Chari Considers Choosing Proteasome Inhibitors in Relapsed Multiple Myeloma

Ajai Chari, MD

Ajai Chari, MD

During aTargeted Oncologycase-based peer perspectives presentation, Ajai Chari, MD, discussed with a group of physicians the treatment options available to patients with relapsed multiple myeloma. Chari, an associate professor of medicine, hematology, and medical oncology; director of the Clinical Research in Myeloma Program; and associate director of clinical research in the Clinical Trials Office at the Icahn School of Medicine at Mount Sinai, explained the various treatment options and the supporting data based around a case scenario of a patient with multiple myeloma who relapses.

Case

In 2015, a 53-year-old African American man was diagnosed with multiple myeloma (Revised International Staging System stage I). The patient was treated with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) for 4 cycles, followed by autologous stem cell transplant (ASCT). He achieved a very good partial response (VGPR). He received lenalidomide maintenance for 2 years.

In 2018, on routine follow-up, no clinical symptoms were observed in the patient. Imaging showed stable disease. His laboratory results were remarkable for hemoglobin of 11.3 g/dL; calcium ions (Ca₂₊) of 9.2 mg/dL; creatinine of 0.8 mg/dL; monoclonal (M) protein of 1.2 g/dL in June, 1.4 g/dL in July, and 1.7 g/dL in August.Cytogenetics/fluorescence in situ hybridization (FISH) did not show any adverse cytogenetics. He had an ECOG performance status of 0.

The patient was started on ixazomib (Ninlaro), lenalidomide, and dexamethasone (IRd).

TARGETED ONCOLOGY:What do you think of this patient’s presentation? What clinical data come to mind for the second-line treatment of multiple myeloma?

Chari:This is a typical patient with multiple myeloma who, based on the SWOG [S0777] study that showed VRd is superior to Rd, was treated with the triplet induction, which is standard.¹

The patient did take lenalidomide maintenance for 2 years but was apparently discontinued, and it looks like approximately a year later, the patient had a biochemical relapse. There was no evidence of hypercalcemia or renal insufficiency, and imaging showed no new bone disease. However, the M spike was progres­sively increasing, and the patient was treated with IRd.

TARGETED ONCOLOGY:Are there any other possible treatment options for frontline therapy?

Chari:Although the SWOG study showed that bortezomib, lenalidomide, and dexamethasone were superior to lenalidomide plus dexa­methasone—ie, triplets are better than doublets, which I think is well understood in practice—the question that is being asked now is: Should carfilzomib [Kyprolis], the more potent protea­some inhibitor [PI], be used in frontline therapy? Basically, the ENDEAVOR study compared carfilzomib at 56 mg/m²with bort­ezomib [1.3 mg/m²] twice weekly and showed superior PFS [progression-free survival] and OS [overall survival].²

However, it is important to note that that was just the PI and dexamethasone. When we add an IMID [immunomodula­tory drug], it is not recommended to give a dose higher than 36 mg/m². It is not clear what the additional value of carfilzomib in frontline therapy would be at a lower dose. That said, many people would do that, and that is something to consider in a high-risk patient, in a patient with neuropathy, or in a young patient. You probably would not do that in a patient with known cardiac history, but the risk of cardiac events is low.

The other work being done in induction therapy right now is with a quadruplet regimen of daratumumab [Darzalex] plus VRd. The GRIFFIN study was just presented at this year’s American Society of Hematology Annual Meeting, although it was primarily the safety [analysis of the safety run-in cohort]. The results were quite impressive. Although we had just 16 patients, the response rate was 100%, and the CR [complete response] rate was 63%.³Those are encouraging data, and I think it will beg the question: What is the role of transplant if we use quadruplet induction? Obviously, those data are still a while away, but in 2019, I suspect quadruplet induction will be morede rigueur.

TARGETED ONCOLOGY:How would high-risk cytogenetics affect the treatment of this patient?

Chari:For a patient with high-risk cytogenetics—which we define, impor­tantly, as deletion 17p [del(17p)]; translocation 4;14 [(t)4;14]; translocation 14;16; and, although not considered truly high risk, the amplification of chromosome 1—the management is impor­tant to talk about because we know that both clonal burden and allele burden matter.

Having a few cells in (del)17p is not necessarily high risk, and we are talking about FISH that is done with CD138[-selected cells]. Depending on the studies, from 20% to 60% deletion is considered high risk. Let us just put the semantics aside and say the patient has standard high-risk myeloma. Then induction therapy would perhaps include carfilzomib, lenalidomide, and dexamethasone or perhaps quadruplet therapy. But transplant consolidation is reasonable, although we still have not improved outcomes of high-risk disease. I think one area where we may tweak the maintenance of high-risk patients is with not just lenalidomide but also dual therapy.

TARGETED ONCOLOGY:Please discuss the maintenance therapy options available for this patient.

Chari:This patient elected to do maintenance therapy, and I do recom­mend maintenance therapy in all my patients. I think every­thing we talk to patients about should involve risk versus benefit. Lenalidomide maintenance in both the CALGB [Cancer and Leukemia Group B] and IFM [Intergroupe Francophone du Myélome] studies published in the same issue of theNew England Journal of Medicineshowed that PFS of nonmaintenance patients is approximately 2 years post transplant. With the addition of lenalidomide, that doubles to nearly 4 years.^4,5

Both those regimens use lenalidomide 10 mg continuously, and 1 of the tradeoffs is that this additional PFS came at the expense of second primary malignancies [SPMs]. Both studies showed that the control arm, which got placebo maintenance, had a 3% to 4% risk of SPMs, and the addition of lenalidomide maintenance doubled that to 6% to 8%. I do recommend for all patients going through maintenance on lenalidomide to keep up with their age-appropriate cancer screening—mammograms, colo­noscopies, skin exams—because the tumors that were developing in these patients were of all types, solid and hematologic.^4,5It is important to pay attention to the blood counts, as well. I think lenalidomide maintenance with that discussion of risk versus benefit is evidence-based medicine and increases PFS.

The 1 thing I do a little differently is that I do not give 10 mg continuously. I think it is nice to give patients that week off, and I think it lets the bone marrow recover a little bit. I have seen less fatigue. In my experience, I have not seen many secondary malignancies, either, so that is something to consider. The initial studies mentioned dosed continuously.

TARGETED ONCOLOGY:How would you treat a patient such as this who relapsed?

Chari:I would probably classify them by patient, disease, and treatment factors. With the disease, we need to think about the biology. Is this a high-risk or standard-risk patient? Is there extramedullary disease? Are they slowly progressive or rapidly progressive? Is it biochemical relapse versus fulminant relapse? Those are a lot of factors. And then in terms of treatment, you must consider oral, IV [intravenous], triplet, and doublet regimens; cost; access; and, of course, adverse effects [AEs].

One of the biggest things we need to think about in the relapsed setting that is not a factor in newly diagnosed disease is: What were the patient’s prior therapies? If a patient has been taking a drug until progression, obviously we should eliminate that and move on. If, however, a patient was taking a drug, tolerated it well, and had a good response, we could certainly use it again.

In this particular patient, since the lenalidomide was discon­tinued—presumably due to patient or physician preference—a lenalidomide-based regimen could be used, unlike in some­body who progressed overtly on lenalidomide maintenance. Such patients are important to consider because they often can get excluded from clinical trials with Rd-containing backbones, because if somebody had lenalidomide maintenance progres­sion, their benefit from adding a third drug might not be as good as somebody who is totally sensitive to it.

TARGETED ONCOLOGY:What data are there to support the use of your chosen regimen in this patient?

Chari:In myeloma, there are a lot of choices and 4 high-impact agents, all of which showed benefit with the addition of the third drug to Rd. The drugs are ixazomib, daratumumab, elotuzumab [Empliciti], and carfilzomib. These are the 4 drugs that we can play with. They all have their pros and cons. I think it is nice to have options, because you can accommodate each patient’s unique needs and AE profile. In this particular case, ixazomib was chosen. What’s unique about this one is that it is the only completely oral regimen, and so that is great for patients. It is definitely something to consider in a patient who does not have a fulminant relapse or in somebody who may not want to come to the cancer center every day. Perhaps somebody who is young, working, and busy—it is nice to have a completely oral regimen.

The TOURMALINE-MM1 study is a randomized phase III study where patients received IRd in the experimental arm, and the control arm received placebo plus Rd. One of the unique features about this study design compared with the other randomized phase III trials is that this was double-blinded, and that can be done because there is no IV medication being given, so patients were randomized to get either placebo or ixazomib. That is important because when we think about the PFS, response rates, and AEs in particular, there was double blinding. There is no bias of over- or underreporting, and so I think that is impor­tant when we look at the results.⁶

The outcomes of the trial were favorable for the addition of ixazomib, there was a 20.6-month median PFS for the addition of ixazomib versus 14.7 months for the Rd arm, which translate to a hazard ratio of 0.74 that favors the triplet-containing regimen.

TARGETED ONCOLOGY:What is the rationale for choosing IRd over another triplet regimen in this line of therapy?

Chari:Now, in terms of why one might switch from bortezomib to ixazomib, it is important to note that in this study, patients who got ixazomib could not have had severe complications with bort­ezomib. Somebody who had terrible neuropathy would not have been eligible. It is important to think about that when we look at the AE profile, and that may be part of why the rates of neurop­athy are low. But it clearly demonstrates that ixazomib given to most patients has resulted in little neuropathy.

Another main reason to switch here is the convenience. Bortezomib on label is given twice weekly, and we give it subcu­taneously as opposed to intravenously. Although that might be important in a newly diagnosed patient who is going to be coming in frequently for [laboratory] testing, in the relapsed setting or in somebody who is out quite a bit from their initial therapy, it is nice to have an oral regimen so they do not have to keep coming in for the injections of whichever drug they are given.

It is also something that we can do off-label in patients who have (t)4;14, and we need to continue a PI. I think that is impor­tant to emphasize because we know from real-world data that the duration of drug use in the real world relative to clinical trials is probably just 50%. So we do these great randomized phase III studies saying that 3 drugs are better than 2, and you are going to get a PFS benefit that can perhaps translate into OS, and then we come to the real world and people are not even using the drugs for 50% of the time. You cannot be sure that you are going to be getting those PFS and OS benefits that are being seen in the study.

TARGETED ONCOLOGY:Can ixazomib be used in other disease settings?

Chari:Ixazomib is the only oral PI, and for that reason, it can be useful in other settings. There are studies combining it with cyclophosphamide and pomalidomide [Pomalyst; NCT03731832]. In a setting where you need a PI, and especially when you have used a potent triplet regimen but the patient has a (t)4;14 or high-risk feature that makes you want to continue the PI until progression, that is a great role for ixazomib. It can be helpful in delivering a durable PI exposure.

TARGETED ONCOLOGY:Do you have any recommendations for community oncologists who are not familiar with prescribing the IRd regimen?

Chari:If somebody is using IRd for the first time, I would say the things to think about are that the dosing of ixazomib is 4 mg once weekly for a 3-weeks-on, 1-week-off schedule on days 1, 8, and 15. It is important to adjust the dose of ixazomib if somebody has impaired renal function. The pharmacokinetics study showed that patients who have impaired renal function with clearance less than 30 [ml/min] do accumulate the drug at higher levels.⁷So for those patients, the ixazomib should be reduced 3 mg.

As with all PIs, zoster prophylaxis is required. We have seen recent data that the new Shingrix [zoster vaccine recombinant, adjuvanted] vaccine has been shown to be safe in patients with multiple myeloma.⁸And, of course, because of the use of lenalid­omide and with dexamethasone, the thrombotic prophylaxis is equally important—typically, aspirin daily. If somebody has a history of thrombotic events or is high risk because of immobiliza­tion, surgery, or airline flights, [then] therapeutic anticoagulation with enoxaparin or Xarelto [rivaroxaban] would be advised.

The 1 thing I would do in personal practice that is not tech­nically on label from the study is [related to the] patients’ least favorite drug: dexamethasone. We do this IRd regimen per proto­col, which is 40 mg per week of dexamethasone, but if you have debulked the patient and now you are just trying to maintain their remission, do you need the patient not sleeping every day, gain­ing weight, and being irritable? I think it is reasonable to taper the dexamethasone off and just maintain patients on ixazomib and lenalidomide to allow them a better quality of life.

It is nice to have so many choices in treating relapsed myeloma. When we consider the patient-specific factors, there will never be 1 right regimen for all patients. In a patient who is looking for a completely oral regimen that is efficacious and can be given out of convenience until progression, IRd is a great option.

References:

1. Durie BGM, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexameth­asone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without 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. Dimopoulos MA, Goldschmidt H, Nievizky R, et al. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial.Lancet Oncol. 2017;18(10):1327-1337. doi: 10.1016/ S1470-2045(17)30578-8.
3. Voorhees PM, Rodriguez C, Reeves B, et al. Efficacy and updated safety analysis of a safety run-in cohort from Griffin, a phase 2 randomized study of daratumumab (Dara), bort­ezomib (V), lenalidomide (R), and dexamethasone (D; Dara‐Vrd) vs. Vrd in patients (Pts) with newly diagnosed (ND) multiple myeloma (MM) eligible for high‐dose therapy (HDT) and autologous stem cell transplantation (ASCT).Blood. 2018;132(suppl 1; abstr 151). doi: 10.1182/blood-2018-151.
4. Attal M, Lauwers-Cances V, Marit G, et al; IFM Investigators. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma.N Engl J Med. 2012;366(19):1782- 1791. doi: 10.1056/NEJMoa1114138.
5. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplan­tation for multiple myeloma.N Engl J Med. 2012;366(19):1770-1781. doi: 10.1056/ NEJMoa1114083.
6. Moreau P, Masszi T, Grzasko N, et al; TOURMALINE-MM1 Study Group. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma.N Engl J Med. 2016;374(17):1621- 1643. doi: 10.1056/NEJMoa1516282.
7. Gupta N, Hanley MJ, Harvey RD, et al. A pharmacokinetics and safety phase 1/1b study of oral ixazomib in patients with multiple myeloma and severe renal impairment or end-stage renal disease requiring haemodialysis.Br J Haematol. 2016;174(5):748-759. doi: 10.1111/bjh.14125.
8. Wang L, Verschuuren EAM, van Leer-Buter CC, et al. Herpes aoster and immunogenicity and safety of zoster vaccines in transplant patients: a narrative review of the literature.Front Immunol. 2018;9:163. doi: 10.3389/fimmu.2018.01632.