Chari Reviews Treatment Options in 2 Case Studies of Patients With Multiple Myeloma

Ajai Chari, MD

Ajai Chari, MD

During aTargeted Oncologylive case-based peer perspective presentation, Ajai Chari, MD, spoke on the treatment options and considerations he makes when treating patients with relapsed/refractory multiple myeloma. Chari, associate professor of medicine and director of Clinical Research, Multiple Myeloma Program, The Mount Sinai Hospital, in New York, explained his treatment decisions with a group of physicians during the meeting based on 2 case scenarios of patients with multiple myeloma.

Case 1

May 2016

A 77-year-old Caucasian man presented to his primary care physician complaining of fatigue. His past medical history revealed osteoarthritis, which limited his mobility. A physical exam later showed pallor, hypertrophic changes at distal and proximal interphalangeal joints, poor grip strength, and bilateral swelling in his shoulder joints. Blood work revealed anemia (hemoglobin [Hb], 10.2 g/dL), hypercalcemia (serum calcium, 12.9 mg/dL), and slightly elevated creatinine (1.5 mg/dL); his creatinine clearance was 50 mL/min. He was then referred to hematology for further evaluation.

Laboratory findings were notable for the following: Hb, 10.3 g/dL; creatinine, 1.3 mg; creatinine clearance, 61 mL/min; M protein, 1.4 g/dL; gamma-free light chains, 4.43 mg/dL; lactate dehydrogenase, 186 U/L; beta-2-microglobulin (B2M), 3.8 μg/mL; bone marrow biopsy showed 43% plasma cells; fluorescence in situ hybridization testing, t(14;16). Additionally, peripheral blood smear showed rouleaux formation. He was diagnosed with multiple myeloma and was considered high risk. He had an ECOG performance status score of 1.

Targeted Oncology: What are your primary goals for this patient?

Chari:This is an important question for this patient. We know that in all patients with multiple myeloma, if you look at the overall survival (OS), it is never flat. You will lose people in every age group, particularly the elderly. One of the questions is, Do you get the opportunity to salvage an older patient as readily? Sometimes, because of their comorbidities, you may not be able to recapture or treat them again when they progress for a variety of reasons. It is an important discussion.

What is the rationale for the use of RVd in this patient?

The SWOG S0777 trial investigated daratumumab (Darzalex), bortezomib (Revlimid), and dexamethasone (RVd) versus lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma without an intent for immediate transplant.¹Importantly, only 43% of patients were over age 65. It was not our typical patient, as in our case scenario.

Patients were given intravenous bortezomib twice weekly [in the RVd] arm, and there was maintenance Rd for all patients. The study showed a progression-free survival (PFS) benefit of 43 months in the RVd arm versus 30 months in the Rd arm. There was also an OS benefit of 75 months versus 64 months, respectively.

The endpoints of these studies involving multiple myeloma are important. Looking for OS takes a long time, but when we have the variety of drugs that we have, unless you are controlling for drug access, you may lose any PFS benefit by the salvage regimens. Multiple myeloma is becoming similar to follicular lymphoma. You are not looking for an OS benefit in follicular lymphoma. Most newly diagnosed multiple myeloma studies are no longer using OS because of all the confounding issues of salvage therapies. I’ve noticed that it is much easier to get an OS benefit when you have an enrollment from outside the United States because the control arm will not necessarily get access to the experimental agent. If you are really looking for OS, we have to be confident that you are controlling the next line of therapy as well. Otherwise, you could have a PFS benefit and it will never translate to an OS benefit if there is differential access to salvage therapy in the control arm.

Would you consider modified RVd (RVd-lite) in this patient?

As I said before, only 43% of patients on the SWOG study were over age 65. In this case, our patient is 77 years old. It is a very different patient population, so [the study of] RVd-lite was one of the few prospective studies investigating 15 mg of lenalidomide (Revlimid), weekly bortezomib, and 20 mg of dexamethasone the day of and after bortezomib.²This was a much older population, with a median age of 73. We saw very high OS rates, at 86%. Stringent complete responses were also observed.

What other treatment options are available to this patient?

The phase III ALCYONE study treated 706 patients with multiple myeloma over age 65 with daratumumab, bortezomib, melphalan, and prednisone (D-VMP).³However, there was an important study design issue. Patients were treated with 9 cycles of VMP, but the experimental arm received daratumumab until progression. In the control arm, everybody discontinues. The primary endpoint in this study was PFS. The median age was 71.

The HR [for PFS] was 0.50, which was very impressive. The PFS at 12 months was 87% for D-VMP versus 76% for VMP. At 18 months, the PFS was 72% versus 50%, respectively. The median PFS was not reached versus 18.1 months, respectively. Additionally, D-VMP was favored across all prespecified subgroups.

When we look at older patients, because our patient in this case is 77, the 18-month PFS is 71% versus 51% for patients over 75. This is not much different from the younger patients. It is nice to see that D-VMP, regardless of age, is better than VMP.

The adverse event (AE) profiles were comparable. The rates of neutropenia, thrombocytopenia, and anemia are not that much different for patients over or under 75 years of age. The infection rates for all grades were 67% versus 48%, respectively. For patients over 75, the rates were 73% versus 52%, respectively. This AE profile is something to pay attention to.

The patient received continuous lenalidomide at 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.

May 2018

His laboratory findings 2 years after diagnosis were notable for the following: Hb, 11.4 g/dL; creatinine, 1.0 mg/dL. His M-protein had risen from 0.6 g/dL to 1.2 g/dL to 1.5 g/dL. The patient reported feeling tired.

June 2018

The patient then complained of increasing back pain, fatigue, and weakness. Laboratory findings revealed: M protein, 2.1 g/dL; serum B2M, 6.2 mg/L; albumin, 2.1 g/dL; creatinine clearance, 32 mL/min. Additionally, a PET/CT scan showed a new lytic lesion and a new compression fracture in the L4/L5 vertebrae. A bone marrow biopsy showed 30% involvement by abnormal-appearing plasma cells, which was confirmed by CD138-positive immunohistochemistry stain. His ECOG performance status was now 2.

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

This patient received continuous Rd and plateaued after 9 cycles of therapy. Single-agent lenalidomide was continued. His Hb had improved a little, and his creatinine normalized. His M spike started to rise, and he reported feeling tired. Now he has increased back pain, fatigue, and weakness. The M spike is even higher, his B2M is higher, albumin is low, and his creatinine clearance is now 32 mL/min. He has a new lytic lesion and a new compression fracture. He has 30% involvement upon bone marrow, and his performance status is impaired based on the bone disease.

I consider his performance status, age, renal function, and disease factors such as rate of relapse, burden, and symptoms. The third factor, which is different from the frontline, is prior therapy and tolerance of prior therapy. Although we have a lot of phase III studies for Rd-based salvage, a lot of these patients would not be eligible for those studies.

Which backbone would you consider for this patient?

In the salvage setting, we have such a busy space. With the lenalidomide backbone, we have daratumumab, elotuzumab (Empliciti), carfilzomib (Kyprolis), or ixazomib (Ninlaro) plus Rd. All of them show that the triplet is superior. Now, when you have a novel agent and you want to go to the FDA to pitch a study investigating a potential agent plus Rd, the FDA has some concerns about doing a doublet comparison arm. If you have 4 pivotal phase III studies showing that the triplet is better, is it ethical in 2018 to randomize a patient to a doublet regimen in the relapsed setting? That was a real discussion coming from the FDA. The consent form should be very clear because the patient is not getting the standard of care.

Additionally, in the relapsed setting, many of us will accept PFS as a primary endpoint and recognize that sometimes it can translate into an OS benefit but with the caveat that we have a major confound of drug access we should be aware of.

Another important point is that response rates and PFS progressively diminish with each successive relapse. If you are using a triplet in the frontline setting, I think it is prudent to use a triplet in the second line because your response rate is going to be even shorter. This patient’s disease is probably more genomically complicated at this point. If you have an early relapse, it is even more complicated.

In this case, you have a high-risk patient who relapsed early, and he should get triplet therapy. The FDA is supportive of that, as we have seen with drug development in the relapsed setting. It is hard to perform a study if you are not going to have a triplet control arm, making it harder for new drugs to get into this space.

For multiple myeloma, you want a rapid and deep response. Personally, I like to be aggressive and de-escalate, rather than being less intensive and then trying to catch up. Anytime you are talking about retreatment, you’re introducing tremendous complexity because there are different types of relapses: biochemical and clinical. Most of the clinical trials we have are skewed to the biochemical relapses, but those are the data that we have.

What is the rationale for using carfilzomib as a backbone for this patient?

The ARROW trial was a phase III study looking at patients with 2 to 3 prior lines of therapy and no prior carfilzomib exposure randomized to 20 mg/m²of carfilzomib once weekly on day 1 and then 70 mg of carfilzomib thereafter versus the standard of 20 mg/m²and 27 mg/m²of carfilzomib twice-weekly dosing.⁴This showed a PFS benefit of 11.2 versus 7.6 months, respectively. The HR was 0.69. The safety profile was comparable between the 2 arms. It seemed to benefit across all the subgroups.

There is a danger here because this is only single-agent carfilzomib. There are no large published studies showing 70 mg/m²of carfilzomib, particularly in combination with immunomodulatory (IMiD) agents. There is some concern regarding increased cardiopulmonary issues. I personally would not do 20 mg/m²and 70 mg/m²with a concurrent IMiD. I would use caution. Another factor to remember is the infusion time. Any dose of carfilzomib above 36 mg/m²must be given over 30 minutes. At our institution, everyone is given the agent above 30 minutes to avoid nursing confusion of accidentally giving 70 mg/m²of carfilzomib over 10 minutes.

He decided to be treated with RVd.

Case 2

May 2013

A 61-year-old Caucasian woman was given a diagnosis of Revised International Staging System stage II multiple myeloma. Genetic testing showed t(14;16). At the time, she was treated with RVd induction therapy, followed by autologous stem cell transplant. She achieved a complete response with RVd and transplant and was later placed on lenalidomide maintenance therapy.

What is the role of transplant as part of frontline therapy for multiple myeloma?

There was a recently published French study treating patients with RVd with transplant versus delayed transplant.⁵The PFS was 50 months versus 36 months, respectively. The interesting thing that people who are against transplant like to point out is that if you are a patient who is minimal residual disease (MRD) negative and are treated with RVd alone, you did just as well as those who had transplant.

If patients were getting to MRD negativity with chemotherapy, would that change your perception of transplant? I think the issue always comes back to risk and benefit. One of the things we have to keep in mind is that for patients over age 70, you typically have to reduce the melphalan dose from 200 mg/m²to 140 mg/m². You are going to get less bang for your buck, but we can’t compromise on safety.

The issue is that when you have a lot of novel agents that are so potent, what is the trade-off? There I think it is a little different for patients who are over age 70 and having difficulty tolerating induction therapy or are not getting into a complete response. That patient may benefit from 140 mg/m²of melphalan. The message is that this is not a treatment of younger or older; it is a treatment or fit and unfit.

Are you using MRD testing today, and, if so, how do you use it?

First we have to talk about the analytics of the test. Who is being tested? There were 30 patients in one study who were MRD negative, but they had measurable disease. MRD is not a specific test. We also have sampling issues. Was it a fresh pull, and how good was the specimen? Those are preanalytic issues. The analytic issues concern the sensitivity. If you had a suboptimal specimen to begin with and it was not run properly, you may be acting inappropriately. And then you have issues regarding what is residual disease. You can be MRD positive with an undetermined significance clone. Conversely, you can be MRD negative and high risk, and that disease may relapse much faster. The type of disease matters.

Lastly, we often ask, Is this a predictive or prognostic test? I think prognostic is very clear. Randomized phase III studies are showing that MRD negativity correlates with better outcomes. What we are lacking are predictive data. If you are positive, do you intensify therapy? If you are negative, do you stop or de-escalate? We have zero data. In 2018, I think it is hard to use.

The only 2 areas where I might consider using MRD testing is in patients who are post induction and averse to going to transplant. If they are averse to transplant and they are MRD negative, I still collect their cells but postpone transplant. The other time that we may consider it is in low-risk patients who are having difficulty tolerating therapy. If they are MRD negative, there is a risk-and-benefit discussion. We could say let’s take a break and see how it goes. I have no data to support that, but I think those are the only 2 uses for MRD testing now. That being said, I think most of us would agree that for MRD testing to be pragmatic in the future, it should be blood based.

May 2018

On routine follow-up, the patient reported having mild fatigue but continued to work full-time; she had grade 1 neuropathy. Laboratory findings revealed the following: M protein, 0.6 g/dL; Hb, 10.3 g/dL; creatinine, 1.3 mg/dL. His light chain levels also continued to rise.

What factors do you consider when choosing the next therapy for this patient with biochemical relapse?

There is a big issue here because clinical trials don’t stratify to these issues. We presume that they are much more representative of biochemical relapse because of where patients get accrued. At our center, everyone at the time of progression is given the standard of care and a research consent. You are enriching for biochemical progressions from academic centers.

The other thing to consider regarding these patients is their risk status. If the patient is high risk, we want to stay ahead of that. The second thing is that physicians may get too complacent and think that it is just a small M spike, but they do not do any imaging. Then you are caught off guard when the patient does show bone disease.

References:

1. Duri GB, 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/S014-6736(16)31594.
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 Haematol. 2018;182(2):222-230. doi: 10.1111/bjh.15261.
3. 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.
4. 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 randomized, phase 3 study.Lancet Oncol. 2018;19(7):953-96 doi: 10.1016/S1470-2045(18)30354-1.
5. Attal M, Lauwers-Cances V, Hulin C, et al; IFM 2009 Study. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma.N Engl J Med. 2017;376(14):1311-1320. doi: 10.1056/NEJMoa1611750.