The availability of numerous new agents for treating multiple myeloma has created some “conundrums” for clinicians, said Sergio Giralt, MD, Deputy Head of the Division of Hematologic Malignancies at Memorial Sloan Kettering Cancer Center and the Melvin Berlin Family Chair in Myeloma Research and Professor of Medicine at Weill Cornell Medical College, New York. At the 2022 Community Oncology Alliance’s Community Oncology Conference, Dr. Giralt offered his thoughts on some of these issues.1
Sergio Giralt, MD
“The diagnosis, workup, and treatment of myeloma have dramatically changed over the past 10 years. The therapeutic goal is to obtain deep remissions that translate into improved progression-free and overall survival. With combination therapy using immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, bispecific antibodies, autologous and allogeneic transplantation as well as chimeric antigen receptor (CAR) T cells, long-term disease control and cures will be achievable in a substantial proportion of patients,” Dr. Giralt said.
The summary here of Dr. Giralt’s presentation focuses on newly diagnosed patients.
Time to Treat Smoldering Myeloma?
“The data emerging from clinical trials are pretty clear: Patients with high-risk smoldering myeloma who start some type of active treatment have a significant benefit in regard to delaying disease progression,” Dr. Giralt said. Still, he added, early treatment remains controversial: “When you treat every patient with smoldering myeloma, everybody gets the side effects, and not necessarily everybody gets the benefit. Also, we all have patients who have been ‘smoldering’ for 10 years, and nothing has happened. They could have spent 10 years on treatment without any discernible benefit.”
Pending further clinical trial data to identify patients most likely to benefit, Dr. Giralt maintains there are some patients who should be treated to prevent progression to myeloma.
Newly Diagnosed Transplant-Eligible Patients
“I tell my fellows that my goal is not to cure myeloma. It’s to give my patients the longest life, with the best quality of life, with the least amount of treatment necessary. That goal is met by achieving the deepest response—by getting to a complete remission. The use of optimal induction, autologous stem cell transplantation [ASCT], consolidation, and maintenance has been shown to achieve that goal in many patients, and the numbers are improving,” commented Dr. Giralt.
Standard induction therapy is moving toward four-drug combinations that include an anti-CD38 monoclonal antibody (isatuximab or daratumumab), the immunomodulatory drug lenalidomide, a proteasome inhibitor (bortezomib or carfilzomib), and dexamethasone. Four-drug regimens for induction are repeatedly proving superior to three drugs in producing more and deeper responses, he added.
Depth of response is critical: Complete response is associated with significant benefits in progression-free and overall survival. The rapidity with which a patient achieves a complete response is also important: When that occurs within 1 year, outcomes are better, as shown in a large analysis of more than 7,000 patients.2 Attainment of a complete response within 1 year vs later has been associated with superior progression-free survival (3.3 years vs 2.6 years; P < .0001) and overall survival (8.5 years vs 6.3 years; P < .0001).
Absence of measurable residual disease (MRD)—ie, MRD negativity—is even more prognostic, as Munshi et al showed in a meta-analysis.3 MRD-negative status was associated with significantly improved progression-free survival (hazard ratio [HR] = 0.41; P < .001) and overall survival (HR = 0.57; P < .001), vs MRD-positive status.
Next-generation sequencing for MRD has a sensitivity of 10-5 to 10-6, reflecting the ability to detect 1 in 100,000 to 1 in 1,000,000 myeloma cells in normal cells. Flow cytometry can also be used but requires special expertise. And although MRD testing is desirable, it is also problematic as a type of monitoring: It requires bone marrow testing and is technically dependent on having a good sample, Dr. Giralt acknowledged.
Considerations for Induction Therapy
Dr. Giralt noted several important factors to consider when planning induction therapy:
- For transplant-eligible patients, melphalan should be avoided, as it affects the collection of stem cells. If carfilzomib or daratumumab is a component of induction, stem cells should be collected between the fourth and sixth cycles for optimal yield.
- For patients with renal failure, the first induction cycle should be with cyclophosphamide, bortezomib, and dexamethasone; a fourth drug, such as daratumumab, can be added.
- For older or diabetic patients, the steroid dose should be reduced.
- For patients with a bleeding or clotting disorder, lenalidomide treatment requires the use of aspirin or another anticoagulant.
- For patients with active neuropathy, bortezomib can worse the condition.
- For patients with high-risk features, carfilzomib and daratumumab are probably the best agents.
Carfilzomib vs Bortezomib
Clinicians now have the choice of two proteasome inhibitors for induction therapy. It appears the two are equally efficacious but have different side effects, as shown in the phase III -ENDURANCE trial.4 The study evaluated two triple-drug induction regimens: the standard regimen of bortezomib, lenalidomide, and dexamethasone (VRd) vs carfilzomib, lenalidomide, and dexamethasone (KRd), which had proven superior to VRd in the salvage setting. “Surprisingly,” Dr. Giralt stated, median progression-free survival was similar, approximately 34 months in both arms; however, the toxicity profiles differed. Carfilzomib was associated with significantly less neuropathy and treatment discontinuation but more hypertension and pulmonary problems than was bortezomib.
Consequently, for older patients with standard-risk myeloma, Dr. Giralt often opts for induction therapy with VRd, reserving KRd for younger patients without cardiopulmonary issues. Daratumumab can be added to either regimen.
Is Upfront Transplantation Still Important?
With novel drugs greatly improving outcomes, questions have arisen recently regarding the importance of upfront transplantation. “I’m a transplanter and have a definite bias that patients should have a transplant,” Dr. Giralt commented. “Transplantation can make a difference for patients in terms of survival.”
The FORTE trial compared 12 cycles of KRd without transplantation (KRd12) with a sandwich approach of 4 cycles of KRd followed by ASCT and then another 4 cycles of KRd (KRd-ASCT).5 A second randomization was to maintenance with lenalidomide or lenalidomide plus carfilzomib. Although response rates were similar for both induction approaches, the “sandwich” approach resulted in better sustainment of MRD negativity and improved progression-free survival, which was not reached with KRd-ASCT and was 57 months with KRd12 (HR = 0.64; P = .023). The findings support the use of high-dose melphalan and ASCT, even in the context of novel induction therapies, he said.
Similarly, the phase III EMN02/HO95 study found that upfront ASCT, vs intensified induction therapy with bortezomib, melphalan, and prednisone (VMP), significantly prolonged overall survival (HR = 0.81; P = .034), the time to second disease progression (HR = 0.76; P = .0002), and the time to next treatment (HR = 0.71; P < .0001).6
“Patients may ask for delayed transplant…. Transplantation is a choice, not a necessity…. But the consequence of that decision is a 66% chance of having to deal with the disease again in 7 years; for upfront transplantation, that risk is significantly less, 54%. The time a patient lives without needing another treatment is almost 2 years…. Also, the disease may become more aggressive, and the patient will no longer be a transplant candidate,” he pointed out.
On the other hand, Dr. Giralt added, patients who undergo upfront transplantation may also “pay a price” in terms of toxicity endured without benefit. Or, they may have to endure the rigors of transplantation despite the real possibility of remaining relapse-free without one.
According to Dr. Giralt, the benefit of transplantation is essentially universal: Even patients with low-risk disease who achieve MRD negativity have been shown to benefit. “It’s nuanced,” he acknowledged, “but certainly, for patients with high-risk disease, I’m going to encourage transplantation, regardless of whether they achieve MRD negativity or not.”
Optimal Maintenance Therapy
Maintenance therapy is recommended until disease progression. However, with many of today’s patients remaining free of recurrence after 3 to 4 years, experts are asking whether some patients can discontinue maintenance therapy earlier. Dr. Giralt uses MRD as a guide, especially for patients finding it difficult to stay on treatment.
The recent MASTER trial was designed to inform the use and duration of daratumumab plus KRd after transplantation and treatment cessation.7 Patients received daratumumab plus KRd induction, ASCT, and daratumumab plus KRd consolidation, according to MRD status. MRD was evaluated at the end of induction, after ASCT, and after every four cycles of consolidation. Patients with two consecutive MRD-negative assessments entered treatment-free MRD surveillance.
The findings from the MASTER trial follow:
- High-dose melphalan deepens response for all groups of patients but particularly for those with high-risk cytogenetic abnormalities.
- Among standard-risk patients with sustained MRD negativity, stopping maintenance therapy was safe, and no patients relapsed.
In contrast, most high-risk patients with sustained MRD negativity who stopped maintenance therapy still experienced disease progression, and for many, their disease was never brought back under control. Investigators concluded that quadruplet therapy and the achievement of MRD negativity “enable the exploration of treatment cessation.”
The use of MRD status to guide decisions regarding maintenance therapy was reinforced by the IFM/DFCI 2009 trial, which evaluated outcomes by MRD status in patients discontinuing lenalidomide after 2 years (whether transplanted or not).8 The risk of relapse was 20% for patients remaining in MRD-negative status, but it was 80% for MRD-positive patients.
“We are thinking this is where we should intervene: If a patient has MRD-positive disease at the 1-year mark, we should think about salvage therapy, perhaps with a bispecific antibody or CAR T-cell therapy [experimentally] or by intensifying maintenance,” such as by adding an anti-CD38 antibody if not previously used, he suggested.
The recent GRIFFIN study further demonstrated the power of four drugs for induction therapy, daratumumab as part of maintenance therapy, and the prognostic nature of MRD status.9 Patients were randomly assigned to VRd alone or with daratumumab for induction and consolidation therapies, followed by ASCT and then by maintenance therapy with lenalidomide alone or with daratumumab. After 2 years of maintenance therapy, complete response or better was achieved by 82% of the arm given daratumumab plus VRd vs 61% of the arm that received VRd alone, with disease progression observed in 1% vs 7%, respectively, and benefit was observed regardless of cytogenetic risk. Curves for disease progression diverged significantly after 3 years, possibly because of the benefit conveyed by the addition of daratumumab to lenalidomide maintenance. Even at 4 years, relapse was rare in the arm given daratumumab plus VRd.
“That is a significant benefit, and it is based exclusively on a significant increase in sustained MRD negativity lasting more than 1 year (44% vs 13%; P < .0001),” he commented. “In terms of our goals for treatment, it’s to try to get most patients to an MRD-negative state that can be sustained for 1 year.”
Although single-agent lenalidomide remains the standard, in high-risk patients, Dr. Giralt recommends adding daratumumab or carfilzomib.
Treatment of ‘Ultra-High–Risk’ Patients
Newly diagnosed patients with a considerable risk of disease progression—ie, the “ultra-high–risk” subset—require more aggressive therapy. The OPTIMUM trial evaluated a five-drug combination—daratumumab plus cyclophosphamide and VRd—followed by ASCT with daratumumab plus VRd as consolidation and daratumumab/lenalidomide as maintenance.10 At the end of induction therapy, the overall response rate was 94%, the complete response rate was 22%, the rate of very good partial responses was 58%, and 41.1% achieved an MRD-negative status.
“The message is that one size does not fit all: Patients with high-risk and ultra-high–risk myeloma probably need to be treated in a different way,” he said.
Transplant-Ineligible Patients
For newly diagnosed patients who are not eligible for ASCT, there are two basic strategies: the reduced-intensity regimen dubbed “VRd-lite” for 8 to 12 cycles, which has not been evaluated in a randomized trial, and daratumumab plus lenalidomide and dexamethasone, which was established in the phase III MAIA trial.11
In MAIA, the addition of the monoclonal antibody to lenalidomide plus dexamethasone significantly increased the rate and depth of response. This translated into a median progression-free survival not reached with daratumumab plus lenalidomide and dexamethasone vs 34.4 months with lenalidomide and dexamethasone alone (HR = 0.53; P < .0001); a 5-year progression-free survival rate of 52.5% vs 28.7%, respectively; and an improvement in overall survival (HR = 0.68; P = .0013).
“There are 70- and 80-year-old patients who, because of this three-drug combination, now have a 50% chance of not having to deal with their disease 5 years later. This is a major advance,” stated Dr. Giralt. “I think daratumumab plus lenalidomide and dexamethasone is much easier to give than VRd-lite…. It really is the go-to regimen.”
DISCLOSURE: Dr. Giralt has served as a consultant to Celgene, Sanofi, Johnson & Johnson, Actinuum, Millennium, Amgen, Kite/Gilead, Novartis, Bristol Myers Squibb, and Pfizer.
REFERENCES
2. Usmani SZ, Hoering A, Cavo M, et al: Clinical predictors of long-term survival in newly diagnosed transplant eligible multiple myeloma: An IMWG research project. Blood Cancer J 8:123, 2018.
3. Munshi NC, Avet-Loiseau H, Rawstron AC, et al: Association of minimal residual disease with superior survival outcomes in patients with multiple myeloma: A meta-analysis. JAMA Oncol 3:28-35, 2017.
4. Kumar SK, Jacobus SJ, Cohen AD, et al: Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): A multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol 21:1317-1330, 2020.
5. Gay F, Musto P, Scalabrini DR, et al: Survival analysis of newly diagnosed transplant-eligible multiple myeloma patients in the randomized Forte trial. 2020 ASH Annual Meeting & Exposition. Abstract 141. Presented December 5, 2020.
6. Cavo M, Gay F, Beksac M, et al: Upfront autologous hematopoietic stem-cell transplantation improves overall survival in comparison with bortezomib-based intensification therapy in newly diagnosed multiple myeloma: Long-term follow-up analysis of the randomized phase 3 EMN02/HO95 study. 2020 ASH Annual Meeting & Exposition. Abstract 142. Presented December 5, 2020.
9. Laubach JP, Kaufman JL, Sborov DW, et al: Daratumumab plus lenalidomide, bortezomib, and dexamethasone in patients with transplant-eligible newly diagnosed multiple myeloma: Updated analysis of GRIFFIN after 24 months of maintenance. 2021 ASH Annual Meeting & Exposition. Abstract 79. Presented December 11, 2021.
10. Kaiser MF, Hall A, Walker K, et al: Depth of response and minimal residual disease status in ultra high-risk multiple myeloma and plasma cell leukemia treated with daratumumab, bortezomib, lenalidomide, cyclophosphamide and dexamethasone: Results of the UK OPTIMUM/MUKnine trial. 2021 ASCO Annual Meeting. Abstract 8001. Presented June 4, 2021.
11. Facon T, Kumar S, Plesner T, et al: Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med 380:2104-2115, 2019.
