Using Frontline Quadruplet Therapy for Transplant-Eligible Multiple Myeloma

Brea C. Lipe, MD (Moderator)

Clinical Director, Multiple Myeloma Program

Associate Professor, Department of Medicine

Wilmot Cancer Institute

University of Rochester Medical Center

Rochester, NY

CASE SUMMARY:

A 54-year-old woman presented to her physician with the following laboratory results:

• Hemoglobin: 7.0 g/dL
• β₂-Microglobulin: 6 mg/dl
• Albumin: 3.2 g/dL.​
• Calcium: 11.3 mg/dL
• Lactate dehydrogenase: 200 U/L
• Creatinine clearance: 45 mL/min​
• Bone marrow: 22% clonal plasma cells​
• Serum κ free light chain: 24 mg/dL​
• Serum monoclonal protein: 5 g/dL​

She had no cytogenetic abnormalities based on fluorescence in situ hybridization and karyotyping. Her EGOG performance score was 1. A PET-CT scans showed multiple bone lesions in vertebrae​. She was diagnosed with IgG-κ multiple myeloma, revised International Staging System (R-ISS) stage II,​ and was identified as being transplant eligible​.

BREA C. LIPE, MD: We have a pretty even split between VRd [bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone] and dara-VRd [daratumumab (Darzalex), bortezomib, lenalidomide, and dexamethasone]. We have 1 vote for VCd [bortezomib, cyclophosphamide, and dexamethasone]. Why did you feel that VCd was your first choice?

ERIC BRAVIN, MD: Because of the renal insufficiency.

LIPE: What’s your concern with starting lenalidomide? Do you dose reduce? Would you ever switch this patient or you would keep them on VCd throughout?

BRAVIN: You could certainly switch the patient, but I might start their first cycle without it.

LIPE: It looks like amongst everybody else, participants are split between dara-VRd versus VRd. Does anybody want to volunteer an idea of what their general approach is for the newly-diagnosed patient, when you add daratumumab or not?

BHUVANA RAMKUMAR, MD: I used to use VRd before for all the transplant-eligible patients, but I think the recent data are pretty strong for doing dara-VRd for transplant-eligible patients.¹ So I switched in the past year or so to dara-VRd.

LIPE: Does anybody who still does not use daratumumab up front? Are there data that you’re waiting for? Do you ever use daratumumab upfront, or do you reserve that for a later line of therapy?

RAMKUMAR: For transplant-ineligible patients, I still keep the daratumumab for the second line. I know there are recent data which are also for transplant-ineligible patients up front, but I usually save it for later for transplant-ineligible patients.^2,3

LIPE: Personally, I use a lot of dara-VRd upfront. I also use dara-KRd [daratumumab, carfilzomib (Kyprolis), lenalidomide, and dexamethasone] in patients who have higher-risk disease. I like the carfilzomib backbone for patients with high-risk disease, personally.

DISCUSSION QUESTIONS

• How do you decide between quadruplet and triplet? ​​
• 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? ​

LIPE: How do you decide between a quadruplet or triplet? What is your preferred upfront regimen?

SANTOSH KUMAR, MD: I [would] use the quadruplet, especially [in this case of] a 52-year-old woman. Even though the creatinine clearance is 45 mL/min, I usually dose reduce the lenalidomide to maybe 10 mg to start. As it improves, I escalate the dose. I had a patient more recently who did not want to have a quadruplet regimen. I usually discuss with the patient. If the patient is not comfortable with having 4 medications, then I do VRd. Otherwise, I use it for everybody. I reserve VCd only for the patients whose creatinine clearance is less than 30 mL/min and usually give them 1 or 2 cycles of the VCd, then try to switch them. If their creatinine clearance improves then I try to switch them.

LIPE: In the hospital, I find that we can’t get the lenalidomide very quickly, so we often use VCd when we’re getting patients started in the hospital as well, or KCd [carfilzomib, cyclophosphamide, and dexamethasone].

KUMAR: Yes, and also [consider] the renal failure.

LIPE: For participants that aren’t using daratumumab upfront, is there any sort of response that you see or don’t see that would make you escalate during induction, or do you wait for transplant to see how patients do? Or is there anything that would make you de-escalate? I don’t think we heard from anybody who said they didn’t use daratumumab upfront.

BRAVIN: In this patient, I would try to clean up the hypercalcaemia first, and if their renal function got better with fluids and zoledronic acid [Zometa], then I would have daratumumab in her induction. But I’ve only done that for the last 6 or 12 months. Before, for the transplant-eligible patients, I was giving them VRd. For the transplant-ineligible patients, I was using daratumumab upfront with VRd. But I remember induction being lenalidomide and steroids. It takes me a while to add new drugs. I think with the administration of daratumumab getting much easier the last couple of years rather than 10 hours in the treatment center, it’s made it much more palatable for patients to have it upfront in their induction.

DISCUSSION QUESTION

• What do you consider an adequate/successful treatment response in your patients following induction therapy in the real-world setting?​

LIPE: How do you judge what’s an adequate treatment response in these patients? How do you know when you decide to send them to transplant? Is there a response that you’re looking for before you send them to transplant or is it a time-based thing, [such as] 4 cycles and then they go? What’s the general approach?

KUMAR: If I feel that if the patient is a transplant candidate, I usually start the referral during the first cycle even before the response, so that they can start the discussion. Mostly they get referred for the transplant. If there’s somebody who is 80 years old, I probably won’t send them. Usually even the patients in their late 70s I send for transplant in the beginning.

RAMKUMAR: I do the same thing. During the first or second cycle, I usually send them to get an opinion, so they’ll be on their radar. Usually after 4, 5, or 6 cycles, they see them back again and they want 2 more cycles, and then I do 2 more cycles before sending them but usually try to do it upfront.

JAIME SUAREZ LONDONO, MD: We do the same, 4 cycles of dara-VRd and then we check for the response and then send for transplant, basically every patient. Usually, [we send] after the first or second cycle, and sometimes even just during the first cycle, so it’s on the radar and they can plan for [transplant].

_References:

_{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}

_{2. Facon T, Kumar S, Plesner T, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380(22):2104-2115. doi:10.1056/NEJMoa1817249}

_{3. Facon T, Kumar SK, Plesner T, et al. Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(11):1582-1596. doi:10.1016/S1470-2045(21)00466-6}