Vij Discusses the Growing Number of Treatment Regimens for Multiple Myeloma in a Case Study

Ravi Vij, MD, MBA

Ravi Vij, MD, MBA

Case

During aTargeted Oncologylive case-based peer perspectives presentation, Ravi Vij, MD, MBA, reviewed with other healthcare professionals the treatment options and considerations he makes when treating patients with multiple myeloma. Vij, professor of medicine, Oncology Division, Section of Bone Marrow Transplantation, Washington University School of Medicine, in St. Louis, Missouri, discussed his treatment decisions with the group during the meeting based on a case scenario of a nontransplant-eligible patient with stage III multiple myeloma.December 2013

A 77-year-old African American man with diagnosed stage III multiple myeloma was not eligible for transplant based on his level of frailty. His cytogenetics showed hyperdiploid disease and he received treatment with lenalidomide (Revlimid; 15 mg daily), bortezomib (Velcade), and low-dose dexamethasone (RVd).

After 9 cycles of therapy, the M-spike plateaued at 0.6 g/dL; therapy with single-agent lenalidomide was continued.

December 2015

Two years after his diagnosis, his laboratory values were notable for the following: hemoglobin, 11.4 g/dL; creatinine, 1.0 mg/dL; and his M-protein had risen from 0.6 g/dL to 1.2 g/dL to 1.5 g/dL. He reported feeling tired but continued to do well functionally.

Targeted Oncology: What are your general impressions of this case?

Vij: Multiple myeloma is the second most common hematologic malignancy, and it is a disease where we certainly have made tremendous progress over the past 2 to 3 decades. But unfortunately, it is still a disease that is not curable for most patients. For transplant-eligible patients, the most recent Clinical Trials Network study suggests that the median survival is approaching 10 years, which I think is remarkable given the fact that a few years ago, we were still in the vicinity of 5 years for transplant-eligible patients. For non—transplant-eligible patients, the median survival is now most likely at the 5- to 6-year mark, or even longer.

The first case is a 77-year-old African American gentleman who was diagnosed with stage III multiple myeloma and was not eligible for transplant based on his level of frailty. He was hyperdiploid. He received treatment with RVd, and after 9 cycles, the M-spike plateaued at 0.6 g/dL. Therapy with single-agent lenalidomide was thereafter continued.

What are your impressions for his initial treatment with RVd?

RVd is the prevailing standard of care. The SWOG study randomized patients to RVd versus lenalidomide and dexamethasone (Rd) in a population that was not intended to be taken to transplant immediately; however, some of the patients could have gone to transplant subsequently.¹This study randomized patients to the full dose of RVd or Rd, and then patients went on to maintenance with Rd.

What we find is a progression-free survival (PFS) advantage for the 3 drugs versus the 2 drugs. What was also surprising to many of us was that there was an overall survival (OS) advantage. We had come to accept that the survival has gotten more difficult to show in myeloma, even in relapsed/refractory disease. We were accepting of PFS as an endpoint because we cannot control for post-trial therapies.

With RVd, bortezomib is administered twice a week with bortezomib at 25 mg and dexamethasone at 40 mg. You may occasionally find a person who is fit enough, but most 77-year-old patients are going to be candidates for RVd-lite instead if you are going to administer a 3-drug regimen. This regimen is only once-a-week bortezomib. The lenalidomide stays at 15 mg, and the dexamethasone is capped at 20 mg. Not every 77-year-old patient will be able to tolerate either of these regimens, so the competitive arm, Rd, is something we will still use.

How would cytogenetics affect your treatment choice for a patient with a new diagnosis?

Cytogenetics do not impact the patient's probability of response; however, it does impact the durability of response. Having said that, I don't use cytogenetics for initial choice of therapy, but I do use it when choosing maintenance therapy.

Would you consider carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRd) instead as induction therapy?

For transplant-eligible patients, we are increasingly using KRd. The neuropathy with bortezomib, although you give it once a week or subcutaneously, can be a huge problem for a lot of patients. My switch to carfilzomib is as much based on the tolerability profile as it is based on the perhaps greater efficacy. We know that in the ENDEAVOR trial with patients in the relapsed/refractory setting, carfilzomib with dexamethasone was superior for PFS and OS compared with bortezomib and dexamethasone.²However, the dose used was 60 mg/m²twice weekly and not many physicians have adopted that yet.

Additionally, there are about 5% to 7% [who] get a carfilzomib-based regimen and have serious pulmonary toxicity. This is thought to be an endovascular-injury pattern for a lot of patients. Because of the higher doses, you can see hypertension and some transient renal insufficiency. This is thought to be pre-renal because it reverses quickly. In one case, I saw a patient who went blind with carfilzomib. This could make you bite your tongue and ask yourself whether or not you did the right thing. But for the vast majority, you are not going to have a very serious event with KRd. There is no consensus on what the best treatment is. I think RVd is still probably the most widely used and is appropriate for a transplant-eligible population.

How do you define progression in multiple myeloma?

There are criteria that define what a relapse is, including a 25% rise from baseline in the light chains or M-protein. Additionally, for the M-protein, there should be a 0.5-g/dL absolute rise. That is the criteria when you are trying to define progression for the purposes of a clinical trial.

When do you start therapy for relapsed disease?

There is no consensus; this is as much art as it is science. Sometimes, you have to take the patient’s wishes into view, particularly if they are experiencing a biochemical progression. If you read the textbook, it will tell you that observation alone is absolutely fine if you have a biochemical relapse. Nothing has been shown to change the natural history. But now we have the proliferation of new drugs, and we know the disease will continue to get worse. Patients are often antsy, and that is why the issue of treating a biochemical relapse often does come up.

It is rare, if you are following these patients closely, for things to go wrong where you regret your decision. There are times when the disease sneaks up on us and we do regret having waited, but it is difficult to treat the majority of patients, for the fear that you will miss those 1 or 2. Unfortunately, you do pay a price for those 1 or 2.

Do you continue the patient on lenalidomide or switch to another therapy upon disease progression?

This patient has been on lenalidomide for 2 years and now has a rising M-protein. He is currently having a biochemical progression, and at my center, we do consider whether a patient is biochemically progressing or having symptomatic progression. This gentleman started to have some fatigue, so one thing that we generally do at this point is to try to get an idea as to where things stand in terms of his disease.

In this scenario, we often get a PET scan. Even if the disease is not showing much in the way of symptomatic progression, this patient is mildly symptomatic—he's mildly anemic. For patients who do have hypercalcemia, renal failure, anemia, bone lesions (CRAB) criteria; have no issues on a PET scan; and relatively mild plasmacytosis, I personally have bias to use elotuzumab (Empliciti). Elotuzumab has very little single-agent activity. It was perceived not to have much activity in the later lines of disease. There are data emerging and that may change [as of the American Society of Hematology Annual Meeting], but right now, based on the positivity of data, we generally try to sneak in elotuzumab to see if we can get durability of disease with that intervention.

In the ELOQUENT-2 study, there was a modest improvement in PFS with the addition of elotuzumab to Rd—nearly a 5-month improvement versus Rd alone.³However, if you look at the shape of the curve, even 5 years out, that curve remain split apart. The curves in all of the other studies have come together. The tail on the curve is fairly low, so we can't yet predict who is going to have that prolonged response to elotuzumab. However, I am biased because of pre-approval of elotuzumab. I had 5 patients that went 5 to 6 years with elotuzumab plus Rd. Granted, that population is probably a little different than what we see today because those patients were not exposed to lenalidomide. The population that we see today is at least exposed to lenalidomide at 10 mg. The question then becomes, would the addition of elotuzumab in that population add any benefit? We don't have any published data in this regard, but there are patients [who] get several months out of this maneuver. That is my rationale for elotuzumab in a patient who is having a biochemical progression.

Lenalidomide was increased to 25 mg daily by the local physician for this patient.

April 2015

Four months later, he was hospitalized for pneumonia.

June 2015

The patient complained of increasing back pain, fatigue, and weakness at this point. His laboratory findings revealed the following: M-protein, 2.1 g/dL; serum beta-2-microglobulin, 6.2 mg/L; albumin, 2.1 g/dL; creatinine clearance, 32 mg/min.

A skeletal survey showed a new compression fracture in the L4/L5 vertebrae and a bone marrow biopsy revealed 30% involvement by abnormal appearing plasma cells, which was confirmed by CD138-positive immunohistochemistry stain. He now had an ECOG performance status of 2.

Which regimen would you choose for the second line?

There are many treatment choices in the second-line setting currently. One of the other drugs that is approved, if the patient is having a slow progression and doesn't want an IV drug because they are feeling well, is ixazomib (Ninlaro). Ixazomib is an oral proteasome inhibitor, which is a convenient drug to administer, and it is relatively well tolerated.

It is when patients have more symptomatic progression or CRAB criteria that I generally go to the daratumumab (Darzalex)-based regimens. When I use daratumumab, I tend to add pomalidomide (Pomalyst). That is my own algorithm, and I think if you were to pull 5 people who are also seeing a lot of patients with multiple myeloma, they would provide a slightly different algorithm to use.

How would cytogenetics affect your decision for maintenance therapy?

Patients with del(17p) tend to have better outcomes in clinical trials that have used bortezomib as posttransplant maintenance. We use both bortezomib and lenalidomide for our patients with del(17p), t(14;16), and t(14;20). I think that is what most centers practice.

What are the options for this patient who is now symptomatic at disease progression?

This patient had a biochemical progression, and the decision was made to increase lenalidomide. There are very little data suggesting that increasing the dose of lenalidomide will improve outcomes and that you can capture much of a response with this decision. Additionally, I would say that this case is hypothetical, because in the real world most people cannot tolerate even 10 or 15 mg of lenalidomide and you actually end up keeping them at 5 mg. To increase them to 25 mg is often not possible.

Now, the patient is starting to have more symptoms. His M-protein has risen, and his creatinine clearance is down. His skeletal survey now shows a new compression fracture. A biopsy is performed, and he has 30% involvement in abnormal plasma cells. This patient has symptomatic progression.

In this setting, there is a move toward daratumumab. There are multiple randomized studies in this setting and all of them were done in an era where lenalidomide was not a part of initial therapy or the exclusion criteria included patients refractory to lenalidomide. In a way, none of these studies are applicable to our current general population and we now need to extrapolate the data.

My practice mirrors what most people are doing, which is to start using daratumumab before carfilzomib. In the trials that looked at daratumumab, they had a better hazard ratio (HR). The HR was 0.37 to 0.39, whereas all of the other studies had HRs of about 0.67 to 0.70 using carfilzomib. You have a nearly 70% reduction in risk with the use of a daratumumab-based regimen, and about a 30% reduction in risk based on the carfilzomib-based regimens. It is difficult to compare across trials, but if there is any one figure that you can use to compare them, it is the HR.

Denosumab (Xgeva) is also approved now. In some regards, it is a better drug for myeloma. It has no renal impairment, and you do not have to reduce the dose. The cost of the drug is the biggest issue that comes up. Additionally, something that I learned is that if you give denosumab and stop the drug, you are going to have a rebound risk of fractures. So, if you do want to stop denosumab, the bone health guidelines are advising you go to zoledronic acid and begin to taper off.

The patient was treated with daratumumab, weekly subcutaneous bortezomib, and dexamethasone.

References:

1. Durie BG, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide with 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):519-537. doi: 10.1016/S0140-6736(16)31594-X.
2. Dimopoulos MA, Goldschmidt H, Niesvizky 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. Dimopoulos MA, Lonial S, Betts KA, et al. Elotuzumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended 4-year follow-up and analysis of relative progression-free survival from the randomized ELOQUENT-2 trial [published online September 11, 2018].Cancer. doi: 10.1002/cncr.31680.