Treating Multiple Myeloma Following Quadruplet Induction Therapy and ASCT

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.

Daratumumab (Darzalex), bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (Dara-VRd) induction therapy was initiated​. She achieved a very good partial response (VGPR) post induction therapy​. She underwent stem cell mobilization and 2 months later underwent autologous stem cell transplant (ASCT).​ Her post-ASCT response was a VGPR​.

DISCUSSION QUESTIONS

• What are the available treatment options for patients with transplant-eligible multiple myeloma in the consolidation and maintenance setting?​
• Does your choice of induction therapy impact your choice of consolidation and maintenance therapy in patients with transplant-eligible multiple myeloma?​
• What is your approach toward maintenance therapy for patients who receive a quadruplet regimen?​
• With the introduction of novel induction therapies, is there a continued role for transplantation in patients with newly diagnosed multiple myeloma?​

CAITLIN COSTELLO, MD: This patient did get a quadruplet regimen with dara-VRd. She achieved a VGPR post-induction, had stem cells mobilized, underwent her transplant, and post-transplant her response is a VGPR. What would you do next?

THOMAS DEKKER, MD: Consolidation with CAR [chimeric antigen receptor] T-cell therapy.

COSTELLO: With CAR T cell, sure. You’re going for it; I like it. This patient is post-transplant, they have a VGPR. The GRIFFIN study [NCT02874742] would give these patients consolidation with dara-VRd.

PREETI CHAUDHARY, MD: I would not do CAR T-cell therapy.

COSTELLO: What would you do?

CHAUDHARY: In my opinion, in multiple myeloma, patients do a maximum of 11 months with CAR T-cell therapy. It has a good response, but I don’t think that’s sustainable.

COSTELLO: I appreciate throwing ideas out there. That is not something we have an option to do right now. It’s an interesting option, and something we can talk about; but yes, I agree with you. I think for the meantime, short of trials that are looking at doing CAR T-cell therapy—particularly for those patients who have not had an adequate response to transplant or consolidation, or patients who relapse shortly after their transplant—I think the standard of care as it stands now is doing consolidation or trying to find a maintenance regimen to get them to minimal residual disease [MRD] negativity.

With all that being said, what are we going to do now for these patients? We’ve talked about what these transplant eligible patients are getting consolidation and maintenance; we’ve talked about maintenance approaches for these patients who get quadruplets, to put them on doublets. Seeing all those deep response rates, is anyone getting cold on transplants? If we are going to get 90% remission rates, does anyone reconsider the role of transplant here?

PAMELA MIEL, MD: I don’t make that call, meaning I still send patients to the transplant doctors to see if they’re going to proceed with the transplant or not. But, if they’re transplant eligible, they get referred.

COSTELLO: As a transplanter, I thank you for that. We want to see these patients, make the decisions, have the discussion with the patients so we can look at their risk/benefit profile, and understand their responses to their current therapy. So, please still send them in their third cycle, if not earlier, so we can have those discussions and make plans.

There are a lot of maintenance regimens that are out there, and different things to choose from; a whole other conversation in and of itself. Lenalidomide is the mainstay where we have an overall survival benefit, where we don’t have it in any other maintenance regimens.¹ But it does allow for the option of continued doublets. I think we will soon see daratumumab and lenalidomide as a doublet get added on to that maintenance therapy once we have some of these randomized trials that are going on that show the continued benefit of patients to get daratumumab in the maintenance setting if they did not receive it in the up-front setting.

DISCUSSION QUESTION

How likely are you to change your practice with respect to management of transplant eligible newly diagnosed myeloma?

DEKKER: I already use quadruplet.

MILAN SHETH, MD: I feel that we still need a lot of long-term data to get a better sense of what it is that we’re achieving with the quadruplet therapy. I’m still not convinced everybody needs quadruplet therapy. I think somebody else had already said that we know we’re going to get better responses because we’re using great drugs, but do we need to use everything up-front? I feel like there’s still a lot of unanswered questions here.

MIEL: I’ve been wanting to put patients on quadruplet treatment. I don’t know if you know Nina Shah, MD, over at UC San Francisco, but I’ve attended some of her talks, and she’s pushing for the quadruplet treatment. The only thing that changed my mind was that when I spoke to the transplant doctor at UC San Diego, he said, “If it’s not very high-risk disease, I’d go with VRd [bortezomib, lenalidomide, and dexamethasone].” So, I put the patient on VRd. But I probably would want to put someone on dara-VRd, given the chance.

COSTELLO: Yes. I think that my takeaway from the data has been that we would, of course, love long-term data to come out, but…we have to wait a long time for it. While we’re waiting for some of these phase 3 studies to go on, which are happening now to look at real randomized data, to play out, I find that this is just too intriguing to not do quadruplets for everybody now.

Since [these data were presented at [the 2021 American Society of Hematology annual meeting], I’ve transitioned just about everyone who’s at least transplant eligible over to quadruplet regimens now.² Any patients who are on the fence, where I’m not sure if they’re going to be eligible for transplant, I still will try and give them the benefit of a quadruplet regimen, and very quickly drop the bortezomib if I get worried about them, and end up with dara-Vd [daratumumab, lenalidomide, dexamethasone]. But I think these MRD negativity rates are just too good, and if that is going to be the true surrogate end point that we’re all aiming for, dara-VRd has been my go-to for the last 6-plus months or so for these patients, until someone tells me otherwise.

_References

_{1. Ho M, Zanwar S, Kapoor P, et al. The effect of duration of lenalidomide maintenance and outcomes of different salvage regimens in patients with multiple myeloma (MM). Blood Cancer J. 2021;11(9):158. doi:10.1038/s41408-021-00548-7}

_{2. Laubach JP, Kaufman JL, Sborov DW, et al. Daratumumab (DARA) plus lenalidomide, bortezomib, and dexamethasone (RVd) in patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): updated analysis of GRIFFIN after 24 months of maintenance. Blood. 2021;138(Suppl_1):79. doi:10.1182/blood-2021-149024}