Improved Induction Therapies Could Eliminate the Need for Transplant in Myeloma

Jeffrey Wolf, MD

As induction therapies continue to improve the depth of response (DOR) in patients with multiple myeloma, it may be possible to eliminate the need for autologous stem cell transplant (ASCT) in this population, provided that deep responses with up-front therapy can be achieved, according to Jeffrey Wolf, MD.

“There are a lot of reasons I would like to get rid of autologous stem cell transplants,” Wolf said. “Newer drugs and newer regimens are going to allow us to get there, [provided] we [conduct] the right studies.”

There has been notable growth of induction therapies within the myeloma space, particularly with regard to triplet regimens, such as lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd), as well as carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRd). Daratumumab (Darzalex) is also making great progress by quickly moving to the frontline setting for patients who are transplant ineligible, as well as for older patients who appear to tolerate the agent well, Wolf explained.

“It’s possible that as our induction therapies improve over the next few years, we may be able to eliminate autologous stem cell transplantation as a form of consolidation if we [can] get deep responses, such as minimal residual disease (MRD) [negativity] with just our initial induction therapy,” said Wolf.

In an interview with OncLive®, Wolf, a clinical professor within the Department of Medicine at University of California, San Francisco (UCSF) and director of the Myeloma Program at the UCSF Helen Diller Family Comprehensive Cancer Center, discusses treatment options for patients with myeloma, in addition to how MRD can be used to inform clinical decisions and improve patient outcomes.

OncLive®: Could you discuss the evolution of induction therapy in multiple myeloma?

Wolf: Induction therapy for myeloma has evolved tremendously over the past few years, [especially] triplet induction [regimens, such as] RVd or KRd, based on recent studies. Daratumumab is certainly making a rapid move to be included in [frontline] therapy, especially in patients who are not eligible for transplant. It seems [that if the agent is] appropriate for them, it could be appropriate for younger patients, as well, but we don’t have an FDA approval [in younger patients yet].

The goal [of treatment] is DOR, [which] is measured by MRD.

What are some of the strategies that are being used for transplant-eligible and -ineligible patients with newly diagnosed disease?

One of the main studies I presented [during my talk] was the ENDURANCE trial, which was just presented at the 2020 American Society of Clinical Onccology Virtual Meeting. The trial was what we thought of as somewhat of a flawed study that [claimed] RVd and KRd were equivalent for progression-free survival (PFS) [in transplant-eligible patients]. The problem is that most patients move on to transplant. What we really should have been looking at was KRd plus transplant versus RVd plus transplant. [The study’s design] eliminated patients from the analysis when they underwent transplant.

In the transplant-ineligible setting, there are a lot more studies to refer to, including the studies that moved daratumumab to the frontline setting. Initially, we learned that maintenance lenalidomide was necessary even in patients who are not posttransplant. Another study showed that daratumumab added to bortezomib, melphalan, and prednisone (VMP) really improved PFS and overall survival (OS). Of course, [there is also the study that evaluated] daratumumab plus lenalidomide and dexamethasone (Rd) versus Rd, [whereby] daratumumab adds tremendous depth and durability.

This morning I put 2 older patients on that regimen. They tolerated daratumumab quite well and can get a DOR that is equivalent to that of a patient who undergoes transplant.

How are you navigating among the agents that are currently available in practice?

It seems complicated because there are so many options, but it tends to sort itself out by circumstance. For example, this morning I saw a transplant-ineligible patient who didn’t get Medicare Part D and, therefore, I couldn’t give them oral therapies such as lenalidomide. Their referring doctor gave them cyclophosphamide, bortezomib, and dexamethasone (CyBorD), which is all [intravenous]. This morning I decided to switch them to subcutaneous daratumumab, bortezomib, dexamethasone.

Most of these regimens will give you the same responses. I often start with preexisting conditions to decide which drugs I eliminate and which drugs I’m going to use instead.

What is the role of transplant in this space right now? Will transplant retain its role in future?

I started out as a transplanter 40 years ago, so it’s hard to say this, but I’ve been thinking for the past decade that we’re on the verge of getting rid of autologous stem cell transplant from myeloma. If our induction therapies are so effective, we may be able to eliminate transplant. I’d like to see us conduct trials, such as the MASTER trial, led by Luciano Costa, MD, PhD, of the University of Alabama’s Birmingham School of Medicine, in which patients who achieve MRD [negativity] with induction therapy do not proceed to transplant. We’re going to have to do those kinds of studies to eliminate transplant. It’s a fairly primitive kind of therapy in that we give high-dose therapy to wipe out as much myeloma as we can, and in doing so wipe out vulnerable bone marrow. Then, we have to [transplant] frozen stem cells from the patient. [The alkylator] leads to increased risk of secondary malignancies. Patients lose their hair, they get sick for 2 or 3 months, and they’re immunocompromised, which is not a good thing to be these days.

How might MRD be used to optimize patient outcomes?

In the world of myeloma, experts are divided over whether to use MRD to make decisions. I happen to be in the group [in favor of MRD]. It’s no different than using monoclonal spike (m spike) or light chain measurements to make decisions. We’re already using MRD in chronic lymphocytic leukemia and acute lymphocytic leukemia to make decisions. The only restriction in myeloma is that, so far, we’ve only been able to [evaluate MRD with] bone marrow and not blood. If we can start measuring MRD in myeloma [through] blood, it would be as commonly used as light chain or m spike measurements to make these decisions. It’ll help us immeasurably because most of the time we’re getting patients into complete remission (CR)—which it really isn’t CR—and then we keep them on regimens for maintenance.

For example, when we don’t know what we’re accomplishing, [it’s worth asking], Are patients getting better? Are patients staying the same? Is the MRD going up while we’re treating patients with drugs that clearly aren’t working? Should we be switching therapies? For patients who are MRD [negative] year after year, is there any reason why we have them on these therapies that are so costly and have so many adverse effects (AEs) and secondary malignancies? There are all kinds of reasons as to why we should be using MRD for measurement. I would argue that the only reason why we aren’t using MRD is because we have to [evaluate] it in bone marrow, which is a little more uncomfortable compared with blood, and maybe because the studies haven’t been completed yet. It’s only a matter of 1 or 2 years before we will be using MRD to make clinical decisions. In terms of frontline therapies, using MRD might allow us to [avoid] transplant or indicate when we’ve given enough treatment and is time to move to maintenance. There a lot of possibilities to using MRD instead of just historically saying, this is how we do it.