Introduction
Shara Pantry (CCO): Good evening.  My name is Shara Pantry and I’m an Associate Scientific Director with Clinical Care Options.  Thank you for joining us for this live webinar titled Targeting CD38 and BCMA in Myeloma: Evidence and Enhanced Outcomes With Innovative Therapies. 

Today’s program is provided by Clinical Care Options and supported by an educational grant from Sanofi. 

Next slide please. 

[00:08:09]

Program chair
It is now my great pleasure to introduce our presenting faculty for today, starting with Dr. Thomas G Martin.  He’s Clinical Professor of Medicine at the University of California in San Francisco. 

[00:08:30]

Faculty
He is joined today by Dr. Craig Cole, who is Associate Professor of Medicine at Karmanos Cancer Institute in Detroit, Michigan, as well as Dr. Noopur Raje, Director of the Center for Multiple Myeloma at Harvard Medical School in Boston, Massachusetts. 

[00:08:49]

Learning objectives
Here are the learning objectives for today’s program. 

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Outcomes analysis
Please note that we will be performing an assessment of the education today with some polling questions being asked twice during the activity, once before the content and again later in the activity.  We would like to thank you in advance for participating in our assessment of the education today. 

[00:09:20]

Polling and questions
Before we get started, I would like to take a moment to introduce you to the features of our virtual player so that you may maximize your participation in today’s webinar.  When a new polling or survey question pops up on your screen, click the circle next to your answer.  Unanswered polls will appear in the Polling window at the bottom of the screen and once the poll is closed, you will no longer be able to answer. 

If you have a question for our faculty during today’s presentation, use the Q&A function at the bottom of your screen.  Our faculty will try to answer as many of your questions as possible during the Q&A session at the end of tonight’s webinar. 

[00:10:01]

General information
If you experience any technical difficulty, also use the Q&A function at the bottom of your screen and at the end of tonight’s session, please click the Resources button at the bottom of your screen and find the Claim Credit link to complete the evaluation and claim your credits.  If you prefer to wait, once the webinar room closes a link will also appear to take you to the evaluation page. 

Finally, slides from this webinar will be available on the CCO website at a link provided in the Resources window. 

[00:10:38]

Closed captioning
Closed captioning will be available for tonight’s webinar.  To view captions, click the Show Captions button on the bottom toolbar. 

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Let’s start with a few questions
And now let’s start with a few quick demographics questions, so that our faculty can get to know our audience. 

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Poll 1

Poll 1.  How many people with multiple myeloma do you provide care for in a typical month: 1‑4, 5‑10, 11‑15, 16‑20, greater than 20, or not applicable?  Please answer now.

[00:11:26]

Poll 2

Poll 2.  Which best describes your practice setting, academic or community?  Please answer now. 

And with that, it is my great pleasure to turn things over to Dr. Martin.

[00:11:48]

CD38‑Targeted Antibodies in Transplant‑Eligible and Transplant‑Ineligible Patients with Myeloma

Introduction
Dr. Thomas Martin (UCSF): Thank you very much, Shara, and welcome, everybody.  Thank you for joining us for tonight.  We have a great faculty, some of my big – my very, you know, warmest friends in the multiple myeloma community.  I think we’re going to have a very nice program tonight.  I’m going to start off and talk about CD38‑targeted antibodies and we’re going to talk about newly diagnosed myeloma and then we’re also going to talk about early relapse multiple myeloma.  So let’s start in the newly diagnosed patient population. 

[00:12:28]

Faculty disclosures
These are my disclosures. 

[00:12:30]

Rationale for targeting CD38 in multiple myeloma
So there’s – I think everybody has, at this point in time, gotten familiar with the CD38 antibodies and that there are multiple mechanisms of which they work. 

[00:12:43]

Immune‑based therapy approaches in MM: CD38 as a critical target
They provide direct apoptosis of targeting multiple myeloma cells.  They do ADCC, ADCP.  They also do complement‑mediated cytotoxicity.  And these mechanisms certainly provide direct toxicity to the multiple myeloma cell and to the cancer cells.  However, there’s also CD38 expressed all along the microenvironment and this includes T cells like T regs, B cells, B regs, NK cells and MDSCs.  And CD38 antibodies hopefully also cause an immune change that allows for better activity of the anti‑myeloma activity and also better host versus myeloma activity.  So the immune system does participate in the anti‑myeloma effect of CD38 antibodies. 

[00:13:40]

Currently approved CD38‑targeted antibodies in MM
Now, these antibodies are currently approved through many indications in newly diagnosed as well as relapsed and refractory disease.  Isatuximab  is, right now, just approved in the early relapse setting, both in combination with pomalidomide and daratumumab, as well as in the combination of carfilzomib and – sorry, pomalidomide and dexamethasone as well as in combinations with carfilzomib and dexamethasone.  And daratumumab is approved for multiple indications in frontline, we’ll talk about one in a minute, which I think has led to really a widespread use of daratumumab in the frontline setting, especially in transplant‑ineligible population as well as transplant‑eligible, we’ll talk about that a little later.  And it’s also used in the early relapse setting in combination with bortezomib or lenalidomide or pomalidomide as well as with carfilzomib, all with dexamethasone. 

[00:14:43]

Optimizing outcomes with anti‑CD38 antibodies in
Now let’s talk about the transplant‑ineligible patient population. 

[00:14:49]

Let’s begin with a patient case
And I’ll begin with a case. 

[00:14:53]

Patient case: newly diagnosed multiple myeloma
This is a 76 year old male with a history of type 2 diabetes, has low back pain for 10 years after a motor vehicle accident and now is presenting with increasing fatigue.  And on laboratory evaluation, the patient is anemic, they have a high total protein, they have an M spike of 4.2 g and it’s found to be monoclonal and IgG Kappa.  A bone marrow biopsy is done, it’s showing 30% plasma cells and they have high‑risk cytogenetic or FISH abnormalities with a (14;16) translocation as well as a TP53 mutation. 

The patient has a low‑dose CT scan and they have multiple lesions consistent with Durie‑Salmon stage III disease.  Creatinine clearance is good, beta 2 microglobulin is low, albumin is relatively preserved, with a normal LDH.  They have Revised‑ISS 2 disease. 

So let’s ask a question in this case. 

[00:15:49]

Pre‑test 1
So which of the following would you recommend for this patient?  Would you treat them with a doublet, lenalidomide and dexamethasone?  Would you treat them with a triplet, a modified lenalidomide, bortezomib and dexamethasone?  Would you treat him with a triplet of a CD38 antibody with lenalidomide and dexamethasone?  Or would you treat them with a four‑drug combination, a CD38, bortezomib, lenalidomide and dexamethasone?  Go ahead and vote. 

OK, looks like we have a little bit of variability in the answers here.  So some would give RVd as the triplet, some would give dara‑Rd as the triplet and then we have more that actually would give the quadruplet.  So let’s talk about transplant‑ineligible population and what regimens that we have out there.

[00:16:52]

DRd vs Rd in transplant‑ineligible NDMM
Now, I think the MAIA study, which has been presented now over the last few years, has really led to widespread use of a CD38 antibody, daratumumab, together with lenalidomide and dexamethasone in the transplant‑ineligible population.  I will remind you that this combination was tested in the phase III study, this was over 700 patients that were randomized either to dara‑Rd versus Rd.  Overall response rate significantly improved in dara‑Rd, 93%.  The median PFS in dara‑Rd was 62 months, really amazing; it’s one of the largest PFS values that we’ve seen in a transplant‑ineligible study.  And just recently, at EHA, Thierry Facon showed us that the median overall survival has been reached and it’s about 90 months, so over 7.5 years of overall survival.  So pretty – you know, pretty important results for transplant‑ineligible patients and I will say that this regimen and these drugs combine very well together and have a very good toxicity profile. 

Now, if we look at MRD and we’ll talk a little bit more about MRD as we go, there was a much higher incidence and achievement of MRD negativity at 10^‑5 with dara‑Rd versus Rd.  And I think we all have grown from the doublets to triplets and in this population really the triplet has been DRd versus RVd, like the previous question. 

Now, the IFM I’ll just mention (on the right) also did a study where, in a frail population, they looked at daratumumab with lenalidomide versus lenalidomide and dexamethasone.  And the goal was to say, OK, if we use a doublet, if we use dara/lenalidomide and minimal dex, just dex to try to get through the first couple of cycles to prevent basically an allergic reaction or a infusion reaction from daratumumab, and then take them off dexamethasone, so really doublet versus doublet, they also showed a very high overall response rate from the doublet DR, 96%.  And so right now we’re looking at what the median PFS will be.  There’s only 24 months of follow up in this study, so we have to have much more follow up to find out what the median PFS is.  And the hope is that the PFS with that DR is going to be close to DRd and therefore would have less toxicity from dexamethasone with the doublet.  So we’ll see how that going forward. 

[00:19:35]

IMROZ: study design
Now, how about – just recently at ASCO and EHA, we heard about the quadruplet from the IMROZ study, and the quadruplet was compared against a triplet in this IMROZ study.  This is a large phase III study, isatuximab/VRd versus VRd.  Patients received four six‑week cycles of induction and then that included isatuximab/VRd versus VRd and then continuous treatment, which was four four‑week cycles of isa/Rd versus Rd.  So one arm got the CD38 antibody, one arm did not get the CD38 antibody.  And the primary endpoint was PFS of the study.

[00:20:16]

IMROZ: PFS and MRD negativity rate
And what we saw at ASCO was at 60 months, the PFS was 63%.  So it looks like this quadruplet is going to have a better reported PFS than the MAIA study.  And in fact, the projected PFS is somewhere in the order of 90 months and so it might be a third – you know, 30% longer PFS with the quadruplet of isatuximab/VRd versus, you know, MAIA, which reported obviously 61 months, so pretty amazing. 

And if you look to the right and MRD negativity rates, you see that the quadruplet has better MRD negativity whether you do MRD negativity in the intent to treat, those that have MRD‑negative CRs and those that have sustained MRD negative for more than 12 months.  Almost 50% of patients had sustained MRD negativity, which we think is going to predict for PFS. 

[00:21:16]

BENEFIT: study design
Now, we also saw at ASCO and at EHA the BENEFIT study and the BENEFIT study was another large phase III study of a quadruplet versus a triplet.  The quadruplet was isa/VRd again and the triplet was actually isa/Rd, so like the MAIA study regimen except isa instead of daratumumab.  And the question is whether bortezomib was actually needed in the community.  And so they had 12 cycles of induction‑based therapy, then they went on to another six cycles of consolidation therapy and then continuous therapy.  And a couple of big things about this.  Number one, the bortezomib in this study was given weekly from the get go, three out of four weeks, with the intent in this transplant‑ineligible population to have less peripheral neuropathy.  The primary endpoint was actually MRD negativity and there was many secondary endpoints.

[00:22:16]

BENEFIT: rate of MRD negativity and ORR in ITT
And you can see from these data that the primary endpoint of MRD negativity rate at 12 months was much higher, more than double in the isa/VRd versus the isa/Rd.  This was one of the surprises for me at ASCO and EHA.  I didn’t think there’d be such a large difference, especially in MRD negativity rates.  We think that will predict to PFS.  If you see over to the right, again only 24 months of – you know, just under 24 months of follow up, the curves are very similar.  They are just starting to separate and we think we will need to have 48 months or longer of follow up to actually see a separation in the curves.  But the thought is that this will have a PFS benefit also, based on such a high difference in MRD negativity. 

[00:23:04]

Summary of treatment for newly diagnosed transplant‑ineligible myeloma
So now that we have – basically in the transplant‑ineligible population, we have great results with dara‑Rd with a PFS of about 62 months.  And now we have great results with quadruplet‑based therapy both in the IMROZ study of isa/VRd and also with the BENEFIT study with isa/VRd where the V is actually given weekly three out of four months.

The CD38 antibody combinations, they appear safe.  I didn’t show you safety data, but they both appear safe and there was no unexpected toxicities with combining the CD38 with the quads. 

I do recommend that you consider frailty status when you’re treating older patients with multiple myeloma and the goals of therapy in the frail might be different.  The treatment endpoints actually may be different.  In the frail population, it may be really to improve quality of life for a longer period of time.  In the more robust people, hopefully it’s to improve our overall survival. 

[00:24:06]

Let’s revisit our patient case
OK, so let’s revisit our case. 

[00:24:09]

Patient case: newly diagnosed multiple myeloma
We again have our 76 year old, type 2 diabetes, low back pain, has anemia and M spike, has Durie‑Salmon stage III, Revised‑ISS II.  And let’s ask the question again.

[00:24:23]

Post‑test 1
What regimen are you going to give to this patient?  A doublet len/dex, a modified len/bortezomib/dex, a CD38 antibody, len/dex, or a CD38 antibody with bortezomib, lenalidomide and dexamethasone.  Go ahead and vote. 

All right.  Well, so we have more people that have selected the quadruplet‑based therapy of CD38 with VRd.  That is what I use in this patient population and certainly in this patient who had high‑risk FISH and cytogenetics, I would definitely use the combination of a CD38 with bortezomib, lenalidomide and dexamethasone.  I didn’t show you data on that, but I think the IMROZ study and other studies are, over time, going to show that these are really beneficial especially in the high‑risk patient population. 

[00:25:31]

Optimizing outcomes with anti‑CD38 antibodies in transplant‑eligible patients with myeloma
Well, let’s talk more about the transplant‑eligible population. 

[00:25:35]

Now, another patient case
And let’s start with another case. 

[00:25:37]

Patient case: newly diagnosed multiple myeloma
This is a 45 year old woman.  She has low back pain.  She has plain films that show multiple lytic lesions and a compression fracture at L1.  She also is found to have an elevated total protein, a high calcium, a low hemoglobin and a low albumin.  And this patient undergoes further workup showing an elevated LDH, multiple lesions by PET scan, and a bone marrow biopsy showing 75% plasma cells, a gain 1q and a (4;14) translocation. 

[00:26:12]

Pre‑test 2
Now let’s have you vote on what recommended regimen you’d use in this case.  You would use continuous triplet‑based therapy until progression; triplet‑based induction followed by transplant and consolidation maintenance therapy; a CD38 monoclonal antibody‑based quadruplet including consolidation and augmented maintenance until PD; and a CD38 monoclonal antibody‑based quadruplet induction followed by upfront transplant and consolidation and maintenance.  So are you going to go the – use everything, a quad plus a transplant?  Are you going to use a triplet, or a triplet plus a transplant?  Go ahead and vote. 

OK, so we have kind of a very interesting result here.  We have a triplet‑based followed by transplant in about 10% of patients.  And then we have CD38‑based quadruplet therapy without transplant with transplant kept in reserve with about 40% of patients.  And then we have half of the responders saying that they’re going to give CD38 quad followed by transplant followed by consolidation and maintenance. 

[00:27:38]

Managing transplant‑eligible NDMM
All right, well, so let’s discuss this further and let’s talk about some of the data from using induction therapy for patients that have transplant‑eligible newly diagnosed myeloma.  Now, as we know, overall response rates and PFS rates are improving as we add additional drugs.  Quadruplet therapies, including the CD38, a PI, an IMiD and dexamethasone, for many of us, have become standard of care as part of induction‑based therapy, with the goal of inducing a rapid, deep and hopefully durable response.  At the end of induction, we’re hoping patients are in a VGPR.  When they get a transplant and consolidation, we’re hoping they’re in CR and hopefully are MRD negative, and our maintenance‑based therapies to maintain the response hopefully have sustained MRD negativity and longer PFS and hopefully, over time, that that will translate into longer overall survival. 

[00:28:40]

Evaluation of MRD as surrogate marker for PFS
So let’s talk a little bit about some of the other factors that we follow closely.  One is MRD.  I do want to bring out that MRD, I think, is an important endpoint especially for transplant‑eligible newly diagnosed patients.  And we recently had an ODAC to look at MRD and the FDA agreed that MRD negativity can be used as an surrogate or an early endpoint for accelerated approval for regimens for newly diagnosed multiple myeloma.  Now, this is accelerated approval, it’s not full approval.  We have to follow patients over time and show that other endpoints are also met like PFS or OS, such that these regimens will receive full approval.  But MRD is becoming an important component and I do think that we should aspire, especially in transplant‑eligible, to try to get patients to MRD negativity. 

[00:29:41]

GRIFFIN: study design
A lot of this came from the GRIFFIN study, which was a phase II randomized study of dara‑VRd versus VRd.  And that study has led to, again, many of us using quads already for frontline therapy.  So they got four cycles of induction, a transplant, two cycles of consolidation of the quadruplet and then they received maintenance for at least two years of daratumumab/lenalidomide or lenalidomide and patients, after that, could continue len at the investigator’s choice.

[00:30:13]

PERSEUS: study design
So that showed a very high overall response rate.  And with that, we went on to do a phase III study.  This is the PERSEUS study.  We just recently saw data at ASH and we saw some more data at ASCO of this year.  And what we saw with dara‑VRd versus VRd, again, a very long PFS. 

[00:30:34]

PERSEUS: PFS and MRD negativity rate
If I show you actually the PFS curves, you can see that at 48 months, 84% of the patients getting a quadruplet followed by an autologous transplant, followed by consolidation and maintenance daratumumab and lenalidomide.  One of the highest, you know, measured PFS values, 84%, at 48 months, that we’ve seen in newly diagnosed studies, and the projected is going to believe to be between at least more than 100 or 120 months.  So the PFS may be longer than 8‑10 years after this study, which is pretty amazing. 

And if you look to the right, you look at MRD‑negativity rates at 10^‑5, 10^‑6, it’s sustained MRD negativity for more than 12 months.  You see that 65% of the patients with this combination is achieving sustained MRD negativity.  That’s really impressive.

[00:31:32]

PERSEUS: MRD negativity in ITT
If you look from end of consolidation up to 36 months, you see that MRD improves over time with continuation of therapy, with 75% of the patients achieving MRD negativity at 36 months at 10^‑5 threshold.  Pretty amazing.  And it’s way better, obviously, in the quadruplet than the triplet. 

[00:31:56]

PERSEUS: MRD negativity and PFS in high‑risk disease
Now, if we look at basically the PFS for the patients in – if we look at the PFS for the patients that are high risk and this is – I want to take out the patients that have high risk, we can see that (to the right) the PFS in the high‑risk patients that are MRD negative looks good both in the patients that have received the quadruplet versus the patients that have received the triplet, but perhaps better, even in the MRD negative, in those that received the quadruplet. 

And if we look at MRD negativity rates (on the left side) here with the quad versus the triplet, you see that the high‑risk patients actually have a higher level of achieving MRD negativity if they got a quad versus a triplet.  This patient in this case had high‑risk disease, had (4;14) and 1q, had double hit, so this patient, in my mind, would be a great patient to receive this aggressive type of therapy.

[00:32:54]

Trials with isatuximab quad therapy in NDMM
Now, there are other trials that also support the use of quadruplets.  The GMMG‑HD7 was also a randomize of isa/VRd versus VRd and this study actually was initially presented at ASH three years ago and was updated at EHA this year, showing a much higher MRD negativity rate in the quadruplet versus the triplet.  The interesting thing about this study, the GMMG‑HD7, is there was a second randomization and the data from the second randomization is not ready yet, but there’s going to be four arms.  One of the arms is going to never receive CD38 antibody, one of the arms is going to receive CD38 as induction and maintenance, and the other two arms, one’s going to get it early, CD38, one’s going to get late.  And it’s going to be interesting to see do you have to use CD38 throughout the entire course, so can you just use in induction, or can you just use it in maintenance?  These data probably, unfortunately, won’t be available for another 3‑5 years, but it’s a great study for us to follow. 

The other thing, the GMMG‑CONCEPT trial was a trial that was quadruplet of isatuximab/KRd in transplant‑eligible versus transplant‑eligible and transplant‑ineligible.  It wasn’t a randomized study, it was just treating all high‑risk patients with quad‑based therapy and if we treated all the patients with quad‑based therapy, there was a very high overall –

[00:34:25]

GMMG‑HD7: MRD negativity after induction and intensification
– I’m going to move past that. 

[00:34:28]

GMMG‑CONCEPT: MRD negativity rate and responses
A very high overall response rate and a higher MRD negativity rate than we would expect in these high‑risk patients, 68% getting isatuximab plus KRd and 54% in the transplant‑ineligible getting isatuximab and KRd.

If you look to the right of this, in the transplant‑eligible and transplant‑ineligible, as you go on to receive more and more therapy these patients are actually achieving deeper and deeper responses.  One of the most important things in the high‑risk patient population is they continue on therapy. In the CONCEPT trial, patients continue on therapy for more than three years of therapy.  It’s a pretty robust protocol for giving triplets – quadruplets and triplet‑based maintenance‑based therapy after the quadruplet‑based induction therapy. 

[00:35:24]

IsKia EMN 24
OK.  Now, we also saw data from the IsKia trial.  The IsKia trial was a EMN study looking at a phase III randomized trial of isa/KRd versus KRd in transplant‑eligible newly diagnosed multiple myeloma patients, again a quad versus a triplet.  The PI is different, it’s carfilzomib here.  They got four cycles of induction, they got a transplant and then they went on to receive consolidation, four more cycles, and then they did another they call ‘light consolidation’, 12 cycles of isa/KRd versus KRd, as, quote‑unquote, ‘light consolidation’/slash maintenance.  And the primary endpoint of this study was MRD negativity. 

[00:36:08]

IsKia EMN24: post‑consolidation MRD negativity in ITT
If you look, the quadruplet was better with CD38 antibody plus KRd versus KRd.  Maybe not as much difference when you use KRd as the triplet backbone.  Is KRd better than VRd?  Really hard to know, but in transplant‑eligible some people like that better. 

[00:36:31]

IsKia EMN24: post‑consolidation MRD negativity by cytogenetic risk
However, if we look at the patients that truly had high‑risk disease, you look at here, the very high risk achieving MRD negativity at 10^‑5 or 10^‑6, the very high risk is the ultra high risk, the ones that have two or more high‑risk cytogenetic abnormalities, you see a marked difference in MRD negativity in people that get the quad versus the triplet.  So I think in the high‑risk patients really doing quadruple‑based therapy is, in my mind, it’s quite important as part of their therapy.

[00:37:01]

Summary of treatment for newly diagnosed transplant‑eligible myeloma
OK, so those were a lot of data.  I’m going to summarize it and say, you know, we’ve had VRd or KRd as part of standard of care for a long time.  More recently, we’ve gone to quadruplet‑based therapy where it’s been CD38 plus VRd or KRd.  These are showing much higher overall response rates and much higher achievement of MRD negativity.  And I do think that the quads are now standard of care and especially in patients that have high‑risk disease.  Right now, we do think that quadruplet therapy should lead, especially in transplant‑eligible patients, to a transplant and then to consolidation and maintenance, but we can talk more about that at the end of this and you guys can ask questions about that too.

In terms of maintenance‑based therapy, in general, in standard‑risk disease lenalidomide until progression is our standard of care.  I personally add daratumumab to lenalidomide or CD38 to lenalidomide even in standard‑risk patients because of the results of the GRIFFIN and the PERSEUS study.  We can talk more about that at the end.  In high risk, I would do a doublet for maintenance.  Well, for many of my patients I actually do a triplet like the GMMG‑CONCEPT trial with CD38 plus PI plus lenalidomide as maintenance‑based therapy. 

[00:38:24]

Let’s return to our patient case
OK.  Let’s go back to our case. 

[00:38:25]

Patient case: newly diagnosed multiple myeloma
So our case is this 55 year old woman who presents with aggressive disease, stage III disease with hypercalcemia, anemia.  They have high‑risk features with a 1q gain and (4;14), the quote‑unquote ‘double hit’, and we want to prescribe frontline therapy. 

[00:38:48]

Post‑test 2
So what would you recommend for this therapy?  Continuous triplet‑based therapy until progression; triplet‑based induction followed by transplant and then consolidation and maintenance therapy; a quad‑based therapy with augmented maintenance until progression and save the stem cells for down the road and keep it in reserve; or quadruplet therapy and then a transplant and then consolidation and maintenance.  So go ahead and vote. 

All right, so we have a lot of peoples staying with a quadruplet‑based therapy and then holding the transplant for down the road, we’ll talk about that.  At the end of this, we’ll ask questions amongst our other advisors here tonight, our other speakers, and we’ll see what people think.  But it looks like we converted some of the people to believers in transplant especially in the high risk.  OK.  All right. 

[00:40:02]

CD38 antibody‑based therapy in patients with R/R myeloma
In the last 5‑10 minutes, let’s talk a little bit about CD38 antibody‑based therapy for patients with relapsed and refractory multiple myeloma. 

[00:40:07]

Now, another patient case
So let’s start off with another case. 

[00:40:11]

Patient case: with progression after quad‑based therapy
We have a 62 year old patient presents with mild fatigue, no anemia, elevated serum total protein.  The patient receives a four‑drug induction regimen containing a CD38, PI, IMiD and dexamethasone followed by a transplant and len maintenance.  And then after 14 months of induction therapy, the patient has disease progression.  This would be considered a functionally high‑risk patient because they relapse, you know, within 18 months of their transplant, etc. 

[00:40:43]

Poll 3
OK.  So for this patient with functional high‑risk disease, what would you choose for salvage therapy?  Pomalidomide, bortezomib and dexamethasone; selinexor, bortezomib and dexamethasone; carfilzomib and dexamethasone; anti‑CD38 therapy, carfilzomib and dexamethasone; anti‑CD38 antibody, pomalidomide and dexamethasone.  Go ahead and vote. 

All right, so we have more variability in this case, like we expected from this question.  But what we saw is that the majority of people, almost 80% of patients – or 80% of responders said a CD38‑based regimen, either with carfilzomib and dexamethasone or pomalidomide and dexamethasone.  OK.  So let’s talk about that.

[00:41:44]

Early relapse: refractoriness is a driver for treatment selection
So when we think about early relapse and what to select for early relapse, there’s many things that we have to consider and the patient – in my mind, the patient always gets to choose and one of – the biggest thing is convenience, how convenient it is for the patient: can they get back and forth?  What toxicities have they had?  Are there things that you want to avoid because of neuropathy?  Are there things they want to avoid because they have bad hypertension, etc?  But one of the main drivers, in my mind, is the refractoriness of what their prior therapy has been.  Are they refractory to any specific agent?  And in this case, the patient was actually refractory to lenalidomide. 

And this is a slide that you guys will have copies of, you can go to it, but I would use it.  You can use it as a benchmark to look if a patient has these types of refractoriness, these are the regimens that we’re thinking about giving in the relapsed/refractory setting.  I do say, number one, if patients have not had CD38 as frontline therapy, then they should have a CD38‑based regimen in early relapse.  If they have had CD38 antibody, but they took it for a short period of time and then came off and they came off for more than a year or more than 18 months or more than two years, then those patients should still be sensitive to CD38 and you can use a CD38‑based therapy.  So I’ll say that as a baseline. 

[00:43:07]

Phase III APOLLO
Now let’s talk about a little bit of the data.  So this is the APOLLO trial that looked – a randomized phase III trial that looked at daratumumab, pomalidomide and dexamethasone versus pomalidomide and dexamethasone.  This is in patients after one or more prior lines of therapy.  And I will point out that 80% of the patients in this study were lenalidomide refractory.  So many of them were lenalidomide refractory and almost half were PI refractory.  We look at pretty good response rates; overall response rate with dara‑Pd about 70%.  But when we look at the PFS, the 12‑month PFS is 52 % or the median right around just over a year.  Now, this is quite good for a lenalidomide‑refractory patient population.  You always have to look at your patient population. 

[00:43:55]

Phase III CANDOR
Now, the CANDOR study was another large phase III study; it was daratumumab, carfilzomib and dexamethasone versus carfilzomib and dexamethasone.  It’s 1‑3 prior lines of therapy.  Actually was a little less heavily pretreated population; only had 32% of the len refractory versus 80% in the pomalidomide‑based study.  But you see in this combination the triplet did a lot better than the doublet.  So almost 29 months of PFS versus 15 months with Kd.  So daratumumab actually combines and CD38 actually combines quite well with a proteasome inhibitor and especially with carfilzomib and it gives you a very high PFS, which is nice to see.

[00:44:40]

Phase III ICARIA‑MM
Now, isatuximab again is approved in these settings.  So isatuximab was also combined with pomalidomide and dexamethasone in a phase III trial versus pomalidomide and dexamethasone in very similar – 80% of the patients – or actually here 94% of the patients were lenalidomide refractory.  Very similar PFS.  Right around a year of PFS, with very good response rates between 60 and 65%.  So CD38 plus pomalidomide/dexamethasone is a very active regimen even in those patients that are lenalidomide refractory and PI refractory.

[00:45:17]

Phase III IKEMA
Now, I was also part of the IKEMA study.  It was a phase III study of isa/Kd versus Kd in relapsed/refractory myeloma.  This is 1‑3 prior lines of therapy.  It was less heavily pretreated.  Thirty‑two percent, again, len refractory, 31% PI refractory.  And here we saw PFS was about 36 months.

And what we showed in an abstract at ASH two years ago, we showed in the functional high‑risk patients, the patients that have relapsed within 18 months of their initial diagnosis, that isa/Kd actually had a median PFS of about 25 months to their second line of therapy.  So their second‑line therapy had a higher PFS than their first line of therapy, which is a pretty remarkable response.  So again, CD38 plus Kd, it’s a very potent regimen.  It’s one of my favorite things.

[00:46:05]

Phase I/II trial of isatuximab in daratumumab‑refractory R/R MM
Now, people always ask can you go from a CD38 antibody – one CD38 antibody study or treatment just to another one?  You know, changing the partners to CD38.  Can you go from daratumumab to isatuximab?  Can you go to isatuximab and daratumumab?  Well, we did a study looking at single‑agent isa after patients were refractory to daratumumab and we saw very few responses.  What we saw is that the longer people were between their last daratumumab regimen, then they’re more likely to get stable disease.  But if you try to do a single‑agent CD38 after a CD38 combination and they were refractory to the CD38, it’s really not a good scenario.  So that’s not a time to do it, in my mind.  You have to have six, maybe even 12 months of difference if you’re refractory to CD38 to go back.  It’s better to go back if they were still sensitive to the disease. 

[00:47:03]

Monitoring and management of AEs associated with anti‑CD38 antibodies
Anti‑CD38 antibody toxicity considerations
OK.  So last thing, a couple of toxicity things for CD38 antibodies.  You know, these, when they’re given in IV, they’re associated with infusion reactions 30‑50% of the time.  They need premeds with acetaminophen.  They need premeds with antihistamines.  They need premeds of corticosteroids.  You do have to watch for infectious complications.  They need acyclovir for VZV.  If they’re combined with steroids initially, I always put them on PJP prophylaxis, and if they test positive for hepatitis B viral serologies, they need therapy to prevent hepatitis B reactivation. 

[00:47:43]

Infection prophylaxis and management with anti‑CD38 antibodies
Also, what I’ll say is that these drugs combine very well with almost all other agents.

[00:47:51]

Phase Ib study of isatuximab SC administration with wearable bolus injector
And when we combine it with all other agents, there’s really no extra toxicity, in my mind.  The biggest thing that we worry about with CD38 antibodies is infection and we look at pneumonias, and so patients need to be treated pretty aggressively. 

Now, obviously the one big difference between daratumumab and isatuximab is the administration of subcu administration, and I will just point out that isatuximab, now data has been presented in a phase Ib study looking at a subcutaneous device.  This is a device that you put on the abdominal wall, you hit the center button, the nurse walks away and over a 3‑5‑minute time, the device actually injects the CD38 antibody into the subcutaneous tissue.  Now, this is now in a phase III study and we’re hoping that this actually will be available in the not so distant future.  And then I think we will have a choice between CD38 antibodies, because both will be quite convenient to be given. 

[00:48:50]

Conclusion
So in conclusion, CD38 antibodies, they combine well with many other anti‑myeloma therapies.  In terms of safety, infusion reactions occur with the IV formulations with subcutaneous administration, it’s only about 10% of the time.  Actually, it’s much better tolerated.  Infectious prophylaxis is recommended and I do recommend using CD38s frontline now for almost all patients, transplant‑eligible, transplant‑ineligible and frail patients.  And if you haven’t used it frontline, then go ahead and use it in the early relapse.

And then finally, there is really no dose adjustments for CD38, it’s unit dose.  So it’s unit dose for daratumumab, it’s unit dose for isatuximab.  There’s no change in the dosing of the antibody. 

Now I hope you have questions about CD38 antibodies.  We will answer the questions at the end.  You can put your questions in the Q&A function button on the lower part of the screen.  You can go put them in right now and we’ll answer them at the end. 

And with that, I would like to turn over the microphone and the presentation to Dr. Noopur Raje, who’s Director of the Center of Myeloma at Mass General.  Noopur is going to talk to us about one of my other favorite things and that’s bispecific antibodies.  Go ahead, Noopur.

[00:50:08]

Bispecific Antibody and CAR T‑Cell Therapies in Relapsed/Refractory Multiple Myeloma
Introduction
Dr. Noopur Raje (Harvard Medical School): Awesome.  Thank you.  Thanks so much, Tom, and thank you all for joining us this evening.  So after that fantastic presentation on anti‑CD38 antibodies in the upfront as well as relapse setting, we’re going to talk about some of the newer immunotherapies out here. 

[00:50:24]

Faculty disclosures
Here are my disclosures. 

[00:50:26]

BCMA‑directed therapies for patients with R/R MM
And we’re going to focus first on the BCMA‑directed therapies and we’ll also touch on some of the other targets which are available as well. 

[00:50:36]

Novel therapies in multiple myeloma
And just as a backdrop out here, you know, we’ve been so fortunate in the myeloma world where we’ve had amazing drugs, and even through the pandemic we’ve had three bispecific antibodies approved.  We did have an antibody drug conjugate approved as well and the hope is that that antibody drug conjugate comes back into practice soon and we’re going to see evidence of that. 

[00:50:36]

Belantamab mafodotin: a BCMA‑targeted antibody drug conjugate
So let’s get started with the antibody drug conjugate.  This is belantamab mafodotin.  It is a BCMA‑targeted antibody drug conjugate.  It is a humanized afucosylated IgG1 anti‑BCMA antibody wherein it uses the MMAF warhead and through ADCC it can actually cause killing of your multiple myeloma cells. 

[00:51:32]

Belantamab mafodotin monotherapy in R/R MM
There was data with belantamab mafodotin monotherapy in the relapsed/refractory setting with DREAMM‑1 and DREAMM‑2 and it actually got accelerated approval.  Unfortunately, the DREAMM‑3 study, this was the phase III, supposedly the confirmatory trial wherein belantamab mafodotin was compared to pomalidomide and dexamethasone, and despite the fact that the response rates as well as the progression‑free survival was superior with the belantamab mafodotin, this was taken off the market only because it did not quite meet the statistical endpoints.  So the P value was not significant, the hazard ratio crossed 1.03.  And unfortunately, in my mind at least, it was a little premature in terms of decision‑making of taking it off the market. 

[00:52:29]

DREAMM‑8: study design
But subsequently, you know, at this year’s ASH and EHA as well as ASCO, you’ll have now seen data with DREAMM‑8.  This is belantamab mafodotin in combination with pomalidomide/dexamethasone compared to the backbone of pomalidomide/dexamethasone.  This was over 300 patients treated.  The primary endpoint was PFS, with secondary endpoints which are very classic in multiple myeloma patients. 

[00:53:02]

DREAMM‑8: progression‑free survival
And what you see with the DREAMM‑8 dataset is the progression‑free survival of belantamab mafodotin in combination with pomalidomide and dexamethasone at 12 months was close to 71% versus 51% in patients who got pomalidomide with bortezomib and dexamethasone.

[00:53:27]

DREAMM‑8: safety overview
Where if you look at the safety overview of belantamab mafodotin, I think most of us are familiar with the toxicity of bela‑maf.  It’s typically the ocular toxicity where you get some kind of, you know, conjunctival irritation and that makes – it can be quite uncomfortable, and most times when you dose reduce and delay dosing, we see that that is quite effective. 

Other toxicities are very typical with belantamab mafodotin. 

[00:54:02]

DREAMM‑8: AEs of special interest
We talked about the eye toxicity, the blurred vision, dry eye, etc, and really the best way of taking care of this is really dose reduction and by combining it, like you saw in the DREAMM‑8 trial with the combination of pomalidomide and dexamethasone, you’re really able to reduce doses without compromising efficacy and by doing so, you’re maintaining responses in these patients.

[00:54:28]

DREAMM‑7: study design
Very similarly, you saw the DREAMM‑7 data.  Now, the DREAMM‑7 data is belantamab mafodotin in combination with bortezomib and dexamethasone.  And this is one of those few trials where an anti‑BCMA has been pitched against an anti‑CD38 monoclonal antibody.  Close to 500 patients treated here. 

[00:54:50]

DREAMM‑7: progression‑free survival
And if you look at the progression‑free survival of belantamab mafodotin in combination with bortezomib and dexamethasone, you see, amazingly, at 18 months, 69% of these patients remain progression free versus 43% when you’re using a dara/bortezomib‑containing arm.  So really quite remarkable results. 

[00:55:12]

DREAMM‑7: safety
Again, if you look at the safety, I’m not going to belabor this and go over this quickly, but most of the safety issues around bela‑maf are the ocular toxicities that we’ve seen, but with DREAMM‑7 and DREAMM‑8 data as positive as it is, I do think that you’re going to see belantamab mafodotin coming back into clinical practice very soon. 

[00:55:12]

Ongoing clinical trials with belantamab mafodotin in R/R multiple myeloma
There’s a whole bunch of ongoing clinical trials with bela‑maf in specific populations like renal failure, hepatic failure.  And it’s honestly a very easy drug to give in the clinical setting.  And with dose reductions, what we have seen is we can also give the drug every eight weeks, every 12 weeks and you tend to maintain the duration of response. 

[00:56:01]

Bispecific antibodies in R/R multiple myeloma
Switching gears now, I’m going to talk about the bispecific antibodies quickly and I’m going to make sure that I give time to my colleague to talk towards the end as well.  So Craig, stay tuned, we’re going to get through this pretty quickly. 

[00:56:18]

Let’s start with a question
Let’s start though with a question here. 

[00:56:20]

Pre‑test 3
And the question here is, when counseling a patient on infection management strategies getting an anti‑BCMA‑targeting bispecific antibody, all of the following would be recommended except:

1. Growth factor support for patients with severe neutropenia
2. PJP prophylaxis for all patients
3. Herpes virus prophylaxis for all patients
4. IVIG administration only for patients with life‑threatening infections, and
5. Antibacterial prophylaxis for patients at high risk for infection

So go ahead and vote. 

All right, so I love this because I think the responses are all over the place a little bit.  It was a little bit of a trick question and it’s kind of late in the day, so we’ll come back to this towards the end. 

[00:57:33]

Bispecific therapy options for multiple myeloma
All right.  Now, talking about bispecific antibody therapies in the context of myeloma, we have two targeting BCMA, teclistamab and elranatamab.  We have others as well.  We have talquetamab targeting GPRC5D and we have several others targeting BCMA, cevostamab, linvoseltamab, and the ABBV‑383 bispecific antibody. 

[00:57:59]

FDA approved bispecific antibody therapies in R/R MM
And the ones which are FDA approved are tec, elran, and talquetamab.  All of them are approved in a very similar setting, so four prior lines of therapy, the lines of therapy should include an IMiD, a PI and an anti‑CD38 monoclonal antibody.  So in essence, the indication for these is pretty similar across the board.

[00:58:20]

Phase I/II MajesTEC‑1
I’m going to jump through the data very quickly because it’s very – you know, most of you are familiar with this data now.  This was MajesTEC‑1.  The overall response rate with tec was about 63% with VGPR or better in close to 60% of patients.

[00:58:39]

MajesTEC‑1: PFS and DoR with teclistamab in R/R MM
And this translated into a PFS, overall PFS of about 11.4 months.  Obviously, patients who went into a complete response did a whole lot better. 

[00:58:52]

Phase II MagnetisMM‑3
Similarly you have MagnetisMM‑3, which got elranatamab approved.  Very similar overall response rate, VGPR or better of 56%.  A slightly more heavily pretreated patient population here.

[00:59:07]

MagnetisMM‑3
And if you look at the MagnetisMM PFS, the overall PFS of the elranatamab  was close to 18 months and for patients who went into complete response at two years, their PFS is north of 90%.  So really remarkable results at kind of the back end of myeloma therapy. 

[00:59:32]

MagnetisMM‑5
Now, this is an ongoing trial and Tom has very nicely shown us daratumumab.  He also mentioned that anti‑CD38 monoclonal antibodies can be quite easily combined with some of the newer drugs as well and this is data with Magnetism‑5 combining it with daratumumab.  And although the data is very preliminary, the overall response rates are really good and we will wait to see what the durability of response here is. 

[01:00:00]

Phase II MonumenTAL‑1
Moving on to now talquetamab, talquetamab is the bispecific antibody targeting GPCR5D, so very different from the anti‑BCMA antibodies.  It was tested in a very similar setting like tec and elran and two different dose schedules were tested, so .4 mg/kg given Q weekly and .8 mg given every two weeks. 

[01:00:30]

MonumenTAL‑1: DoR and PFS outcomes
And if you look at the data out here at the .8 mg two‑weekly, which is what I tend to use in my practice, is duration of response of a little short of a year in this patient population. 

[01:00:51]

Phase Ib RedirectTT‑1
So obviously we’ve shown you data wherein we’ve combined these bispecifics with anti‑CD38s, but there is data wherein two bispecifics are being combined.  This is the RedirectTT study wherein teclistamab was combined with talquetamab in a very high‑risk patient population and by combining these two bispecifics, you’re seeing response rates north of 95% and this translates into really remarkable disease control in patients who have high‑risk disease.

[01:01:27]

Ongoing phase I/II trials with bispecific antibodies in R/R multiple myeloma
There’s a whole bunch of ongoing phase I and II trials with these bispecific antibodies.  Some of these are the newer ones.  So cevostamab targets FCRH5 and we will see what the long‑term data looks like. 

We also have other anti‑BCMA targeted agents which are in clinical development.  We have linvoseltamab, which hopefully will get approved by the end of the year; August is what it’s slated for, for FDA approval.  And then we have the AbbVie compound targeting BCMA as well. 

[01:02:13]

Management: infection prophylaxis and vaccinations
All right, so I think a couple of things when you talk about these bispecifics.  I think the overwhelming toxicity of these bispecifics is infections.  And I think when you saw the question, all of the answers were correct, but the biggest thing when you’re using a BCMA targeted bispecific antibody, what you’re causing is B‑cell aplasia.  So IVIG should be used and should be used in all patients, because you are getting rid of not just plasma cells but all B‑cells, so all your immunoglobulin‑producing cells.  And there’s enough data now to demonstrate that if you are actually repleting the IVIG in these patients, the risk of infection is significantly down. 

[01:02:56]

Now let’s revisit our question
Now let’s revisit that question where we had a whole splay of answers and hopefully we’re going to get this right. 

[01:03:04]

Post‑test 3
So if a patient is on a BCMA bispecific antibody, you would recommend all except: so growth factor support for patients with neutropenia; PJP prophylaxis for all patients; HSV prophylaxis for all patients; and IVIG administration only for life‑threatening infections.  So which is the not correct, OK?  That’s what we’re trying to get at.  And antibacterial prophylaxis only for patients at risk.  So go ahead and vote. 

Excellent.  I think you were all listening.  Most of you were listening to me, there’s some not.  But I think everybody who’s on an anti‑BCMA bispecific should be getting IVIG and it should not be saved only for life‑threatening infections.  But we can talk about it during the Q&A session as well.

[01:04:13]

CAR T‑cell therapies in R/R MM
Moving quickly now to CAR T‑cell therapies in the relapse/refractory space.

[01:04:18]

FDA approved autologous CAR T‑cell therapy for R/R MM
We have two CAR T‑cell products which are approved, idecabtagene vicleucel (or Abecma) and ciltacabtagene autoleucel (or cilta‑cel).  Both of them target BCMA.  There’s subtle differences between the two, and we’re not going to go into the details of those. 

[01:04:35]

KarMMa
You’ve all seen the data with KarMMa.  The KarMMa trial was in a very highly refractory patient population.  High overall response rates.

[01:04:45]

KarMMa: PFS
And in patients who actually achieve a complete response the PFS was close to two years. 

[01:04:50]

KarMMa: DoR
If you look at the data with – even the durability of response in patients was quite high. 

[01:04:59]

CARTITUDE‑1
Switching gears now to cilta‑cel, the overall response rate’s exceedingly high, close to 100%.

[01:05:06]

CARTITUDE‑1: progression‑free survival
And the PFS of this patient population was about 35 months median PFS.

[01:05:13]

Phase III data of approved CAR T‑cell therapies in R/R multiple myeloma
Now, we have got two trials done.  This is the KarMMa‑3 trial and the CARTITUDE‑4 trial.  Both of these trials have been done in slightly earlier patient populations and you saw both of them had ODAC meetings earlier this year.  And the good news is we have these now approved in earlier lines of treatment.  For Abecma (or ide‑cel) it’s between two and four lines of treatment.  And for cilta‑cel, based on CARTITUDE‑4, if you have relapsed and are lenalidomide refractory, you can actually access cilta‑cel.  So everything which works at the back end has been brought forward earlier on. 

[01:05:56]

KarMMa‑3: treatment response and final PFS analysis
This is the data with KarMMa‑3 which got the approval for ide‑cel.

[01:06:02]

CARTITUDE‑4: outcomes
And this is the data for CARTITUDE‑4, which again got the approval for len‑refractory patients at the time of first relapse.

[01:06:10]

Spectrum of clinical toxicities associated with CAR T‑cell therapy
If you look at the spectrum of toxicities, you know, with CAR T‑cells we have CRS and neurotoxicity, but there’s a whole bunch of other toxicities also seen.

[01:06:21]

CAR T‑cell therapy: acute toxicities
With CAR T‑cells, most of the acute toxicities are managed at a center.  You know, the CARs are being done at my center, we take care of the initial two weeks to a month of treatment.  I think the management delayed toxicity is the bigger issue wherein there’s a subset of patients who develop neutropenia, they could be predisposed to infections and those are things which have to be managed with the community oncologists as well. 

[01:06:51]

CAR T‑cell therapy: delayed toxicities
So these are the delayed toxicities that I’ve talked about.  The big ones are infections.  Most of these also, because CART T‑cells are sort of one and done, lasts for about six months and after six months most of the toxicities with CAR T‑cells are resolved. 

[01:07:11]

Selection of BCMA‑targeted agents
So now that we have so many anti‑BCMA‑targeted agents I think, you know, it’s a good news story, but it’s also a little bit of a challenge, because how do you pick and choose what kind of treatment?

[01:07:25]

Factors to consider when selecting therapies
And really there is no right answer out here and this is where I think shared decision making is a big part of what we do.  There are certain factors though, from a patient standpoint, which would clearly tell us which way to go.  For example, if a patient has significant renal failure, we’re not going to be able to give LDC chemotherapy.  Will I do CAR T‑cells?  Probably not.  If somebody is progressing very rapidly, you do not have the time, the 4‑6 weeks of making the CAR T‑cells and therefore you would much rather use the bispecific. 

[01:08:06]

Comparing BCMA options
There is a little bit of data on how we sequence some of these treatments and that kind of gives us a clue as to what we should be doing before the other and we’ll look at that very briefly.  But if you compare all of these anti‑BCMA targeted agents now, well, hopefully we are going to have bela‑maf on the market, we have the CAR T‑cells and we have the bispecifics and there’s subtle differences and there are certain advantages and disadvantages.  A lot of them are logistics, some of them are response related and some of them are toxicity related as well. 

[01:08:40]

Role of prior BCMA‑targeted therapies on CAR T‑cell therapy outcomes
Now, a couple of things to remember here when you’re picking – if you have the luxury of choosing whatever is best.  There is some data on role of prior BCMA targeted therapies on CAR T‑cell therapy outcomes.  If you see the data for patients getting CAR T‑cells if they’ve had a bispecific before, the outcomes are not that great.  That’s true for both ide‑cel as well as cilta‑cel.

[01:09:10]

Outcomes wit bispecific antibodies after prior BCMA‑directed therapy
If you’ve had a prior CAR T‑cell, though, the outcomes with the BCMA bispecific is not that bad.  So if you have the luxury of choosing one over the other, you know, most of us believe that I would preferentially used CAR T‑cells before the bispecific, if I was able to in my patient population.

[01:09:32]

BCMA immunotherapy treatment failure
There’s a lot of work which is being done on trying to identify BCMA immunotherapy treatment failure.  They could be inherently related to the tumor itself or the microenvironment, but in general, the BCMA antigen target is retained in the context of myeloma, so you can actually use some of these antibodies sequentially. 

[01:09:57]

Conclusions
So in conclusion, BCMA and other targets offer great promise.  We’re seeing amazing results.  T‑cell redirection with CAR T‑cells as well as bispecific antibodies are now moving even in frontline settings.  I think focusing on supportive care so that we get rid of the infectious toxicities is really going to be important and the future will be exploring some of the alternate dosing schedules, combinations and sequencing of all of these approaches. 

So with that, it is my great pleasure to introduce Craig Cole, who’s going to take us to the end of this discussion.  Craig, it’s all you.  Thank you.

[01:10:43]

Health Disparities in Multiple Myeloma
Introduction
Dr. Craig Emmitt Cole (Karmanos Cancer Institute): Thank you, Noopur, and thanks, Tom, for inviting me to talk about health disparities in multiple myeloma.

[01:10:51]

Faculty disclosures
There are my disclosures. 

[01:10:53]

Outline
So we’re going to talk about the differences between race and ethnicity with the incidence of this disease, some differences in the biology, risk and presentation.  Then I’ll talk about some of the disparities of myeloma care, clinical trials, and then talk about some solutions. 

[01:11:12]

Race and incidence of multiple myeloma
So race and incidence.

[01:11:15]

Incidence of multiple myeloma by race, ethnicity, and gender
So I think that hopefully a lot of people now know that myeloma in the United States, based on SEER data, is overexpressed in the African American population, is more common in men than in women, and we see that with African Americans.  But also, you know, we should recognize that this is a worldwide phenomenon; that it’s not only black United States that have twice the incidence multiple myeloma but that’s actually an event that we see around the world.  It was first described in Jamaica back in the 1960s, but you still see everywhere that there are blacks, there are – or people of African descent, there’s a higher incidence of this disease.

[01:12:03]

US multiple myeloma: incidence and mortality by race/ethnicity
In concordance with that, when you look at the incidence for African Americans, based on the SEER database, has been climbing over the past several years per 100,000.  And then the mirror to that is the incidence of mortality associated with myeloma being higher because of the higher incidence.  And thank goodness that has been falling over the past several years. 

[01:12:03]

Multiple myeloma in the United States: incidence and mortality by state
When you look at the incidence per state, you’ll see the differences of incidence and mortality and that is because – and I’ll show you towards the end of my talk that a lot of the difference between incidence and mortality of this disease is related to access.  That there are states that have high incidence of this disease that have low access to the wonderful therapies that Noopur and Tom had mentioned earlier, and states that have a higher incidence but very good access like New York where the mortality is not as high. 

[01:13:00]

Differences in multiple myeloma risk, biology, and presentation
Prevalence of MGUS by race and ethnicity
So when we look at the differences, you know, all myeloma begins with MGUS and why is there such a high incidence of myeloma in people of African descent is because of the high – is partially because of the high risk of MGUS.  That when you look at the National Health Nutrition Examination Survey of thousands of patients – of individuals, including a fair number of blacks, you’ll see that the incidence of MGUS is higher in blacks – significantly higher in blacks compared to whites at 3.7 compared to 2.3.  That it occurs about 10 years earlier.  And we have looked for years and years about why do we have this higher incidence of MGUS and myeloma in blacks and it’s still been elusive to us.  That it’s not related to tobacco or education, socioeconomic status or autoimmune disease or chemical exposure.  There’s some signal that increased BMI may be related, but it is something that is deeply genetic.  That even when you look at – and this was at ASH this year – at a small African country, Eswatini, that the incidence of MGUS was very high at 13.2% with the majority of those being light chains, very similar to what we see in the United States. 

[01:14:21]

Multiple myeloma is different in black patients
So myeloma is different in people of African descent.  That it occurs earlier in the same way that MGUS occurs earlier.  That black patients are a lot more likely to present with more anemia, hypercalcemia and renal failure, not so much of bone fractures, because people of African descent have a higher bone density than their Caucasian cohorts.  Black patients are more likely to have chromosome 14 translocation and abnormalities.  And including there was earlier a signal that (11;14) may be more common in people of African descent, and I’ll show you a study that that really needs some more investigation.  What has been shown in multiple studies is that blacks are less likely to have those high‑risk mutations such as deletions of chromosome 17 and amplifications and additions of chromosome 1. 

[01:15:11]

Comparison of mutational signatures of patients with MM of African and non‑African ancestry
There was a study that was at ASH that I really loved, I think I lingered at this poster for like a couple months, that looked at the mutational studies using whole‑genome sequencing between people of European dominance, African dominance and American dominance. 

[01:15:31]

Multiple myeloma in African and non‑African ancestry is biologically different
And they showed that tumor mutational burdens were higher in the African cluster than in the European cluster and that African Americans in this study had higher – had lower incidence of clock‑like mutational signatures as compared to their Caucasian counterparts.  And APOBEC activity was different in European as compared to their African American cohorts.  And you can see in the light blue box that the mutational burden was much higher in whites as compared to other ethnic and racial cohorts.  In this study, when it looked at (11;14) not so much that the African cohort was enriched with (11;14), so I think we need more investigation to see if that is true. 

The one thing that was true, and this is one of several studies that have shown that based on mutational signatures, that African American myeloma is biologically different in terms of genomic drivers and mutational signatures, so it is a different disease.

[01:16:42]

Disparities in myeloma care
Racial disparities in utilization of treatment modalities among patients with multiple myeloma
Looking at disparities of care, again looking at the SEER database, there was lower use of lenalidomide among blacks, lower use of bortezomib among Asian patients.  When you look at stem cell transplant and triplet induction of therapy, again black patients lagging behind white patients and actually Hispanic patients having a higher number of days before the start of bortezomib and lowest utilization of stem cell transplant.  And some people would say, well, that was a long time ago, but just at ASH this year, a electronic health record, a Flatiron study looked at utilization and found that for newly diagnosed patients that there were fewer black patients than white patients that had received FISH cytogenetic testing.  And again the same thing just recently proven, you know, electronic medical record, that there’s less doublet and triplet therapy utilized in African and black patients than in Caucasian patients. 

Again, there’s a longer time to start novel therapy for black patients over a six‑month period, where it took black patients and Hispanic patients six and four months compared to two months for white patients.  And although over the past several years there’s been improvement in the start of novel therapy, still black patients and Hispanic patients are behind the white patients, which again in showing how critical it is for adequate and effective therapy as upfront therapy for myeloma, the fact that this is not being given equally among the races and ethnicities is a problem, in that in the treatment initiation in a recent study again showing delayed in women and in black patients compared to white patients. 

[01:18:35]

Disparities in myeloma care: ASCT
With stem cell transplant, again, this has seen that white patients receive transplant more so than their black, Hispanic and Asian counterparts, and that one in seven – the racial disparities prevent one in seven potential transplants.  And again the utilization is, I would say, dismal for ethnicities and races compared to whites.  Why is that?  Well, there’s a lower likelihood of obtaining a stem cell transplant if you’re a black, Asian or Hispanic, older age, low socioeconomic, low – if you’re a resident in a metro area or little or no insurance.  All that is not necessary.  All these patients could receive some sort of transplants, but are unable to.  And it is probable that a lot of patient and physician bias play a role in the decision.  And I have seen with my own two eyes.  I receive second opinions of patients that were clearly stem cell transplant candidates, however, weren’t even offered stem cell transplant, wasn’t even discussed, because they had nonrelated comorbidities such as obesity or differences in their performance status. 

[01:19:55]

Underutilization of maintenance therapy and bone‑modifying agents
We’re looking at some of the mainstays of long‑term myeloma therapy, the backbones of long‑term myeloma therapy, maintenance therapy and bone‑modifying age.  Several studies show that black and Hispanics are less likely to receive bone‑modifying agents and maintenance therapy as compared to their white cohorts. 

[01:20:16]

Access, insurance and socioeconomic status is associated with outcomes in MM
And this is one of the slides that always kind of gets me.  That when you look at patients who are over the age of 65 – so, you know, a lot of the studies that Noopur and Tom showed that maybe they didn’t have great overall survival differences because our therapies do so well that patients live a long time.  Here are some overall survival statistics.  That if you are poor with this disease, your overall survival is lower; private insurance patients live longer than those with Medicare.  Patients that get their treatment at academic centers and with myeloma doctors live longer, overall survival differences.  And there was improved overall survival in patients that had higher income, younger age, fewer comorbidities and treatment at academic centers and the likelihood of death remained higher with those on Medicaid, no insurance, compared to those who are privately insured.  Again, those are survival differences seen with this disease that I would say are necessary.

[01:21:22]

Disparities in clinical trials
All things being equal… the VA myeloma study
All things being equal, when you are the VA which receives – where everyone receives the same therapy, that blacks – the overall cohort, that blacks actually did a bit better than whites when everyone is treated equally, more so in the under 65 than the over 65 area.  And again there was no racial disparity at the VA, based on race or ethnicity, for novel agents or stem cell transplant.   

[01:21:49]

But there are differences…Toxicity of immunomodulatory drugs
Again, there are differences.  You know, the IMiDs have been with us for, you know, about 15 years and it’s taken – and there was a study that was done in 2021 that showed that there are differences in the toxicities of the IMiDs and I have seen this with my own two eyes, that black patients have hyperpigmentation and darkening of the skin associated with the IMiDs.  It has taken 15 years for that to be reported and how many patients have discontinued therapy because they didn’t know it was happening, because it’s so poorly reported?

[01:22:27]

But there are differences… Outcomes with CAR T‑cell therapies by race and ethnicity
Even recently when you’re looking at CAR T therapy, that there are differences between the races and ethnicities.  That in using ide‑cel in 207 different patients with relapsed/refractory myeloma that black patients were more likely to develop CRS than the white or Hispanic cohorts.  Longer hospital stays, but thank goodness there are no differences in grade 3 CRS, ICANS or ICU admissions based on race. 

One thing that was also seen is that the overall response rate was a bit lower – or it was lower for Hispanic patients compared to black and white patients, but there was no racial or ethnic differences in PFS and OS. 

So again, we need more studies that enrich for ethnicities and races to really tease out some of these differences, so we can attack some of these differences and compensate for them and not just assume that everyone performs at the same level as white –has the same toxicities as white patients. 

[01:23:36]

But there are differences… phase III DETERMINATION trial race analysis
When you look at the DETERMINATION study, again a fantastic study that looked at VRd without transplant versus VRd with transplant.  This study, the big headline a few years ago was that there was a longer PFS with stem cell transplant overall, but no difference in overall survival.  This setting was fantastic because of the number of African Americans and blacks that were enrolled in it.  But one difference that it showed that was very interesting, very provocative, is that the median PFS was actually not reached for VRd without transplant than VRd with transplant and that the median PFS was longer for VRd versus VRd and transplant in black patients, especially those with a higher BMI. 

And when you look at some of this subgroup analysis, again the white patients being in purple, that most of them tended to be on the transplant arm was better, but you see that there’s some differences.  That does not mean, by any means, that you should not offer stem cell transplants to black patients.  What it means is that we need more studies in order to investigate this and this phenomenon, and could it be related to the Duffy null phenotype or those patients that have what we used to call the ‘neutropenia of ethnicity’ and does that play a role in some of the differences that we see. 

[01:25:13]

Importance of minority participation in clinical trials
Again, there are differences that we should be aware of bias, which is why it’s so important to have minority participation in clinical trials.  Because if clinical trials do not include minorities, and I think I’ve showed you there are differences in this disease and differences in drugs between the different ethnicities and races, that then there’s a question of whether or not the results of these studies are relevant across everyone involved. 

I always tell our fellows that when you are reading a new paper about a new therapy, you have to ask yourself, is the patient in front of me reflected in the study that I’m reading, that I’m basing this patient’s therapy to?  Because if they don’t match very well, you cannot rely on those results being identical for the patient in front of you, which is why we need diverse populations in our clinical trials. 

[01:26:08]

Relative differences in multiple myeloma incidence, mortality, and enrollment in clinical trials leading to FDA drug approval
Because when you look at the incidence – the number of the population of myeloma in the United States, about 20% are black.  However, only 5% of blacks are in the FDA registration trials of the drugs that we use every day to treat this disease. 

[01:26:27]

Availability of clinical trials: clustered around academic medical centers
Again, and if you remember some of the mortality map that I showed you, this is based on county, showing high mortality and minority representation versus – and with African Americans in orange, whites in gray and Asians in light blue and Hispanics in green.  And you can see through the southeast that there are huge swathes, huge areas of high myeloma mortality without the blue clinical trials.  While you have states like Florida where there are lots of clinical trials and low mortality, you have Appalachia where there’s lots of whites and very few clinical trials.  And you go out West and there are huge areas of Native Americans, Hispanics and whites where there are no clinical trials present.  And of course, where those clinical trials are, you have the newest therapies that again Tom and Noopur were talking about that have the fantastic response rates.  Without those clinical trials, those patients, again, when you look at overall survival and survival, you know, compared to academic versus community settings, this is part of the reason why and why I know, you know, spoiler alert, we need to decentralize our clinical trials to bring some of these clinical trials to those areas that have high myeloma mortality.

[01:27:56]

Race and ethnicity in clinical trials supporting multiple myeloma drug approvals (2003‑2017)
This study has been quoted several times.  When the FDA looked at their new drug applications between 2003 and 2017, that the median enrollment of black patients in those studies was only 4.5%.  It was better in the United States and here – at 10%.  And here are those studies that went up for FDA approval and you can see that it ranges from 18% to very, very low numbers.  And remember that darkening of the skin that it took 15 years to report, this is why, because the low numbers of blacks that were on those clinics trials, because again, there are differences in how these drugs perform in the way of efficacy and toxicity. 

[01:28:46]

Race and ethnicity in clinical trials supporting multiple myeloma drug approvals
Is this something – what about today?  Is the same thing true today?  Well, the FDA looked at 10,000 patients over 19 clinical trials that were submitted for FDA approval between 2006 and 2019.  Again, very poor enrollment of patients over the age of 85.  They get myeloma just like everybody else.  In fact, higher incidences of myeloma, but poorly enrolled in clinical trials.  Blacks and Hispanics all – you know, a lot – most of those single digits and for blacks, again low numbers compared to whites.  And again for Hispanics, you know, talking single‑digit percentages. 

Looking at FDA approval for CAR T therapies, again, you’re talking single digits for other races and ethnicities being involved in those clinical trials that went up for FDA approval. 

[01:29:44]

Solutions: clinical trial disparities
Low race trial enrollment has MM guideline consequences
And so does that have any consequence?  Yes.  Now, when you look at the IMWG guidelines, the International Myeloma Working Group, we just had our meeting in Madrid a few weeks ago, out of 59 publications that the IMWG used to come up with their recommendations, over five million patients, only 2.6 of those patients were – percent, were black.  And the authors of this paper were right on target in saying ‘Guidelines developed based on clinical trials that don’t reflect the racial composition of the population that we see every day may lead to inaccurate recommendations’.  And again, spoiler, we’re working on an abstract looking at other guidelines and finding very similar results of low representation of blacks in the studies used to create guidelines to treat patients every day. 

[01:30:48]

Solutions: clinical trial disparities
FDA initiative to increase racial and ethnic diversity in clinical trials
So what are the some of the solutions?  Well, thank goodness, a couple of years ago the FDA took the initiative to have a recommendation to sponsors that bring clinical trials to the FDA for their IND that they need a race and ethnicity diversity plan early in clinical development, and this is taken seriously by the FDA which is – and again now, thank goodness, when we look at clinical trials we always talk about how are we going to enroll diverse populations in our trial. 

[01:31:21]

FDA analysis of trial screen failures in myeloma
When you look – one way is that the FDA also looked at screen failures for myeloma clinical trials that went for submission and looked in trial ineligibility rates and saw that black patients and patients of other races had higher ineligibility rates compared to white patients, with that being for blacks, a failure to meet hematologic criteria, particularly neutrophil counts and treatment‑related criteria, which related on types of therapies that needed to have been given before it can go on those clinical trials.  And so – and the phase III DETERMINATION study again had, again, great enrollment of black patients, so that among the black patients, they had – 64.7% had that Duffy null phenotype.  They had lower neutrophil counts than their Caucasian counterparts.  So if you had a clinical trial that had a neutrophil count cutoff of 1.5 or 2 and which is, you know – and for the Duffy null phenotype it’s lower than that, you’re excluding patients based on the neutrophil counts they were born with, not because of neutrophil counts that will actually affect their therapy. 

[01:32:44]

Acceptance in clinical trial does not vary by race/ethnicity
So more recent clinical trials address this and take in account the Duffy null phenotype, which is an easily available test to test for to see if Duffy null patients can also be included in clinical trials. 

One thing I also hear repeatedly as well, black patients, Hispanic patients, Asian patients don’t want to be on clinical trials.  There’s no point in even asking them.  That is not true.  That is not true.  When you look at agreement rates participating in clinical trials, blacks, Hispanics and Asians actually have higher rates of agreement than their Caucasian counterparts.  The main reasons of non‑participation were choice, that their doctors may not have offered it to them, or lack of interest, their doctors weren’t excited about enrolling them on clinical trials, which is what we have to do.  And in a study that interviewed black myeloma patients, they were willing to participate in clinical trials regardless of prior experience.  So people say that, you know, black patients don’t want to be involved in clinical trials because of Tuskegee and Henrietta Lacks and if you address those issues and you gain your patient’s trust by being a really good doctor, those patients are willing to go on to clinical trials just as much as everybody else.

[01:34:01]

Solutions for diversity in multiple myeloma clinical trials
And we wrote a paper with Monique Hartley‑Brown earlier this year that talked about ways that we can improve diversity in clinical trials.

[01:34:11]

Recommendations for diversity in myeloma clinical trials
One is coming up with a diversity plan early in development of your clinical trial, expanding eligibility criteria that I have mentioned, and using some of the guidance documents that the FDA and the AACR have available.  Also, minimize the burden on clinical trial participants, decentralize those clinical trials, bring the clinical trials to the people instead of having your patient having to drive two hours for clinical trials.  Promote diversity among healthcare professionals and trial support staff and make implicit bias training mandatory, because again a lot of the problem doesn’t lie with patients not wanting to be in clinical trials, but based on doctors not offering the clinical trials to diverse populations. 

Get patient input from the start.  One fantastic thing that’s happened over the past several years is how sickle cell has had a phenomenal enrollment and FDA approval – of patients and FDA approval of drugs.  And that’s because they had patients involved in the drug development and clinical trial process and that was part of the key which brought those clinical trials to the community and had high, very high levels of enrollment.

[01:35:35]

Conclusions
So with equal delivery of care, patient survival of people of color may be equal with a suggestion that myeloma biology may favor people of African descent, but there has been a – and the minority race have had a less increase in population‑level survival.  We need appropriate representation of clinical trials to ensure these new drugs will work and we can identify toxicities that may be hidden in people of different ethnicities.  And I would say that socioeconomic is a significant risk for myeloma survival.

[01:36:13]

Quotation
And I hopefully have now imparted to you some information.  Now that you are aware, you cannot help but change and we can make a change and bring myeloma survival more equally and these fantastic drugs more equally across the country to our patients. 

[01:36:35]

Let’s answer a few final questions
And that’s all I have, but how about we answer a few final questions? 

[01:36:42]

Poll 4
So this is – one polling question is do you plan to make any changes in your clinical practice based on what you’ve learned in today’s program?  Yes, no or uncertain. 

[01:37:12]

Poll 5
And take a moment to enter one key change that you plan to make in your clinical practice based on today’s presentation.

[01:37:28]

Question and Answer Session
Dr. Martin: Craig and Noopur, both wonderful talks.  You know, we’re right at time, but maybe we could do a quick some rapid‑fire questions and see what you guys think.  So the first rapid‑fire question: quads and transplant for everybody who’s transplant‑eligible?  Noopur, Craig?  I take it it’s a yes and yes.

Dr. Cole: Definitely yes.

Dr. Raje: I’m a yes for transplant‑eligible and ineligible; 2024, quads for everybody.

Dr. Cole: I have to say I agree with that.

Dr. Martin: How about transplant‑ineligible?  Quads for everybody, or are you going still with triplets for a few or maybe doublets?

Dr. Raje: Quads for everybody.

Dr. Cole: Quads for everybody.

Dr. Martin: It’s really amazing how it’s really come full circle, right?  When we were trying to tease out what’s the best, this or that, I think it’s quads for everybody, which is great.

In the high risk, any reason to not use a transplant in the high‑risk patients if they’re transplant‑eligible?  If they were MRD negative, would you still take them to transplant if they’re high risk?

Dr. Raje: I would.  I only think, you know, that is an area of unmet medical need, Tom, the high‑risk patients.  So as of right now, we have transplant which seems to be doing better than something else, but as we move these immunotherapies earlier and if they are in the frontline setting, this is the patient population that I would very quickly use CAR T‑cells followed by bispecifics.

Dr. Cole: Yes, I think that, you know, we have clinical trials that are ongoing looking at, you know, transplant versus CAR T and I just can’t wait.  You know, it’s like Christmas Day.  I just can’t wait for that trial to show up, because that’s a question I ask myself all the time.  But, you know, I was happy to see that with some of the new CAR T data showing that those functional high‑risk patients do so well with having a CAR T, you know, closer to upfront.

Dr. Martin: Yes, and pretty amazing.  Noopur, for bela, any patient population, specific population that you’re thinking that’s going to be –  that’s the patient population for belantamab?

Dr. Raje: You know, very exciting data with bela‑maf and again a very easy drug to combine with.  I think if a patient has logistic issues, because with both the CARs and the bispecifics remember you have to do, even with the bispecifics the step‑up dosing is done at the main academic medical center.  The community is not yet geared to take care of it.  As we have, we have our first bispecific approved in the solid tumor world, so I think the oncologists are going to get used to using bispecifics, but until then, you know, bela‑maf is something, once it gets open to the US market, will be used.  I do think the dosing has to be adjusted and you have to do it less frequently, so that doing it every 8‑12 weeks is actually very convenient. 

The big thing though is I’m not so sure how early we will use bela‑maf because of the ocular toxicity, because it does impact your lifestyle, it does impact how you drive, how you read, so on and so forth.

Dr. Cole: I think that, you know, bela‑maf is going to really help, I think, a lot of those – you know, when I showed you that map of high myeloma mortality, you know, and not a lot of patients can get to the CAR T and the bispecific area – bispecific centers.  But if you have a mall that has an eye doctor, you can give bela‑maf, because all they have to do is take that slip into that eye doctor in the mall and you can pick up, you know, a T‑shirt or something and get that eye doctor to fill out that form and you can get a BCMA therapy in very rural areas and areas that have poor access to some of these resources.  And so I think that, you know, our poor patients are ones that have difficulty in getting to the centers, that I think this is really going to bring that, you know, high‑end therapy to patients that really need it.

Dr. Martin: I completely agree, and there’s less infections with bela‑maf, which I think is really interesting.  And as you guys know, the CD38 and the BCMA antibodies, there’s a lot of infections with them and, you know, a lot of the infectious prophylaxis is very similar.  Maybe the one difference in my mind is the IVIG.  Noopur, you said IVIG for everybody with bispecifics.  Completely agree.  What about with CD38s?  Do you do any IVIG with CD38s, or Craig?

Dr. Raje: I think I’ve started doing more of it, Tom, and we do go by – I think there’s a question in the chat box here about immunoglobulin levels.  Yes, we do look at IgG levels.  If they’re less than 400, I would certainly use IVIG.  With the BCMA ones, also, we tend to follow 400, but it’s almost easier to tell folks that you are going to be immunoglobulin deficient and just giving it to them is the right thing to do.

Dr. Cole: Yes, I’ve definitely – I’ve taken a look back at all the CD38 patients, you know, since I’ve been giving more IVIG and definitely my threshold – I mean, I check – you know, I check, guidelines in everyone, every time I see them and I kind of make – you know, I’ve been more likely to do that for my patients, because I think it mitigates a lot of those infectious risks.

[01:43:35]

Go online for more

Dr. Martin: Well, that was wonderful.  We’re five minutes over and thank you, everybody, for attending for tonight’s discussion and for staying over for our rapid‑fire questions.  Noopur, Craig, wonderful job.  That was awesome.  Everybody out there, you can go online for more CCO.  You can download the slides and you can even send in questions late, if you want, and somebody might answer them, we’ll see.  Have a nice night everyone.

Dr. Raje: Thank you.  Thanks.

Dr. Cole: Thank you.

Dr. Martin: And lastly, you can claim your credit.  Go to clinicaloptions.com/MyelomaTargetsLive2024 to access the online evaluation, do your evaluation and, boom, you get the credit.  Have a nice night.

[END OF TRANSCRIPT]