Stewart Gives His Insight on New Data Presented at ASH for Multiple Myeloma

Keith Stewart, MB, ChB

Keith Stewart, MB, ChB

During aTargeted Oncologycase-based peer perspectives program, Keith Stewart, MB, ChB, discussed his clinical considerations for the management of multiple myeloma, especially in light of new data from the 2018 American Society of Hematology (ASH) Annual Meeting that could be reaching the clinic soon. Stewart, professor of medicine, Mayo Clinic, explained his treatment decisions during the live event based on 2 case scenarios.

Case 1

A 77-year-old Caucasian man presented to his primary care physician complaining of fatigue and his past medical history later revealed osteoarthritis with limited mobility. On physical exam, he was noted for pallor, hypertrophic changes at distal and proximal interphalangeal joints, poor grip strength, and bilateral swelling in the shoulder joints. Additionally, blood work indicated anemia (hemoglobin [Hb]: 10.2 g/dL), hypercalcemia (corrected serum calcium [csCa]: 12.9 mg/dL), and slightly elevated creatinine (1.5 mg/dL), with a creatinine clearance (CrCl) of 50 mL/min. Based on these findings, the patient was referred to hematology for further evaluation.

The following laboratory findings were deemed notable: Hb, 10.3 g/dL; creatinine, 1.3 mg/dL; CrCl, 61 mg/dL; M-protein, 1.4 g/dL; lambda free light chains, 4.43 mg/dL; lactate dehydrogenase (LDH), 186 U/L;β2 microglobulin (B2M), 3.8 mcg/mL; and bone marrow biopsy showed 43% plasma cells. Additionally, peripheral blood smear showed rouleaux formation and fluorescence in situ hybridization (FISH) testing revealed t(14;16). He was diagnosed with multiple myeloma with high risk and had an ECOG performance status of 1 at the time of diagnosis.

TARGETED ONCOLOGY:What are the treatment options for this patient and which would you seriously consider?

Stewart:There is some market research that suggests that for an elderly patient there are several options. Fifty percent of this patient population are getting doublet therapy, mostly lenalidomide and dexamethasone (Rd), and about 50% are getting triplet therapy, usually modified lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone, [called] RVd-lite. My bias for a patient such as this would be RVd-lite.

TARGETED ONCOLOGY:Are there data comparing these regimens?

Stewart:The SWOG S0777 trial compared RVd versus Rd in patients who were not eligible for transplant.¹This is 1 of the many trials suggesting the use of a triplet is probably preferable. There are still people who would choose Rd, but most of us feel a little bit better about using a third drug or an immunomodulatory agent. The primary endpoint of this trial was overall survival (OS). With the triplet regimen, it was 43 months versus 30 months with Rd. The hazard ratio (HR) was 0.71, which is good. In general, the thought is to use triplet therapy when you can.

TARGETED ONCOLOGY:What is RVd-lite and when would you use it?

Stewart:RVd-lite is a subcutaneous weekly lower-dose dexamethasone and lower-dose lenalidomide. In the trial that looked at this regimen, the median age was 73.²The overall response rate (ORR) was 86%, and 32% of patients achieved a complete remission (CR), which is encouraging.

TARGETED ONCOLOGY:Are there any other triple regimens you would consider?

Stewart:The interim results from the phase III MAIA study [was recently] presented as a late-breaking abstract [at the ASH Annual Meeting].³It is a study of Rd versus the same 2 drugs with daratumumab (Darzalex). [Based on interim findings presented at the meeting], 737 patients were a part of the study, which is a larger population. The study was done mostly in Europe, which always means the patient population is a little different. But since the patients were newly diagnosed, it shouldn’t be make a huge difference in findings. The HR for progression-free survival (PFS) was 0.56. It is not reached for Rd plus daratumumab (DRd) versus 31.9 months in the Rd group. It looks like DRd is going to be around 4 years in terms of PFS. We suspect this will get FDA approved sometime in 2019 and people are very excited about this.

TARGETED ONCOLOGY:Would you ever consider a 4-drug regimen?

Stewart:ALCYONE was published a year ago investigating daratumumab plus bortezomib, melphalan, and prednisone (VMP).⁴That is also an option for this patient, and 10% of patients who are newly diagnosed are already getting daratumumab in this country. I think next year it will probably be around 50%. The median PFS for daratumumab in combination with VMP was not yet reached versus 18.1 months with VMP alone. This trial did allow daratumumab to continue.

The patient received continuous lenalidomide 15 mg and low-dose dexamethasone. After 9 cycles of therapy, the M-spike plateaued at 0.6 g/dL; therapy with single-agent lenalidomide was continued.

Two years after diagnosis, his laboratory values included: Hb, 11.4 g/dL; creatinine, 1.0 mg/dL; M-protein rose from 0.6 g/dL to 1.2 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. Laboratory findings were notable for the following: 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. Additionally, his bone marrow biopsy showed 30% involvement by abnormal-appearing plasma cells, confirmed by CD138-positive immunohistochemistry stain. At this point, he had an ECOG performance status of 2.

TARGETED ONCOLOGY:What factors do you consider when deciding treatment upon disease progression?

Stewart:This patient was treated with Rd and is now 79-years-old. He was able to get 9 cycles of therapy and had a partial response. He stayed on drugs for 2 years and then started to progress biochemically. His numbers started to climb and he needs treatment.

We now have 8 clinical trials where 3 drugs have beaten 2 drugs. Some of them included OS data, such as daratumumab, lenalidomide, and dexamethasone (RDd), daratumumab plus Vd, and carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRd). They are all positive for PFS and they all have high response rates. Three of the trials so far have improved OS data. Most of the patients on these trials, however, are younger patients.

In general, there are a lot of choices at this point and I think it is an individualized choice for this specific patient. There is no wrong answer here. At my practice, carfilzomib, pomalidomide (Pomalyst), and dexamethasone (KPd) or daratumumab, pomalidomide, and dexamethasone (DPd) is what we are using for most of our first relapses. But the question then becomes: What is going to happen when we start using daratumumab upfront?

TARGETED ONCOLOGY:If you decide to give carfilzomib, what dose do you normally use in your practice?

Stewart:I participated in the ARROW study, which was designed to see if we could give patients carfilzomib once weekly.⁵The expectation was that it would be as effective as giving it twice weekly, but more convenient. The dosing for the control arm was the FDA-approved dose of 20 mg and 27 mg for carfilzomib. The experimental arm was 20 mg and 70 mg, which is a big dose. I would probably step up to that and go from 20 mg up to 56 mg and then up to 70 mg. Remember, this is a single-agent study. If you are combining carfilzomib with a third drug, the 70-mg dose is too high.

Surprisingly, but also encouraging, the once-weekly dosing was actually better. The weekly dosing had a PFS of 11.2 months versus 7.6 months with the twice-weekly dosing. The response rate was slightly higher as well. Also, changing to once-weekly dosing didn't change the cardiac profile in terms of overall numbers.

Case 2

July 2011

A 61-year-old Caucasian female was diagnosed with stage II multiple myeloma and her genetic testing showed t(11;14). At the time, she was treated with RVd induction therapy, followed by autologous stem cell transplant (autoSCT) and achieved a CR. The patient was placed on lenalidomide maintenance therapy.

TARGETED ONCOLOGY:Discuss the rationale for the choice of upfront therapy in this patient. What do you think of using KRd instead?

Stewart:Seventy-two percent of young patients are getting RVd in the US. About 10% to 15% are getting KRd. There are a small percentage that are getting cyclophosphamide, bortezomib, and dexamethasone (CyBorD), among others. She is on lenalidomide maintenance as well, and that is pretty standard.

I think most of my colleagues within the academic centers are beginning to switch over to carfilzomib even though we do not have a randomized phase III trial yet. It is being been done. The trial has enrolled about 1000 patients through ECOG (NCT01863550). Most likely next year we will get a fresh taste as to what it looks like. The obvious question is going to be: If you get a slight bump in response and PFS, is it worth the increase of toxicity, which no doubt we will see in 3% to 4% of patients? In the meantime, people seem to be voting with their feet and they are gradually switching. However, the jury is still out, and we still do not have randomized trial data to support using KRd versus RVd yet.

TARGETED ONCOLOGY:In your practice, is there still a role of transplant as part of frontline therapy for myeloma?

Stewart:There was an abstract recently presented where someone gave KRd with a transplant and then more KRd or they gave 12 months of KRd without transplant.⁶They did minimal residual disease (MRD) testing and they looked at the ORR—they did not have PFS data yet. The conclusion was that the ORR and MRD negativity rates were identical between both arms. It has made the whole role of transplant a little bit less dogmatic. There are patients with deep molecular remissions who may not need transplant. There have been at least 2 studies now showing that if you get a deep molecular remission—it doesn't matter how you get there—your outcome is going to be good whether you add transplant or not.

TARGETED ONCOLOGY:Would you consider another agent other than lenalidomide for maintenance therapy?

Stewart:There was a phase III trial presented recently with ixazomib (Ninlaro) versus placebo for maintenance therapy.⁷It was a small study, but there was a 4-month difference in PFS. You have to treat ixazomib for 2 to 3 years to get a 4-month benefit. It is definitely a positive trial, but I think it was a little disappointing to see that small of a difference.

TARGETED ONCOLOGY:What duration do you recommend for maintenance?

Stewart:In the case of lenalidomide maintenance, I personally get a little uncomfortable of the idea of never stopping it. There are data suggesting that staying on it is better, but I worry about the long-term consequences of that and not to mention the financial burden that that puts on a patient. In the trials I mentioned previously, daratumumab maintenance was given indefinitely.

TARGETED ONCOLOGY:Are you doing MRD testing and how are you using the information?

Stewart:Patients with MRD negativity clearly do better, and a CR alone is not enough. However, most people with MRD negativity are still relapsing. Many of my colleagues are evaluating for MRD on day 100 post-transplant, but no one really knows when the correct time is. Since I'm using consolidation on my patients anyway, I don't see any value doing it then. I consolidate them no matter what, give them another 4 cycles of treatment, and then test for MRD and then annually thereafter. I find it to be very helpful information.

August 2016

On routine follow-up, the patient reported having mild fatigue, but continued to work full-time; she had grade 1 neuropathy. Laboratory findings were notable for: M-protein, 1.4 g/dL; light chain levels continued to rise; Hb: 10.3 g/dL; creatinine: 1.3 mg/dL.

References

1. Durie BG, 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. 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 Heamatol. 2018;182(2):222-230. doi: 10.1111/bjh.15261.
3. Facon T, Kumar SK, Plesner T, et al. Phase 3 randomized study of daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma (NDMM) ineligible for transplant (MAIA). Presented at: ASH Annual Meeting and Exposition; December 4-8, 2018; San Diego, CA. Abstract LBA-2. ash.confex.com/ash/2018/webprogram/Paper120737.html.
4. 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.
5. 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.Lancet Oncol. 2018;19(7):953-964. doi: 10.1016/S1470-2045(18)30354-1.
6. Gay F, Cerrato C, Scalabrini DR, et al. Carfilzomib-lenalidomide-dexamethasone (KRd) induction-autologous transplant (ASCT)-Krd consolidation vs Krd 12 cycles vs carfilzomib-cyclophosphamide-dexamethasone (KCd) induction-ASCT-Kcd consolidation: an analysis of the randomized forte trial in newly diagnosed multiple myeloma (NDMM). Presented at: ASH Annual Meeting and Exposition; December 4-8, 2018; San Diego, CA. Abstract 121. ash.confex.com/ash/2018/webprogram/Paper112093.html.
7. Dimopoulos MA, Gay F, Schjesvold F, et al. Maintenance therapy with the oral proteasome inhibitor (PI) ixazomib significantly prolongs progression-free survival (PFS) following autologous stem cell transplant (ASCT) in patients with newly diagnosed multiple myeloma (NDMM): phase 3 TOURMALINE-MM3 trial. Presented at: ASH Annual Meeting and Exposition; December 4-8, 2018; San Diego, CA. Abstract 301. ash.confex.com/ash/2018/webprogram/Paper112079.html.