What treatments are available for patients with relapsed refractory myeloma who have received at least two prior lines of therapy but less than 4 lines of therapy?

Relapse after initial myeloma treatment can be overwhelming, but there are effective options available. In this video, we'll break down the treatments commonly used when a patient experiences a relapse after 1 or 2 lines of therapy, explaining how each works and what factors doctors consider when choosing the best approach.

What treatment options are available. Apps after 1 to 3 lines.

So when we're talking about two or more lines of therapy, we're talking about two different treatments, meaning usually it's because the myeloma has relapsed after, an initial therapy. Most patients that have had two or more lines of therapy have been treated with drugs like lenalidomide, have been treated with drugs like, bortezomib or Velcade. And in this setting, the FDA approvals, include drugs the CD38 monoclonal antibodies, daratumumab and isatuximab, and also another monoclonal antibody called elotuzumab.

So elotuzumab can be combined with pomalidomide or Velcade, I think actually and then Isatuximab can be combined with carfilzomib or pomalidomide. And ixazomib is also an option here in combination with pomalidomide. And so essentially, when I think about patients that have had prior relapses, I'm always asking myself what are they relapsing on? So for instance, if they've just relapsed on IMiD based regimen, then I might choose a proteasome inhibitor type based combination. If they're relapsing on a proteasome inhibitor based combination, I might reach for IMiD based combinations.

The other option that's available for patients with two or more relapses is CAR-T cell. So we have currently available two different CAR-T cell products. One is called cilta-cel or CARVYKTI, one's called ide-cell or a ABECMA. Cilta-cel is actually approved after one prior line of therapy. So you know you can get it after one or even after two. Ide-cel is approved after two prior lines of therapy. So this is where you could consider either of these options. And then there are like things that we use kind of off label things like venetoclax and for patients with t(11;14) so there's not exactly a FDA approval for these medications. And so we can always consider them.

the myeloma treatment landscape is changing very frequently. In the past one year we've had CAR-T cell therapy approved actually in second and third line therapies. So we know that based on CARTITUDE-4, cilta-cel, which is, an anti BCMA targeted CAR-T cell therapy is approved for patients after first relapse. So as a second line therapy and idel-cel is approved for patients after a second relapse. So essentially they're able to get it in third line. Now that wasn't the case before last year.

Traditionally before that patients were mostly able to get Daratumumab Kyprolis(carfilzomib) dexamethasone, so DKd combination. Or Daratumumab pomalidomide and dexamethasone, DPd combination. So your traditional at one time I used to call these agents novel therapies. And now they're sort of becoming your non immunotherapy traditional options. So for a patients who's relapsed after, who's had their first or second relapse, these options are still available. So for the right patient, we have the right and appropriate therapy actually. But we also have now, CAR-T cell therapy available earlier,

How does the increasing upfront use of Daratumumab impact its use at relapse? What is the upfront utilization of Daratumumab. And in induction as well as maintenance. So I think our ability to use a drugs at first or second relapse really depends on what they have been exposed to. And also what they have been refractory to. Exposure does not necessarily equal refractoriness.

So I think based on the priciest data, and even Griffin, many of us adapted using quadruplet therapies with Daratumumab in the upfront setting in 2020, long before even Perseus came out. Many patients would get Dara-RVd induction, a stem cell transplant if they were eligible, and then mostly revlimid maintenance. I think the maintenance has not changed so much in multiple myeloma. So many patients at first and second relapse are actually Dara exposed, but not necessarily Dara refractory. So I think for those patients I would still think I would use Daratumumab in combination with a pomalidomide or a carfilzomib in that setting.

However, for patients who are under maintenance or where the time to last Dara use and the subsequent relapse is very short, But if they're relapsing rather quickly post induction post-transplant, I am actually shifting gears and thinking about more of an immunotherapy based approach. And then also like you know I think belantamab mafodotin may become available in the near future. So that's going to that's going to change our landscape as well. Belantamab mafodotin or Blenrep is now approved in combination with bortezomib and dexamethasone for adults with relapsed or refractory multiple myeloma who have received at least two prior therapies.

Should all patients who are eligible for CAR-T cell therapy in second line choose that option? I often get asked a question. Hey, CAR-T is approved in second line. Should everyone get it? And I think the answer to that is a very nuanced one. Ideally, yes, because CAR-T offers a patient a treatment free interval. It is an upfront investment of time 2 to 3 months with the pre collection. And then obviously waiting for the cells to be manufactured and engineered. And then actually the infusion and the post CAR-T care within the first 30 to 60 days, right. Or 30 to 90 days with frequent blood checks, frequent visits to your doctor.

So it's an upfront investment of time, but then subsequently it offers the patients time off of monthly infusions. So, you know, ideally that looks very wonderful. And as a CAR-T person, I want to be able to offer that to my patients. But not everybody in second line is going to get CAR-T. Number one is just logistics. And, you know, not every myeloma patient lives near a CAR-T center. I know that there are mechanisms in place in bridging that gap, actually.

And social factors as well, having a caregiver, which we underestimate actually. Right. We, we underestimate the social burden of getting treatment for a patient. So it's a practically not everybody's getting it. But then there's, you know, there's a risk as well with these therapies such as delayed neurotoxicity such as the Parkinsonian features. And then lately there's an emergence of secondary malignancies that's coming out as well. Now it's really hard to pinpoint whether the CAR-T is the culprit or it's the prior Melphalan or it's the prior Revlimid the patient has gotten.

Myeloma patients because of the advances in therapy, are living a long time. During this time they are getting, a lot of treatments which increase their risk of getting these secondary malignancies. So it's hard to pinpoint what exactly is the culprit. But I think that information should give us pause. It should give us time to reflect and pick the right candidates for second line therapy. And I often consider somebody who's younger, with high risk disease or functionally high risk disease who relapses probably within 12 to 18 months, post stem cell transplant as as the main, selection of patients for second line CAR-T.

Now, I think my answer, if you ask me in the next 2 or 3 years, might shift because I know that there are strategies to enhance these CAR-T cell therapy. So there is an off switch in case the CAR T-cell causes a problem. As we await for those, new, improvements in CAR-T design, come, I think CAR-T in second line is being given by to a carefully selected patient, population keeping in mind logistics, hospitals, constraints and social factors and overall patient preference.

How are bispecific antibodies being used in early relapse? Bispecific antibodies, initially were approved for the treatment of late relapsed refractory multiple myeloma and at least four prior lines of therapy. But because they've been very effective in the setting, there has been multiple trials looking at bispecific antibodies in earlier relapsed refractory multiple myeloma and even a newly diagnosed myeloma patients as well.

And so there was one clinical trial called the MajesTec3 study that looked at patients with 1 or 3 prior lines of therapy, and patients were randomized to either receive a BCMA bispecific antibody teclistamab plus daratumumab versus standard myeloma treatments, namely daratumumab, pomalidomide, and dexamethasone or daratumumab. bortezomib, and dexamethasone.

And the initial results of this trial were then presented and really were quite astounding as sort of a mic drop moment where we saw a significant improvement not only of progression free survival, but actually overall survival in patients that received a teclistamab daratumumab combination. It wasn't just a mild improvement, it was a pretty significant improvement to the magnitude of both progression free zero and overall survival.

And so based on these very positive results, the Food and Drug Administration in the United States reviewed the results of this trial very, very quickly. And in less than 60 days, since their initial review, it led to the approval of this combination teclistamab, daratumumab for patients at first relapse. So I think this is a really important moment for patients with multiple myeloma, because this provides another, weapon against myeloma is a very effective, hopefully accessible to patients in need of these therapies at the time of first relapse.

Could selinexor be considered at this point? Selinexor Velcade and dex is actually approved be used after I think one line of therapy. So it can be is pretty early on oddly selinexor and dexamethasone the two drug combination has to be after four lines of therapy. In terms of FDA approval. I've actually had very nice results with, especially for patients that are trying to, get to CAR-T or something like that in the future.

Sometimes tolerability can be a little bit of an issue with these medications. We have other agents such as selinexor, you know, selinexor velcade dex combination or selinexor pomalidomide dexamethasone combination. So for those patients, I would even consider that in that patient population.

What's the role of alkylating agents in this population? So when we talk about activating agents, I think the main ones that come to mind are going to be cyclophosphamide, bendamustine, doxorubicin might be the ones that come to mind. Cyclophosphamide is frequently used in combination with velcade in a combination called VCD, sometimes called CyBorD and then can be used in combination with carfilzomib or even actually the IMiDs.

So I think these are cyclophosphamide is one that we frequently reach for, especially if someone's experiencing disease relapse and hasn't had it before. Bendamustine, however, was something that I was reaching for a lot in the past. But in this era of thinking about bispecifics and CAR-T cell, bendamustine is actually very toxic to T cells. And so if I think somebody might be getting bispecific or CAR-T in the future, I try to avoid bendamustine because it can be really lymphoid depleting.

A Pace based protocol is an intensive combination chemotherapy regimen used mainly for aggressive or relapsed multiple myeloma. It includes four core drugs p-cisplatin, A-doxorubicin, C-cyclophosphamide, E-etoposide. Other drugs may sometimes be added to this base regimen to tailor treatment to a patient specific disease or prior therapy.

Is there still a role for PACE based protocols? I think there's always going to be a role for PACE. When I think of using PACE, I think of using it. Typically, if somebody has a very rapid relapse of disease where chemotherapy is needed to get disease control. So this might be in patients who experience extremely rapid relapse or very bulky disease that hasn't responded to IMiDs and proteasome inhibitors.

What is a PACE based regimen? PACE is a chemotherapy based regimen. And frequently we will combine it with proteasome inhibitors and IMiDs as well. But this is where we're using drugs like cisplatin, etoposide, doxorubicin, cyclophosphamide in order to control disease. So it's a multidrug like a 96 hour infusion of chemotherapy. And it's actually quite effective in myeloma at keeping things under control but comes with a lot of toxicity especially low blood counts, increased risk for infection, need for transfusions.

And then we always get concerned that it could maybe impact the T cells again if we're thinking about future T-cell collection. On the other hand, it's very effective at controlling myeloma. And so when we need quick disease control, it is something that we could consider. It is something that's difficult for people to tolerate over and over again. So usually we do one, maybe two cycles of PACE, to get disease under control.

What factors are considered when choosing a treatment at relapse? We keep in mind several factors that help us decide what therapies are appropriate for a patient. So we look at the timing of relapse. How soon after their diagnosis or induction and transplant are they relapsing? Are they functionally high risk patients. Or they are actually, you know, biology wise, you know, 17p deletion or t(4;14). So the genetics of the disease, the timing of the relapse actually plays a role in us deciding a therapy.

You know, the the burden of disease also plays a role. Is it just some someone who's having a biochemical relapse. And that means just the M spike or the light chains are trickling up slowly. Right. That's a biochemical relapse. Now that relapse is very different from someone having a clinical relapse where they're presenting with hypercalcemia or new bone lesions or new plasmacytomas. Two different types of relapses that require two different types of thinking about it. Right.

And then what they have been exposed to and what they are refractory to. And other social factors that we don't talk about as much. So such as where does the patient live. Do they how far do they live from an academic center? What is their social, you know, setting? Do they have a caregiver? So I think several factors play a role. It looks, you know, it looks very easy that, oh, boom, I will do this and I will do that. But actually, it's a very nuanced discussion between the patient and the doctor and the whole care team. And in in figuring out what is the most appropriate therapy for a patient.

Relapsed myeloma can be treatment options like CAR-T therapy. bispecific antibodies. and other combination startegies help patients and caregivers make informed decisions. Always discuss with your healthcare team to find the approach that best fits your situation.