CE / CME
Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit
Nurse Practitioners: 1.00 Nursing contact hours, includes 1.00 hour of pharmacotherapy credit
Released: May 16, 2024
Expiration: May 15, 2025
Factors to Consider When Determining Transplant Eligibility
Now we are going to talk about transplant-ineligible patients with MM.
Many factors are taken into consideration when determining if a patient is eligible for a transplant. Age is an important consideration because in general older adults can have more comorbidities. However, that does not mean that all younger patients are transplant eligible. You can have a younger patient with many comorbidities who would not be a good candidate for transplant. Age of transplant has varied in some areas of the world though in the United States, we have transplanted older patients.16 As a field, we are taking a more individualized approach to determining transplant eligibility.
When thinking about comorbidities, people with uncontrolled hypertension, heart disease, and diabetes are not eligible for a transplant at most institutions. But, with clearance from their cardiologist some patients with well-managed hypertension or heart disease might be able receive a transplant after completing induction with a gentle chemotherapy regimen.
Frailty is also a consideration when thinking about transplant eligibility. Frail patients may have poor drug metabolism or poor creatinine clearance and may not be suitable for transplant. However, in some cases, a patient on dialysis can receive a transplant, so that is also not a limiting factor.8,17
When deciding on whether to take a patient to transplant, we also need to think about individual patient characteristics and preferences. Some patients may opt not to receive a transplant due to limited independence or mobility and limited social support. This is where we need to engage in shared decision-making with our patients. It is important to have conversations about the risks and benefits of transplants and to consider their preferences.
Treatment Considerations for ASCT-Ineligible Patients
Here is a general overview of treatment considerations for transplant-ineligible patients.8,16 Again, we know that patient fitness is important. For fit patients, we still want the benefit of a multiple drug regimen, so we deliver 3-drug regimens in a gentler way with dose reductions. If a patient is unfit, you might consider starting with a doublet and then adding that third agent if it can be tolerated. Many patients have baseline peripheral neuropathy, and bortezomib can make that worse. If peripheral neuropathy is a concern, we can opt to use SC bortezomib with weekly dosing. An alternative to SC bortezomib is to consider an all-oral regimen of ixazomib, lenalidomide, and dexamethasone. Renal and cardiac dysfunction will also affect treatment selection. For renal dysfunction, lenalidomide can be dose adjusted based on creatinine clearance. For any patient with cardiac dysfunction, you would avoid using carfilzomib. We also need to think about the risk of thromboembolic events and infection, and maintaining bone health, which we will discuss later.
Proposed Treatment Algorithm for Newly Diagnosed Multiple Myeloma
Now we are back to our algorithm for managing NDMM.8 We talked about managing transplant-eligible patients and showed you data that adding a fourth drug—in this case an anti-CD38 antibody—to standard of care regimens improved survival and led to deeper responses.
For patients who are not transplant candidates, we still utilize multidrug regimens but in a gentler way. This can be Dara-Rd or VRd-lite. For maintenance, the preferred regimen in the NCCN guidelines is lenalidomide. However, other regimens such as bortezomib monotherapy or bortezomib with lenalidomide may be used. For patients with high-risk transplant-ineligible MM, dual maintenance is usually recommended. Again, patients with MM receive continuous therapy, and maintenance is recommended for all.
Combination Therapy in Patients With Newly Diagnosed Transplant-Ineligible Multiple Myeloma
There have been different combination therapies investigated in the management of transplant-ineligible patients with NDMM.
The phase III SWOG S0777 study looked at VRd vs Rd, and the 3-drug regimen resulted in significantly improved median PFS (41 vs 29 months) and median OS (not reached vs 69 months).18
Another phase II trial investigated the VRd-lite regimen which delivered VRd at a different frequency and dose.19 So, instead of twice weekly bortezomib, patients received it once a week. The median PFS with VRd lite was 41.9 months, so patients still received the benefit of a multidrug regimen with it being delivered in a lighter way.
The phase III MAIA trial looked at the addition of daratumumab to Rd.20 At the time, many transplant-ineligible patients were still receiving a doublet, and here we see that patient outcomes were better with the triplet regimen. The ORR was 92.9% vs 81.6%. A survival benefit was also seen with the addition of daratumumab, with a median PFS of 61.9 vs 34.4 months (P <.0001) and a median OS of not reached vs 65.5 months (P = .0003). Many frail patients have trouble tolerating a PI, and here we see good response with a PI-free regimen.
The phase III CLARION trial looked at KMP (carfilzomib, melphalan, prednisone) vs VMP (bortezomib, melphalan, prednisone). We don't commonly use these regimens in the United States, but they are still used in European countries. When you look at the ORR, it was similar in both arms (84.3% vs 78.8%) and median PFS and OS were also similar (median PFS: 22.3 vs 22.1 months; median OS: not reached in both arms).21
Finally, the phase III TOURMALINE-MM2 trial looked at an all-oral regimen for the treatment of transplant-ineligible MM.[22] This trial compared ixazomib (a PI) plus Rd vs Rd. The ORR was slightly better with the addition of ixazomib (82.1% vs 79.7%) and the median PFS was 35.3 months vs 21.8 months (P = .073).
Dara-Rd vs VRd in Transplant-Ineligible NDMM
Looking at more recent data, a retrospective analysis compared time to next treatment or death with Dara-Rd to VRd in 643 transplant-ineligible patients with NDMM and was presented at ASH 2023.23 Patients included in this analysis had available data in the Ascentrus electronic medical records database and initiated treatment between January 2018 and May 2023. There are no head-to-head trials comparing Dara-Rd with VRd, but in this analysis patients who received Dara-Rd were able to have a longer interval before receiving additional treatment or dying. The median time to next treatment or death was 37.8 months vs 18.7 months [adjusted HR: 0.58 (95% CI: 0.35-0.81); P <.001].
Summary of Newly Diagnosed Transplant-Ineligible Myeloma
To summarize, for transplant-ineligible myeloma you want to adapt therapy to the patient’s functional status, but also look at their disease risk. You can start at a lower dose or with a doublet for patients who have poor functional status and then escalate as tolerated. When possible, we want to get the benefit of a multidrug regimen.
I also want add that sometimes we have a patient who does not have a planned transplant, but their performance status changes with treatment and we are later able to collect stem cells and send the patient to transplant. So, you want to continue to monitor your patient throughout treatment.
Moving CAR T-Cell Therapy and Bispecific Antibodies to Earlier Therapy Lines
Before I move on to discuss AEs, I’d like to briefly touch on some of the new emerging therapies for NDMM. Currently, the CAR T-cell therapy ciltacabtagene autoleucel (cilta-cel) is FDA approved for patients with relapsed or refractory MM who have received 1 or more prior line of therapy, including a PI and an IMiD, and are refractory to lenalidomide. Idecabtagene autoleucel (ide-cel) is approved for patients after 2 or more prior lines of therapy including an IMiD, a PI, and an anti-CD38 monoclonal antibody.24,25 The bispecific antibodies teclistamab and elranatamab are approved for the treatment of adult patients with relapsed or refractory MM who have received 4 or more prior lines of therapy including a PI, an IMiD, and an anti-CD38 monoclonal antibody.26,27 Ongoing clinical trials are asking the question of whether or not CAR T-cell therapies and bispecific antibodies can be moved upfront.
Cilta-cel is being investigated in the phase III CARTITUDE-5 (NCT04923893) and CARTITUDE-6 (NCT05257083) trials. In CARTITUDE-5, cilta-cel is being investigated after VRd induction in patients who do not have an ASCT planned. In CARTITIUDE-6, cilta-cel after Dara-VRd is being compared to Dara-VRd followed by ASCT.
The phase I KARMMA-4 (NCT04196491) trial is investigating upfront treatment of high-risk NDMM with ide-cel. In KarMMa-4, patients will be treated with ide-cel followed by lenalidomide maintenance. This trial was slated to be completed in late 2023, and we are looking forward to the results.
For bispecific antibodies, the ongoing phase III MajesTEC-4 (NCT05243797) trial is combining the bispecific antibody teclistamab with or without lenalidomide as maintenance therapy following ASCT, and MajesTEC-7 (NCT05552222) is evaluating teclistamab with Dara-R vs talquetamab with Dara-R vs Dara-Rd in transplant-ineligible NDMM. Another bispecific antibody, elranatamab is being investigated in the phase III MagnetisMM-6 (NCT05623020) and MagnetismMM-7 (NCT05317416) trials. In MagnetisMM-6, elranatamab is being combined with Dara-R and compared with Dara-Rd in transplant-ineligible NDMM. In MagnetisMM-7, elranatamab is being compared with lenalidomide as maintenance in patients who are MRD positive after transplant. We are all awaiting the results of these clinical trials, not only because of the potential efficacy advantages, but also because these agents come with distinct AEs to manage and discuss with our patients.
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