Biotechnologies’ clonoSEQ test]?

CHEN: It’s done by the university. I don’t personally order those. I just get the report from them.

SBOROV: Does anybody else have thoughts on MRD?

SUMIT MADAN, MD: Yes, I think we are using MRD mainly like [Dr Chen] and we are doing flow [cytometry] as well, 10^-5. So, the main time point where we are looking for is post-transplant, around day 100. Then we are following it serially once a year. In terms of if we are making treatment decisions, not towards intensifying therapy, but sometimes towards de-intensifying therapy if a patient has [become] MRD-negative, standard risk, for 2 or 3 consecutive years. That is the time when we give them the option of coming off the maintenance therapy. So, that’s the only time we are using MRD to make any decisions.

SBOROV: Yes, and I know that that’s a movement, especially in those standard-risk patients, to say, “Do these patients need to be on indefinite maintenance therapy?” I will go back to CALGB 100104 [NCT00114101], and say that indefinite maintenance is the right thing to do in all comers, but again, that’s [a study of] all patients.⁴ So, there may be that sub-population that would benefit from coming off therapy, and their disease is going to be fine. I’m looking forward to seeing some of these data come out to tell us what to do in those patients, because there’s financial toxicity and there are prolonged toxicities from the drug when the patients are on lenalidomide for 3, 4, or 5, years, or on daratumumab/lenalidomide for a prolonged period of time.

Your practice fits very well with ours, as well. We have ARUP Laboratories here, and every bone marrow biopsy I do, I get standard-of-care 10^-5 flow [cyrometry] on. So, I’m pretty fortunate in that I’m getting a baseline assessment right before transplant, post-transplant, before maintenance, and then generally go out a year; unless a patient has highly-aggressive disease, I may get a [bone marrow biopsy] a little bit sooner than that 1-year post-transplant mark. But, it’s certainly interesting. I think that we’re starting to see some evolution of the MRD decision-making in so many different trials.

_References:

_{1. Clinical Practice Guidelines in Oncology. NCCN. Acute lymphoblastic leukemia, version 1.2022. Accessed April 4, 2022. https://bit.ly/37eUINA}

_{2. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394(10192):29-38. doi:10.1016/S0140-6736(19)31240-1}

_{3. 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}

_{4. Holstein SA, Jung SH, Richardson PG, et al. Updated analysis of CALGB (Alliance) 100104 assessing lenalidomide versus placebo maintenance after single autologous stem-cell transplantation for multiple myeloma: a randomised, double-blind, phase 3 trial. Lancet Haematol. 2017;4(9):e431-e442. doi:10.1016/S2352-3026(17)30140-0}