Depth of Response With Quadruplet Regimens Considered in Newly Diagnosed Multiple Myeloma

Timothy Schmidt, MD (Moderator)

Hematology, Medical Oncology and Palliative Care

Assistant Professor

Department of Medicine

Clinical Science Center

University of Wisconsin School of Medicine

and Public Health

Madison, WI

EVENT REGION Illinois

PARTICIPANT LIST Stan Nabrinsky, MD | Alkarim Tajuddin, MD, MBA | George Sloan, MD | Bety C. Ciobanu, MD | Isoken Koko, MD | Ajaz M. Khan, MD, MBA, CPE

CASE SUMMARY

A 54-year-old woman presented to her physician with back pain, fatigue, nausea, constipation, and occasional recurring dizziness. Her laboratory results showed 7.0 g/dL hemoglobin, 5 mg/dL β2 microglobulin, 3.2 g/dL albumin, 11.3 mg/dL calcium, 200 U/L lactate dehydrogenase, and 1.5 mg/dL creatinine. Her bone marrow biopsy showed 22% monoclonal plasma cells, and her serum free light chain testing showed κ 240.0 mg/L, λ 2.0 mg/L, and κ/λ ratio 120. Further, IgG-κ was present on results from her serum immunofixation electrophoresis test. Overall, her testing and scans led to a diagnosis of Revised International Staging System (R-ISS) stage 2/R2-ISS stage 3 IgG-κ myeloma and was identified as being transplant eligible.

DISCUSSION QUESTIONS

• How do you decide between triplet and quadruplet regimens for patients with transplant-eligible newly diagnosed multiple myeloma?
• What do you consider an adequate/successful treatment response in your patients following induction therapy in the real-world setting?

NABRINSKY: I don’t decide anymore. The [data published in] The New England Journal of Medicine [NEJM] decides for me. Those data were very convincing for the use of quadruplet regimens for both transplant-eligible and -ineligible patients.

SCHMIDT: Are you referring to the recent PERSEUS trial [NCT03710603] publication in NEJM [From the Data¹]?

NABRINSKY: Yes.

SCHMIDT: Yes, that was a recent NEJM paper for the use of subcutaneous daratumumab [Darzalex] plus bortezomib [Velcade], lenalidomide [Revlimid], and dexamethasone [D-VRd]. Does anybody else try to decide between [a triplet and a quadruplet regimen]?

TAJUDDIN: A young patient case with multiple end organ problems or challenges might be in a better position to get a quicker response, so you could send the patient to transplant quickly. For a rapid response, that might be a choice to make.

SCHMIDT: If she were not symptomatic— say this was caught by some laboratory parameters—would that change your mind to use the triplet regimen?

TAJUDDIN: [With the patient having] hypercalcemia…I may have to use the quadruplet regimen. If she didn’t have hypercalcemia or the renal insufficiency was for some other reasons, then I probably would not.

SCHMIDT: That makes sense. I’m curious to hear from anyone who would choose carfilzomib [Kyprolis], lenalidomide, and dexamethasone. It’s certainly a reasonable decision.² Is there anybody who still uses triplets and has a situation where they might want to use those?

NABRINSKY: I was forced, recently, to use a triplet regimen when insurance refused to approve [D-VRd for the patient].

SCHMIDT: That is unfortunately one of the realities that we all have to practice with, too. I think it’s been getting a lot better here recently. It seems like most of the people in this discussion here, and in similar discussions I’ve had among colleagues up here in Wisconsin, are moving more toward 4-drug induction regimens. I’m also curious about the second question here: What do you consider to be an adequate or successful treatment response to induction therapy? Do you even pay attention to what the response is? Are there any initial thoughts about that?

SLOAN: I follow the patient’s labs. If their monoclonal protein is decreasing and if the problems, such as anemia, thrombocytopenia, [or the hypercalcemia], are improving…I think they’re responding [to therapy well].

SCHMIDT: Is there a point when you feel happy about that response, or do you have something you try to treat to?

SLOAN: I treat to transplant.

CIOBANU: Well, the goal with the induction is to get the response before transplant. So, if possible, a VGPR [very good partial response] or better would be an appropriate response. A partial response [PR] is not quite an optimal response, in my mind. If the patient does not get a good response, which rarely [happens], then you may choose to change the treatment sooner. Though this patient seems to have the good cytogenetics, she lacks deletion 17p or a gain of 1q21; that would sometimes make people more refractory or progress faster, but this is not the case here. So, a VGPR or a complete response [CR] would be the aim, right?

SCHMIDT: Generally, yes. We’re trying to treat to one of those deeper levels of response. VGPR stands out as one of those criteria we try to get to. Whether they’re at the 90% cutoff or close to it is a little arbitrary but, yes, generally you’d want to see a nice response prior to transplant.

KOKO: What do you consider a VGPR? Is it 90% or more decrease in the monoclonal protein?

SCHMIDT: The [International Myeloma Working Group] set it as a 90% reduction in the monoclonal protein, or greater than that.³ If there’s anything still present on the immunofixation, you cannot call it a CR.

CIOBANU: I have a question about that, because I had a patient I referred for transplant after 4 cycles with a VGPR. The transplanter requested to continue with 2 more cycles to see [whether] we [could] get a better response. Is there any sort of better outcome with the transplant for the patient…if you get the CR vs VGPR?

SCHMIDT: It’s hard to justify saying that you have to get them to a certain place before you would consider a transplant. Most of those data come from the era prior to where we’ve got our current induction regimens. But generally speaking, patients who respond better are going to have better outcomes from transplant. But that doesn’t necessarily mean that, if a patient isn’t responding at a certain level, you need to deepen their response to have a benefit from transplant. You just feel better [about] how it’s going to go for patients who are in a deeper response. There is something to be said for being more comfortable about mobilizing and collecting stem cells, depending on what their response has been and how many cycles they have had. I often want patients to have at least 3—if not 4—cycles of therapy and be starting to reach their maximal responses before I will do that. But rarely is it something that if they are close to a VGPR after about 2 cycles when I’m seeing them, I don’t necessarily [think] you’ve got to change treatment to deepen their response. Or if they’re already 4 cycles in, do I need to extend it before I collect them? That’s my take on it. But yes, we do want to see good, nice, and deep responses to induction therapy before moving forward with a transplant. That’s always what we’re looking for.

TAJUDDIN: So there is no standard or universal criteria that we have in the community oncology setting? We say, “Well, that’s not enough. Now do the transplant.” Does it all depend on the transplant, or is that what it is?

SCHMIDT: Depending on who you ask, they may have different criteria. I even know the differences [we have among our group]. Myeloma physicians who do transplant here seem to have slightly different ways of looking at how that response has been before they want to collect cells. But generally speaking, there is a study—I believe it was published in 2015—looking at the outcomes of transplant for patients who had either achieved a PR or not.

[This study looked] to see, for patients who hadn’t achieved a PR—so not even a 50% reduction in their M spike—whether intensifying therapy prior to stem cell collection improved their overall survival, and it didn’t. Those patients who didn’t respond as well had worse outcomes than the good responders, but you couldn’t overcome that by doing more treatment. It may change my strategy in terms of how I mobilize them. I might give cyclophosphamide or something like that, but it also depends on how much therapy and what type of therapy they’ve had before I [decide]. Some of it is just a gut feeling in terms of understanding myeloma, its kinetics, their risk, and things like that. So, yes, that’s a long-winded answer to say it depends on the transplanter.

CIOBANU: With more lenalidomide, sometimes the patients had a difficult time collecting the stem cells necessary for the transplant. I referred another patient…in their early 70s, for transplant after 4 cycles, and they were not able to collect stem cells from her.

SCHMIDT: Was this patient also getting daratumumab?

CIOBANU: Yes, D-VRd.

SCHMIDT: We certainly have seen more difficulty mobilizing and collecting stem cells, especially with the use of quadruplets. It does seem like waiting until after 6 cycles is even harder than doing it after 4. That also gets into another thing about what an adequate cell yield for transplant is, and I don’t know [whether] they were sharing that with you or how many cells they wanted. We are usually able to at least get the minimum with the use of granulocyte colony-stimulating factor and plerixafor [Mozobil], but we’re having to use a lot more plerixafor or CXCR4 agonists to collect the number of cells we want, so that is a good point.

KHAN: Do you do minimal residual disease [(MRD) testing] up front, pretransplant? Do you offer [MRD testing] post transplant and any specific assays?

SCHMIDT: We do bone marrow biopsies as a part of the pre-and posttransplant assessment. That’s what we have to do for the Center for International Blood and Marrow Transplant Research. We’re generally sending MRD by the clonoSEQ MRD test at some of these key time points, and pretransplant MRD is not something we have been doing as consistently, but [we are] definitely assessing for it after transplant. I have started to send it for my patients in the pretransplant time because I want to see how that is changing with transplant. I also think we’ll see how the data emerge in the coming years, and I just like to have that information if I’m already going to be sending a patient for a bone marrow biopsy. But I’m not necessarily using that information to make treatment decisions, at least as a sole factor. It’s just a component of assessing that patient’s responding and their risk, and just an overall picture of how they’re doing.

REFERENCES:

1. Sonneveld P, Dimopoulos MA, Boccadoro M, et al; PERSEUS Trial Investigators. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;390(4):301-313. doi:10.1056/NEJMoa2312054

2. Tan C, Nemirovsky D, Derkach A, et al. Carfilzomib, lenalidomide and dexamethasone (KRd) vs bortezomib, lenalidomide, and dexamethasone (VRd) as induction therapy in newly diagnosed high-risk multiple myeloma. Blood. 2022;140(suppl 1):1817-1819. doi:10.1182/blood-2022-169161

3. International Myeloma Working Group (IMWG) uniform response criteria for multiple myeloma. International Myeloma Foundation. Accessed June 20, 2024. https://tinyurl.com/3mh3rw4x