Recap: Emory Experts Review Treatment Strategies for Transplant-Ineligible Multiple Myeloma

In this special edition of Around the Practice: Institutional Insights, physicians from Emory University in Atlanta, Georgia, engaged in a discussion on topics in multiple myeloma, with a focus on those patients who are ineligible for transplant. The experts were Sagar Lonial, MD, chief medical officer of the Winship Cancer Institute as well as professor and chair in the Department of Hematology and Medical Oncology and Anne and Bernard Gray Family Chair in Cancer; Nisha Joseph, MD, assistant professor in the Department of Hematology and Medical Oncology and co-director of the Winship Summer Scholars Program; Jonathan L. Kaufman, MD, medical director and section chief of the Winship Cancer Institute as well as professor in the Department of Hematology and Medical Oncology; and Ajay K. Nooka, MD, MPH, medical director of the Winship Data and Technology Applications Shared Resource of the Winship Cancer Institute as well as associate professor and director of the myeloma program in the Department of Hematology and Medical Oncology.

CASE 1

• An 82-year-old woman presented with solitary plasmacytoma in November 2018 and received definitive radiotherapy.
• In March 2019, she was admitted from clinic with hypercalcemia (Ca 12.3 mg/dL) and anemia (hemoglobin 8.8 g/dL).
• Immunologic studies: serum protein electrophoresis (SPEP), 0.2 g/dL; immunoglobulin (Ig) A-κ, free κ light chains (FKLC), 600; and serum free light chain ratio (FLCr), 215
• Bone marrow biopsy: 40%-50% plasma cells, normal female karyotype, fluorescence in situ hybridization (FISH) positive for t(11;14)
• Skeletal survey: diffuse lytic deposits throughout the axial and appendicular skeleton with compression deformities at T6, T7, L4, and L5

Treatment

• She underwent inpatient kyphoplasty and was discharged with close follow-up.
• Daratumumab (Darzalex) plus lenalidomide (Revlimid) and dexamethasone (DRd) was initiated in April 2019.

Response

• The patient had normalizations of her FLCr by cycle 6 and continued with treatment.

Progression and treatment

• In April 2021, she had rising serum free light chains meeting progressive disease.
• She was transitioned to a strategy of bortezomib (Velcade), pomalidomide (Pomalyst), and dexamethasone.

Lonial: How do we differentiate between what we use for the fit, transplant-eligible patient and the older, frail, transplant-ineligible patient? When we think about regimens that we use in this clinical situation, historically a standard has been modified RVd [lenalidomide, bortezomib, and dexamethasone]. But DRd has been another standard, and then of course we give some patients just lenalidomide and dexamethasone (Rd). How do you think about choosing a treatment?

Joseph: I think about 3 different things: performance status; frailty and comorbidities; and then disease status, high vs standard risk. In general, even though we’re talking about transplant-ineligible disease, I reserve doublets for the very frail populations, such as a patient in their 90s who has a poor performance status. Rd might be a good option for them. Other frail patients who aren’t quite so frail tolerate triplets quite well, particularly DRd [from] the MAIA study [NCT02252172].¹ For higher-risk patients, recognizing the utility of proteasome inhibition in high-risk disease, I often go for RVd, [with evidence of] benefit in the SWOG 0777 [NCT00644228] study.

Lonial: Can you provide a rundown of the updates from the MAIA trial?

Nooka: The regimen used in the MAIA trial has shown the best depth of response in transplant-ineligible patients as of today. Combining daratumumab with Rd in the MAIA trial was able to deliver these responses, with an overall response in [more than] 9 of [every] 10 people, for a [greater than] 90% overall response rate [92.9%]. These are deep responses, with MRD [minimal residual disease] negativity in 15% of the patients. And again, these patients did not receive any transplant. [In total 737 patients were] randomized between DRd vs Rd, which was the standard of care in the United States. DRd has been shown to be superior to Rd across all end points: response rate, [progression-free survival], overall survival [OS]. Updated data that were presented at [the European Hematology Association Congress in 2021] showed that the 5-year OS rate is reaching 67%, so 2 in 3 people who were transplant ineligible are alive at the 5-year mark. If you look at the same numbers for the control group of Rd, the rate is 53%, which is 1 in 2 people who are alive at the 5-year mark [HR, 0.68; 95% CI, 0.53-0.86; P = .0013]. This is not only showing a clear improvement in OS, but in the depth of response, with MRD negativity beyond the 12-month mark in 15% of the patients on DRd vs less than 5% in the Rd group.²

Lonial: A third of the patients on MAIA were aged more than 75 years, and a significant fraction were aged more than 80. How do you use that MAIA subset analysis to decide if you’ll use a triplet or a doublet?

Kaufman: While frailty still was important overall in outcomes, frail patients, no matter what treatment arm, did worse than nonfrail patients. The frail patients who were treated with the DRd vs Rd did better. I need to think about how I am going to get the patient through this regimen. Do I need to start out with a lower dose of dexamethasone? Do I need to start out with a lower dose of lenalidomide in order to get the benefits from that regimen?

Lonial: How do we define high-risk disease in 2022?

Joseph: For the most part, we follow revised [International Staging System] staging in terms of cytogenetics. At our center, we also look at complex karyotypes—so, multiple abnormalities on chromosome analysis. Then outside of cytogenetics, we would think of [certain] disease biology features, such as extramedullary disease and circulating plasma cells for primary refractory disease, as high-risk features as well.

CASE 2

• A 78-year-old man presented to the emergency department in December 2019 with worsening lower back pain, 3 times per month, with acute worsening now with lower extremity weakness.
• Laboratory work-up: Ca, 10.5 mg/dL; SPEP/immunofixation, 2.9 g/dL; IgG-k, IgG, 4261; IgA, 108; IgM, 10; FKLC, 636; FLCr, 107
• Bone marrow biopsy: 25% plasma cells, normal male karyotype, FISH with +3, +7, and +9
• Skeletal survey/MRI of lumbar spine: diffuse osseous disease with multiple compression fractures, with large enhancing lesions in L3 and extraosseous extension into the epidural space.

Treatment

• The patient received radiotherapy to L3 lesion.
• He was started on Vd as an inpatient with improvement in his pain and was discharged.

Follow-up

• The patient was deemed transplant ineligible and started on RVd-lite (lenalidomide, 15 mg on days 1-21; bortezomib, 1.3 mg/m2 on days 1, 8, and 15; and dexamethasone, 20 mg on days 1, 8, and 15) for 28-day cycles beginning in January 2020.
• He completed 8 cycles and achieved complete remission (CR) after cycle 4.
• He was transitioned to lenalidomide maintenance in September 2020.
• At the last follow-up in January 2022, he remained in CR.

Lonial: What do you consider an adequate treatment response? And when do you consider changing treatments vs staying on that same one and just going with continuous therapy?

Nooka: I take a couple of things into consideration when I make the determination. Number 1 is the risk status. If it is a higher-risk patient, it is not difficult to attain that response, but it’s difficult to maintain that response. I try to maintain that combination treatment for as long as the patient can tolerate. Fully understanding that a transplant-eligible or -ineligible patient comes with a lot of comorbidities, [you realize that] diabetes and neuropathy are more common in these patients. If that is the case, [I have to consider what treatment will not result in] worsening this neuropathy.

Number 2 is the tolerance. The earlier the time that I get to a CR helps me to streamline this to get to the best depth of responses; then, we can maintain these responses for a longer time without having to give those combination treatments.

Lonial: If we had a blood-based MRD assessment, how could that impact the way you make clinical decisions?

Kaufman: With our current technology, doing a bone marrow biopsy gets [MRD results] down to 10–6. With that same assay in the blood, it’s 10–4, so we can’t use that. But maybe blood tests 10 years from now [will be able to detect] much deeper responses. I see a future [where we are] basing our treatments not on a paraprotein level rising or waiting for a patient to become symptomatic in the relapse setting, but looking at very low-level disease and making modifications.

Lonial: We know MRD is prognostic; people who achieve those depths of response historically will do better. What we don’t know is if you take the patients who have not achieved MRD negativity and change their treatment, whether you’ve changed their natural history. Those trials are currently
ongoing in risk-adaptive maintenance and consolidation trials. We need those data to help make those kinds of decisions.

Can you discuss maintenance strategies in the transplant-ineligible patient population?

Joseph: That depends on the regimen that I’ve started with and the risk status of the patient. For example, in patients who start on DRd, I tend to follow the study. I keep them on DRd and if I think about tapering anything down or even off, it might be the dexamethasone, in this older patient population. For those who are on RVd, if they are standard risk, I tend to give at least 8 cycles of therapy. If they’ve achieved a [very good partial response], I consider downgrading them to lenalidomide alone. For high-risk patients, I get anxious about putting them on monotherapy, so I prefer 8 cycles. For a deep response, I consider a triplet, but I might switch out the bortezomib for ixazomib [Ninlaro] or DRd to reduce neuropathy rates.

Lonial: You bring up a really important point, which is that just because they’re on treatment doesn’t mean they need to stay on dexamethasone. Most of us tend to get the patients off dexamethasone by the end of the first year, if not sooner.

In terms of duration of therapy, do you treat to progression or to a specified end point?

Nooka: We’ve seen time and again that continued treatment is the best way to maintain that response for the longest period. I don’t see it any differently for the transplant-ineligible relative than I do with the transplant-eligible patient population. The only difference is the tolerance among an elderly patient population compared with a much younger patient population at the time of transplant. Unless I’m hitting any wall in terms of adverse effects, I’m continuing to use that maintenance until progression.

Lonial: When patients ask me how long am I going to be on this, I say forever is not a bad thing, in the sense that if they can tolerate the treatment and the disease control is good, that really is a win for patients overall.

References

1. 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
2. Facon T, Kumar SK, Plesner T, et al. Overall survival results with daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in transplant-ineligible newly diagnosed multiple myeloma: phase 3 MAIA study. Presented at: European Hematology Association Annual Meeting; June 9-17, 2021; virtual. Abstract LB1901.