Ailawadhi Explains How Best to Use the Many Approved Agents for Multiple Myeloma

Sikander Ailawadhi, MD

Sikander Ailawadhi, MD

During aTargeted Oncologycase-based peer perspectives program, Sikander Ailawadhi, MD, reviewed with other physicians his clinical considerations for the management of multiple myeloma. Ailawadhi, associate professor of hematology and medical oncology at Mayo Clinic in Jacksonville, Florida, discussed his treatment options and other factors that go into his decision making with the group during the meeting based on a case scenario of a patient with high-risk, transplant-ineligible multiple myeloma.

Case

A 77-year-old Caucasian man presented to his primary care physician complaining of fatigue. His past medical history included osteoarthritis and limited mobility. His physical exam showed pallor, hypertrophic changes at distal and proximal interphalangeal joints, poor grip strength, and bilateral swelling in shoulder joints. He had an ECOG performance status of 1.

Blood work indicated anemia (hemoglobin [Hb], 10.2 g/dL), hypercalcemia (calcium, 12.9 mg/dL), and a slightly elevated creatinine (1.5 mg/dL); creatinine clearance (CrCl), 50 mL/min. He was later referred to hematology for further evaluation.

Notable laboratory findings included the following: Hb, 10.3 g/dL; creatinine, 1.3 mg/dL; CrCl, 61 mL/min; M protein, 1.4 g/dL; λ-free light chains, 4.43 mg/dL; lactate dehydrogenase (LDH), 185 U/L; β₂-microglobulin (B2M), 3.8 μg/mL; bone marrow biopsy showed 42% plasma cells; fluorescence in situ hybridization, t(14;16). Additionally, his peripheral blood smear showed rouleaux formation.

The patient was given a diagnosis of multiple myeloma with high-risk cytogenetics.

Targeted Oncology:What are the treatment options for this patient?

Ailawadhi:This a 77-year-old high-risk patient with good performance status. He has anemia and some kidney disfunction and hypercalcemia. There are some urgent things that we should probably address, including the calcium and the more immediate things. It is possible that correcting the calcium will take care of the kidney function a bit.

From a treatment standpoint, there are several options. Now, we know that we can combine a lot of different agents across the board. For myeloma, the National Comprehensive Cancer Network (NCCN) guidelines are not that helpful. It lists a lot of the regimens in alphabetical order with the level of evidence. We do have quite a few regimens that meet the category 1 benchmark, which is the highest-level, randomized study meeting the primary endpoint and showing overall survival (OS) benefit. The biggest advantage to having a study listed there is that you can go to insurance and get it reimbursed. This is how the NCCN guidelines help us in the treatment of multiple myeloma, but they don’t necessarily help us pick the right regimen.

Targeted Oncology:Are there recent trials comparing regimens listed in the NCCN guidelines?

Ailawadhi:The SWOG S0777 was released around 2 years ago, comparing lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd) to lenalidomide and dexamethasone (Rd).¹This study was a very large, randomized trial done in the United States. It is important to keep in mind that the primary endpoint was progression-free survival (PFS) and the initial intent was that these patients were not supposed to go to transplant. Across the board, patients were in different age groups and it was not a transplant-ineligible patient population. However, the intent was that the patients would do not go to transplant. From that standpoint, half the patients received RVd, and half of the patients were treated with Rd. They had 6 cycles versus 8 cycles, and although the number of cycles was different, the duration of treatment was pretty much the same. Everyone went on to maintenance and follow-up.

The triplet RVd did better than Rd. In addition to the PFS, the [results from the] study showed an improved OS. Patients who started off with RVd lived longer than the patients who started on Rd. There was a hazard ratio of 0.7, which means there was a 30% reduction in the risk of death if the patients started on RVd compared with Rd. From our standpoint, this was a very important study because it was the first frontline study [whose results showed] OS benefit done in the United States.

The phase III, randomized ALCYONE trial is another trial that looked at bortezomib, melphalan, and prednisone (VMP) versus daratumumab plus VMP.²Based on this trial, daratumumab is now FDA approved in the frontline for patients who are transplant ineligible in combination with VMP. This combination did much better than VMP alone, and some patients had long-term benefit. Despite this particular study and the FDA approval, most of us are not using frontline daratumumab right now. Going forward, data will change, and more studies will come down the pipeline. It is possible that daratumumab will become a frontline standard with different regimens.

Targeted Oncology:Would you choose RVd-lite for a patient such as this?

Ailawadhi:In multiple myeloma, there are FDA approvals, and then there is what we do. The FDA brings us the drugs, and we do a lot of variations [in how we use] them. Our thought is, we are going to keep the patient on and give them the maximum benefit of a regimen. That will involve making modifications along the way.

This patient is a 77-year-old with a good performance status, but he is still older. There are 2 possibilities in this case. You can start with the full doses, and when the patient doesn’t tolerate the regimen, you have to make changes. Or you can start with the modified regimen itself. RVd-lite is a modified version of RVd, consisting of 15 mg of lenalidomide, 1.3 mg of bortezomib once weekly subcutaneous, and the standard 20 mg of dexamethasone.

In the phase II study of RVd-lite, the median age was 73 years old, which is closer to this particular patient’s age.³The overall response rate [ORR] for these patients was 86%; however, this was a smaller study, and there was no comparison. In the original phase II RVd study, the ORR was 100%.⁴Still, 86% is decent, and there were a number of complete responses in the study. The thought is that with a modified regimen, across the board we have [results from] many studies showing 3-drug combinations that are always going to be better than 2-drug regimens. So could we modify a regimen to give the patient the triplet versus giving them the doublet?

He was started on treatment with RVd-lite. After 6 months of therapy, the M-spike plateaued at 0.6 g/dL. Therapy with single-agent lenalidomide was continued.

Two years after diagnosis, his notable laboratory findings included: Hb, 11.4 g/dL; creatinine, 1.0 mg/dL; M protein rose from 0.6 g/dL to 1.5 g/dL. He also reported feeling tired.

One month later, the patient complained of increasing back pain, fatigue, and weakness. Notable laboratory findings included: M protein, 2.1 g/dL; serum B2M, 6.2 mg/L; albumin, 2.1 g/dL; CrCl, 32 mL/min. A PET/CT showed new lytic lesion and new compression fracture in the L4/L5 vertebrae and his bone marrow biopsy showed 30% involvement by abnormal-appearing plasma cells, confirmed by CD138-positive immunohistochemistry stain. His ECOG performance status was now 2.

Targeted Oncology:What factors do you consider when choosing the next therapy for this patient?

Ailawadhi:There are data out for a couple of a retrospective studies that suggest that if a patient is progressing, even on labs, go ahead and do something about it. Don’t wait for them to become asymptomatic. This goes together with how the definition of myeloma has changed. We no longer have to wait for organ damage or the calcium, renal failure, anemia, and bone lesions criteria to start treatment.

Targeted Oncology:Would you do a bone marrow biopsy for this patient after disease progression?

Ailawadhi:We would like to get a bone marrow biopsy every time if possible, but I think it is reasonable to get more data and information at this point. You could make the case either way. In this case, we have a now 79-year-old patient who has slow progression, and it is less likely that anything has changed. You could also argue that a 79-year-old patient is progressing, and, if there is the small likelihood that the patient has progressive disease, our choice of treatment may be different.

Targeted Oncology:What are the treatment options for patients with relapsed/refractory multiple myeloma?

Ailawadhi:The ARROW study was a randomized, phase III study of almost 500 patients that compared once-weekly carfilzomib (Kyprolis) plus dexamethasone versus twice-weekly carfilzomib with a primary endpoint of PFS.⁵Patients had to have 2 to 3 prior lines with prior exposure to an immunomodulatory and a proteasome inhibitor and they did not have carfilzomib before the trial.

The setup for this was that the twice-weekly carfilzomib was the standard of 20 mg on day 1 and 2 and 27 mg starting on day 8. The dexamethasone was given once a week. The once-weekly regimen gave carfilzomib starting at 20 mg beginning on cycle 1, day 1. It was then increased to 70 mg on day 8. Before this randomized study was done, there were several phase II studies looking at weekly carfilzomib to establish the dose and dose scheduling. Again, the dexamethasone was given once a week in the once-weekly arm.

There was a difference of 11.2 months versus 7.6 months in PFS between the once-weekly arm and the twice-weekly arm, respectively. There was an update on the safety profile because we are all concerned about the 70-mg dose, and there were no new adverse events (AEs) out of this study. They noticed that the patients who were younger than 65 had a better benefit compared with the older patient population. The median age was 66 years.

Targeted Oncology:Was cardiac failure a concern with carfilzomib in this ARROW study?

Ailawadhi:In this particular study, there was not a significant difference in safety profile between the 2 arms. Another SWOG trial is going to be published later this year to discuss standard versus high-dose twice-weekly carfilzomib. Even in that study, there is not a significant difference in cardiac signal. It seems that the patient who is supposed to develop a cardiac AE from carfilzomib will get it regardless of the dose or the dose schedule.

Targeted Oncology:Are there any other options to consider in patients with relapsed/refractory multiple myeloma?

Ailawadhi:If we thought that the frontline regimen choice was not very helpful with NCCN guidelines, the relapsed/refractory setting is much worse because the list has now doubled. Studies have tried to put all the large trials together for cross-trial comparison. Carfilzomib, lenalidomide, dexamethasone (KRd); elotuzumab (Empliciti), lenalidomide, dexamethasone; ixazomib (Ninlaro), lenalidomide, dexamethasone; and elotuzumab, bortezomib, and dexamethasone all require 1 to 3 prior lines of therapy. Then daratumumab, lenalidomide, and dexamethasone (DRd), and daratumumab, bortezomib, and dexamethasone require 1 prior line of therapy.

In our patient, because he had previous RVd-lite and progressed on maintenance, a lot of this will be considered. Even within Mayo Clinic, our practice sites have some differences in how we would treat this patient. In Florida, if a patient is progressing on a low dose of lenalidomide, we will give them DRd or KRd. We will use these regimens. It is a matter of not just preference but also that particular patient and what is applicable to them. If you put the patient on any of these regimens, it is important to keep in mind that the rest of the regimens are completely out the door. The patient will not strictly meet the criteria for any of the other regimens. This is a huge challenge for these patients.

References:

1. Durie GB, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma with intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial.Lancet. 2017;389(10068):519-527. doi: 10.1016/S0140-6736(16)31594-X.
2. Mateos MV, Dimopoulos MA, Cavo M, et al; ALCYONE Trial Investigators. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma.N Engl J Med. 2018;378(6):518-528. doi: 10.1056/NEJMoa1714678.
3. O’Donnell EK, Laubach JP, Yee AJ, et al. A phase 2 study of modified lenalidomide, bortezomib and dexamethasone in transplant-ineligible multiple myeloma.Br J Haematol. 2018;182(2):222-230. doi: 10.1111/bjh.15261.
4. Richardson PG, Wanling X, Jagannath S, et al. A phase 2 trial of lenalidomide, bortezomib, and dexamethasone in patients with relapsed and relapsed/refractory myeloma.Blood. 2014;123(10):1461-1469. doi: 10.1182/blood-2013-07-517276.<1i>Moreau P, Mateos MV, Berenson JR, et al. Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W): interim analysis results of a randomised, phase 3 study [erratum inLancet Oncol. 2018;19(8):e382.Lancet Oncol. 2018;19(7):953-964. doi: 10.1016/S1470-2045(18)30354-1.