ASCO 2024 Multiple Myeloma

As FDA Weighs Use of MRD, Negativity Rates in PERSEUS Linked to Improved PFS in Newly Diagnosed Transplant-Eligible Multiple Myeloma

An in-depth analysis presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting highlighted links between rates of minimal residual disease (MRD) negativity and progression-free survival (PFS) seen among transplant-eligible patients treated with subcutaneous daratumumab (Darzalex Faspro; Janssen) and a standard backbone triplet in the phase 3 PERSEUS trial.^1,2

Primary results for PERSEUS (NCT03710603), presented in December 2023 at the American Society of Hematology meeting in San Diego, showed PFS was 84.3% at 4 years for patients treated with daratumumab and a triplet of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone, known as VRd, vs 67.7% for VRd alone (HR, 0.42).²

In PERSEUS, 709 patients were randomly assigned 1:1 to receive the daratumumab-VRd combination or VRd alone. Patients in both arms received up to 6 cycles of VRd, with 4 prior to autologous stem cell transplant (ASCT) and 2 post ASCT consolidation. Subcutaneous (SC) daratumumab and placebo were administered on a separate schedule from VRd, with daratumumab SC and lenalidomide given as maintenance in the investigational arm; patients in the placebo arm received lenalidomide maintenance. Those in the investigational arm who achieved MRD negativity could stop daratumumab SC, with the chance to restart the therapy if there was a loss of CR or MRD negativity.

Measures of MRD negativity could soon become even more important, as the FDA must weigh whether they can be used as surrogate end points following a unanimous endorsement from the Oncologic Drugs Advisory Committee.³ As the number of therapies for multiple myeloma increases—along with the length of time needed to demonstrate overall survival—experts in the United States and Europe have demonstrated evidence that supports this change.^4,5

Paula Rodriguez-Otero, MD, PhD | Image: Clinica Universidad de Navarra

The presentation by Paula Rodriguez-Otero, MD, PhD, of the Department of Hematology, Cancer Center Clinica Universidad de Navarra in Pamplona, Spain, reviewed data on MRD negativity at sensitivity of both 10^–5 and 10^–6. According to the Multiple Myeloma Research Foundation, this difference refers to MRD tests that can detect at least 1 myeloma cell in 100,000 healthy bone marrow cells (for a threshold of 1 x 10–5) vs tests that can detect 1 myeloma cell in 1 million (1 x 10^–6).⁶

“In newly diagnosed multiple myeloma, minimal residual disease negativity has been associated with prolonged survival,” Rodriguez-Otero said during the oral abstract session at ASCO. “Moreover, deeper responses with a sensitivity level of 10^–6 have been associated with superior outcomes compared to 10^–5 and 10^–4 current [MRD] testing. This sensitivity level of 10^–6 and sustained for over 5 years translates into very good survival and a potential for cure for patients with newly diagnosed multiple myeloma.”
Data showed that 88% of transplant-eligible patients achieved a complete response (CR) or better, and 47% of patients treated with daratumumab-based induction, consolidation, and maintenance therapy remained MRD negative after 12 months. The MRD negativity rate, as measured by the clonoSEQ test, deepened over time, Rodriguez-Otero reported. The rate was defined as the share of intent-to-treat patients who achieved both a CR or better and MRD negativity.

Results. According to the ASCO abstract,¹ at the end of consolidation, MRD negativity rates were 44.5% for the daratumumab SC arm vs 34.7% for the VRd-only arm (P = .0078). Data from the abstract report overall MRD negativity rates of 87.9% for the daratumumab SC arm vs 70.1% for the VRd-only arm (P < .0001).

“Importantly, the rates of conversion from patients that were MRD-positive at the end of consolidation and converted to MRD negativity during maintenance was also higher with D-R treatment as compared to lenalidomide alone,” Rodriguez-Otero noted.

Rates of MRD negativity deepened over time as follows, all favoring the daratumumab SC-VRd arm (daratumumab SC) at both levels of sensitivity (all P < .0001). First, to a 10^–5 sensitivity:

• At 12 months, rates were 65.1% for daratumumab SC vs 38.7% for VRd only.
• At 24 months, rates were 72.1% for daratumumab SC vs 44.9% for VRd only.
• At 36 months, rates were 74.6% for daratumumab SC vs 46.9% for VRd only.

Second, to a 10^–6 sensitivity:

• At 12 months, rates were 43.9% for daratumumab SC vs 20.9% for VRd only.
• At 24 months, rates were 57.7% for daratumumab SC vs 27.4% for VRd only.
• At 36 months, rates were 63.9% for daratumumab SC vs 30.8% for VRd only.

During her presentation, Rodriguez-Otero focused on MRD negativity rates for patients with high-risk cytogenetic abnormalities; she noted that the rates of sustained MRD negativity at least 12 months out from the start of treatment were higher in the daratumumab arm: 30% for daratumumab vs 14% in the VRd-only arm. “This translates into a prolonged progression-free survival for high-receptor genetic abnormality patients when treated with D-VRd followed by D-R maintenance.”

Will the MRD negativity rate take on greater meaning going forward? An official with Adaptive Biotechnologies, which makes the clonoSEQ test used in PERSEUS, weighed in with this statement to The American Journal of Managed Care:

“In recent years, the significance of MRD as a prognostic biomarker has become increasingly clear. The unanimous recommendation by the FDA’s Oncologic Drugs Advisory Committee to accept MRD as a primary end point for accelerated approvals in multiple myeloma trials, based on its strong correlation with progression-free survival and overall survival, underscores the clinical benefit of specific and sensitive MRD testing with clonoSEQ, as highlighted by the data presented at the ASCO annual meeting,” said Adaptive Biotechnologies’ Susan Bobulsky, chief commercial officer, MRD.
The test, she continued, is “well positioned” to continue as the preferred testing option in clinical trials. “We are proud to contribute to this paradigm shift in clinical trial end point consideration, which may help bring us closer to a cure for people living with multiple myeloma.”

“MRD-negativity is an important measure in predicting long-term progression-free survival for patients with multiple myeloma,” Rodriguez-Otero said in a statement.7 The higher rates of deep and sustained MRD negativity with a subcutaneous daratumumab-based regimen show the potential of this quadruplet and daratumumab-based maintenance “to shift the treatment paradigm for transplant-eligible patients with newly diagnosed multiple myeloma and bring us closer to the potential for a functional cure.”

References
1. Rodriguez-Otero P, Moreau P, Dimopoulos MA, et al. Daratumumab (DARA) + bortezomib/lenalidomide/dexamethasone (VRd) in transplant-eligible (TE) patients (pts) with newly diagnosed multiple myeloma (NDMM): analysis of minimal residual disease (MRD) in the PERSEUS trial. J Clin Oncol 2024;42(suppl 16). Abstract 7502. doi:10.1200/JCO.2024.42.16_suppl.7502
2. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;390(4):301-313. doi:10.1056/NEJMoa2312054
3. Durie BGM. A historic turning point: ODAC unanimously votes in favor of MRD testing as an early endpoint in myeloma clinical trials to support accelerated approvals of new treatments. International Myeloma Foundation. April 18, 2024. Accessed June 3, 2024. https://www.myeloma.org/blog/dr-duries/odac-unanimously-in-favor-mrd-testing-early-endpoint-myeloma#:~:text=ODAC%20Unanimously%20Votes%20in%20Favor%20of%20MRD%20Testing%20(12%2D0)&text=This%20was%20a%20historic%20unanimous,the%20FDA%20questions%20regarding%20implications.
4. Avet-Loiseau H, Ludwig H, Landgren O, et al. Minimal residual disease status as a surrogate end point for progression-free survival in newly diagnosed multiple myeloma studies: a meta-analysis. Clin Lymphoma Myeloma Leuk. 2020;20(1):e30-e37. doi:10.1016/j.clml.2019.09.622
5. Cavo M, San-Miguel J, Usmani SZ, et al. Prognostic value of minimal residual disease negativity in myeloma: combined analysis of POLLUX, CASTOR, ALCYONE, and MAIA. Blood. 2022;139(6);835-844. doi:10.1182/blood.2021011101
6. Answers to FAQs from our 7/14/23 webinar on minimal residual disease. Multiple Myeloma Research Foundation. July 14, 2023. Accessed June 3, 2024. https://themmrf.org/mmrf-blogs/answers-to-faqs-from-our-7-14-23-webinar-on-minimal-residual-disease/
6. Darzalex-based regimens significantly improve clinical outcomes in both transplant-eligible and transplant-ineligible patients who are newly diagnosed with multiple myeloma. News release. Johnson & Johnson. June 3, 2024. Accessed June 3, 2024. https://bit.ly/4b6Kz0J

IMROZ: Adding Isatuximab to SOC in Transplant-Ineligible Newly Diagnosed Multiple Myeloma Cuts Risk of Disease Progression or Death 40%

Adding isatuximab (Sarclisa; Sanofi), an anti-CD38 monoclonal antibody, to both phases of the standard regimen for patients newly diagnosed with multiple myeloma not eligible for transplant cut the risk of disease progression or death by 40%, according to results presented June 3, 2024, at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

Thierry Facon, MD | Image: ASCO

Results for the IMROZ trial (NCT03319667), presented in an oral session by Thierry Facon, MD, professor of hematology, Department of Hematology at Lille University Hospital in France, were simultaneously published in The New England Journal of Medicine (NEJM).²
Facon described IMROZ as the first worldwide phase 3 study of an anti-CD38 agent combined with the standard-of-care (SOC) combination of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone to show significant improvements in progression-free survival (PFS), along with deep responses based on measures of minimal residual disease (MRD), in transplant-ineligible patients newly diagnosed with multiple myeloma.

The triplet therapy that is the current standard regimen for these patients, known as VRd, is followed by maintenance with lenalidomide and dexamethasone only (Rd). In his presentation, Facon noted that several phase 3 trials are building off this triplet background therapy to seek even better results with quadruplet therapy.

In an interview with The American Journal of Managed Care before ASCO, Facon said the results for isatuximab in IMROZ were highly significant in part because of the results in the comparator arm were so strong—a point also noted in the NEJM paper.

“The PFS benefit, to be honest, is very significant, both from a clinical and a statistical point of view,” Facon said. “One thing is that the VRd control arm did very well; you will not see so many VRd regimens doing so well.”

He compared not only PFS but also the number of cycles of therapy between the 2 arms: “It’s totally true to say that the median duration on therapy is 31 months for VRd and 53 months for isatuximab. So the median number of cycles is 29 vs 52. That’s a big difference.”

In IMROZ, 446 patients aged 18 to 80 years were randomly assigned 3:2 to receive either isatuximab plus VRd or VRd alone; 4 induction cycles (6 weeks per cycle) were followed by 4-week cycles of continuous treatment of isatuximab-Rd for patients in the isatuximab-VRd group vs Rd for patients in the VRd group. Patients were treated until disease progression or an unacceptable adverse event (AE).

Results are as follows:

• The primary end point was PFS. At a median follow-up of 59.7 months, the median PFS with the isatuximab-VRd combination was not reached vs 54.3 months with VRd.
• The estimated PFS at 60 months was 63.2% in the isatuximab-VRd group vs 45.2% in the VRd group, for an HR of 0.60 for disease progression or death (98.5% CI, 0.41-0.88; P < .001).
• For the secondary end point of complete response (CR), 74.7% of patients receiving isatuximab-VRd achieved a CR or better vs 64.1% among those who received VRd alone (P= .01).
• For the secondary end point of MRD-negative status among those with a CR, the percentage of patients with MRD-negative status and a CR favored the isatuximab group (55.5% vs 40.9%; P = .003).
• No new safety signals were reported among patients taking the isatuximab-VRd regimen. Grade 3 or higher treatment-emergent AEs were seen in 91.6% of patients taking isatuximab-VRd and 84% of those taking VRd.
• The incidence of serious AEs leading to discontinuation was similar between the 2 groups; 22.8% of patients in the isatuximab-VRd group and 26% taking VRd.
• At the time of data cutoff, 47.2% of patients (125/263) receiving isatuximab-VRd and 24.3% of patients (44/181) treated with VRd were still on treatment. The median treatment duration for the isatuximab-VRd combination was 53.2 months compared with 31.3 months for VRd.

“The improved efficacy of [isatuximab] VRd, combined with a consistent safety profile, provides an important treatment option for frontline treatment in this population, establishing isa-VRd as a new standard of care for patients less than 80 years of age with transplant ineligible multiple myeloma,” Facon concluded.

In a commentary on 3 related presentations, Carl Ola Landgren, MD, PhD, of the University of Miami/Sylvester Comprehensive Cancer Center, agreed that isatuximab-VRd should be the standard of care, although he asked whether the lines between “transplant eligible” and “transplant ineligible” are still needed in the era of anti-CD38 therapy.

MRD status. The FDA is deciding whether to make MRD negativity a surrogate end point following a recent unanimous endorsement from the Oncologic Drugs Advisory Committee.³ The NEJM paper noted that 46.8% of those in isatuximab-VRd group and 24.3% of the VRd group had sustained MRD negative status for at least 12 months, based on a sensitivity of 10–5. IMROZ also had an exploratory analysis of the share of patients with both MRD-negative status and CR at a sensitivity of 10–6 and results were consistent (40.0% vs 22.7%; with an OR of 2.27; 95% CI, 1.48-3.48).²

In addition, a PFS benefit was seen in the isatuximab-VRd group among MRD-negative patients compared with MRD-positive patients (HR, 0.22; 95% CI, 0.14-0.35), and this benefit was larger than what was seen among the VRd patients who were MRD-negative (HR, 0.31; 95% CI, 0.19-0.52).

During the interview, Facon was asked if the results provide evidence that MRD is a valid surrogate end point. “I think I could tell you that FDA would be happy with the study results,” he replied. “They will not complain.”

Ahead of his ASCO presentation, Facon said he anticipated questions about results that show patients with high-risk cytogenetic features did not receive additional benefits from isatuximab vs VRd (HR, 0.97; 95% CI, 0.48-1.96). The NEJM paper said this area warrants “further analyses and longer follow-up.”

References
1. Facon T, Dimopoulous MA, Leleu XP, et al. Phase 3 study results of isatuximab, bortezomib, lenalidomide, and dexamethasone (Isa-VRd) versus VRd for transplant-ineligible patients with newly diagnosed multiple myeloma (IMROZ). J Clin Oncol. 2024;42(suppl 16). Abstract 7500. doi:10.1200/JCO.2024.42.16_suppl.7500
2. Facon T, Dimopoulous MA, Leleu XP, et al. Isatuximab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. Published online June 3, 2024. doi:10.1056/NEJMoa2400712
3. Durie BGM. A historic turning point: ODAC unanimously
votes in favor of MRD testing as an early endpoint in
myeloma clinical trials to support accelerated approvals
of new treatments. International Myeloma Foundation. April 18, 2024. Accessed June 3, 2024. https://www.myeloma.org/blog/dr-duries/odac-unanimously-in-favor-mrd-testing-early-endpoint-myeloma

No CRS in First 10 Patients in Teclistamab Pilot With Prophylactic Tocilizumab

The first 10 patients with multiple myeloma given a prophylactic dose of tocilizumab prior to treatment with teclistamab have not experienced cytokine release syndrome (CRS) or immune effector cell–associated neurotoxicity syndrome (ICANS), according to data from a pilot study presented at the 204 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

Early findings from the OPTec study (NCT05972135) could signal a breakthrough in patients’ ability to receive teclistamab, a bispecific antibody sold as Tecvayli,² in community settings. More patients could access teclistamab if clinicians could prevent patients from experiencing an adverse event (AE) requiring hospital admission.
Teclistamab is the only FDA-approved therapy with weight-based dosing to target B-cell maturation antigen (BCMA) on multiple myeloma cells and CD3 on T cells to activate an immune response.² The therapy has a step-up dosing schedule, which allows some flexibility on when it is administered to deal with CRS or ICANS.

Robert M. Rifkin, MD | Image: The US Oncology Network

The pilot, led by Robert M. Rifkin, MD, medical oncologist/hematologist of Rocky Mountain Cancer Centers of Denver, Colorado, is based on findings from a cohort of the MajesTEC-1 study,3 which led to approval for teclistamab in patients who have received at least 3 therapies for multiple myeloma. CRS was seen in 72% of patients in cycles 1 and 2, with 33% seeing recurrent CRS. However, among a group of patients who had a prophylactic dose of tocilizumab, only 26% of patients had CRS.

The purpose of the pilot is to evaluate whether giving a prophylactic dose of tocilizumab can prevent neurologic AEs when teclistamab is administered in a community setting. This requires carefully following patients to ensure that tocilizumab, normally given at the onset of CRS, does not alter the efficacy of the therapy.

“All of the safety end points are early,” cautioned Rifkin, who explained the pilot’s methodology.

This process required investigators to treat 5 patients, present findings to the data review committee (DRC); treat 5 more patients, then present those findings to the DRC. Under the study’s protocol, with the DRC’s blessing, the study can then expand from 4 sites to 12 and enroll an additional 40 patients.
“We’ve completed our first 10 patients,” Rifkin said in an interview. “The next data review committee will be within the next 2 weeks, and we’re optimistic we’ll be able to then open it up and accrue the remaining 40 patients.”

In addition, he said, “a talquetamab arm will be added,” referencing the bispecific antibody sold as Talvey, which is a GPRC5D-directed CD3 T-cell engager.

Both teclistamab and talquetamab are made by Johnson & Johnson, which sponsored the study with the Sarah Cannon Research Institute.

Rifkin was enthusiastic about the results, but he noted that giving patients teclistamab will still require a community practice to have resources to properly administer the therapy, which is given through subcutaneous injection. Patients must still have a caregiver present, there is still the likelihood of fever, and results show that other AEs such as headaches or nausea remain.

“It’s still a team effort,” Rifkin said. One approach being considered is that after a few weekly doses, patients in the study could return to their local oncologist, because the window for CRS or ICANS to appear will have passed.
Methods. Study protocol call for the following¹:

Patients eligible for the pilot must be at least aged 18 years and have received at least 4 prior lines of therapy for multiple myeloma.

Those with rapidly progressing multiple myeloma, active infection, or central nervous system involvement are excluded.

Tocilizumab is given in doses of 8 mg/kg intravenously 2 to 4 hours prior the first dose of teclistamab in an outpatient setting; teclistamab is then given weekly for 12 cycles until disease progression or unacceptable toxicity.

Results: Data presented at ASCO include the following¹:

• Median age was 70 years (range, 53-83).
• Six female patients and 5 male patients have enrolled.
• Patients received a median of 8 (range, 5-11) prior systemic therapies.
• Criteria for stopping, which are grade 3 or higher CRS or neurotoxicity/ICANS, were not met for the first 11 patients.
• Common AEs were headache (5), nausea (5), neutropenia (4), and injection site reaction (4).
• No patient had CRS or ICANS.
• No patient was hospitalized due to tocilizumab or teclistamab.
• One patient had a grade 2 infection of the upper respiratory tract and urinary tract; 2 patients had 1 each of respiratory tract or yeast infection.

Ten patients completed the step-up dosing regimen. One patient with diffuse bony lesions and pain did not complete the regimen and withdrew due to physician’s decision; the patient later died.

References
1. Rifkin RM, Schade HH, Simmons G, et al. OPTec: a phase 2 study to evaluate outpatient (OP) step-up administration of teclistamab (Tec), a BCMA-targeting bispecific antibody, in patients (pts) with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2024;42(suppl 16). Abstract 7528. doi:10.1200/JCO.2024.42.16_suppl.7528
2. Tecvayli (teclistamab-cqyv) biweekly dosing approved by the U.S. FDA for the treatment of patients with relapsed or refractory multiple myeloma. News release. Johnson & Johnson. February 20, 2024. Accessed June 3, 2024. https://bit.ly/3V5EQ53
3. Moreau P, Garfall AL, van de Donk NWCJ, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2022;387(6):495-505. doi:10.1056/NEJMoa2203478

Promise in Halting Myeloma Maintenance Therapy

Being able to discontinue maintenance therapy for multiple myeloma is the goal of the MRD2STOP study (NCT04108624), which is using the cumulative result of 3 methods to detect presence of sustained measurable, or minimal, residual disease (MRD) as potential indicator that a patient can stop treatment for the hematologic malignancy, according to data presented at the 2024 American Society of Clinical Oncology Annual Meeting.¹

MRD can potentially be used to identify the absence of disease in certain cancers, including multiple myeloma, and there is research being done in how MRD negativity or positivity can guide treatment decision-making.2 The FDA is weighing whether measures of MRD negativity can be used as surrogate end points.

This prospective study is ongoing, with 3 primary end points: progression-free survival (PFS), overall survival, and MRD resurgence rate at a threshold of 10^–6.
“Measurable residual disease negativity, we know now, is strongly associated with improved prognosis in myeloma, and in particular at 10^–6, or less than 1 clonal cell within 1 million, seems to carry superior prognosis over less-sensitive thresholds,” said Ben Derman, MD, assistant professor of medicine, University of Chicago. “It may be the most important prognostic indicator in all of myeloma.”

However, some patients will still experience disease progression, he added, which leads to the question: Is it possible that a deeper level of MRD testing may be able to improve prognostication further? His team was seeking a more sensitive test that could get them to a sensitivity of 10^–7.

PET/CT, flow cytometry (limit of detection, 10^–5), and next-generation sequencing by clonoSEQ (threshold, 10^–6) are being used in MRD2STOP to measure patients’ blood samples in the trial. In this preliminary analysis, data were provided from standard myeloma blood testing conducted every 3 months, while patients’ yearly bone marrow aspirate samples were enriched via CD138-positive immunomagnetic enrichment—a method that helps to pull out the plasma cells from the sample—using clonoSEQ to achieve MRD 10^–7 sensitivity. Expression of CD138, or syndecan-1, is a glycoprotein expressed on the surface of both plasma cells and multiple myeloma cells; when tested for, a positive result can indicate either lymphoma or myeloma.

Patients with disease progression went off trial protocol and on to their treatment of choice.

Of the initial 83 patients screened, 47 were able to discontinue maintenance as of January 1, 2024, of whom 17 had high-risk disease, 9 were in their first line of therapy, and 40% received quadruplet treatment. The most common maintenance treatment, by far, was the immunomodulator lenalidomide, a once-daily oral medication; however, Derman explained, there is no hard-and-fast end date for the maintenance treatment.

Over a median follow-up of 30 months, 30% of patients were on consolidation/maintenance treatment for less than 27 months; the median overall duration of consolidation/maintenance was 36 months (range, 12-95). There was disease progression in 5 patients and MRD resurgence rate at the predetermined threshold in 6 patients. Three patients were MRD 10–7–positive in the year leading up to MRD 10–6 resurgence.

One patient died during the study due to development of B-cell acute lymphoblastic leukemia. At the 3-year mark, the PFS rate of 85%, jumped to 93% among the patients tested at MRD 10^–7–negative at baseline; the MRD-free survival rate—or the time from treatment discontinuation to MRD 10^–6 resurgence, disease progression, or death—at this mark was 68%, which again was higher (78%) among patients tested at MRD 10^–7 negative.

Derman also highlighted the potential cost savings of ceasing lenalidomide in the 47-patient cohort alone: For a total of 1250 months of observation at $18,000/month for lenalidomide, MRD2STOP so far has saved $22.5 million.

References
1. Derman BA, Cooperrider JH, Kibicki T, et al. Discontinuation of maintenance therapy in multiple myeloma guided by multimodal measurable residual disease negativity. Presented at: ASCO 2024; May 31-June 4, 2024; Chicago, IL. Abstract 106. https://meetings.asco.org/2024-asco-annual-meeting/15870?presentation=234914#234914
2. Joszt L. MRD testing is valid in the real world, can be cost-effective over lifetime of patients with MM. The American Journal of Managed Care. May 30, 2019. Accessed June 13, 2024. https://www.ajmc.com/view/mrd-testing-is-valid-in-the-real-world-can-be-costeffective-over-lifetime-of-patients-with-mm