Cellectar Biosciences, Inc. (CLRB) Earnings Call Transcript

Good morning, and welcome, everyone, to Cellectar Biosciences KOL call. Today's conference is being recorded. At this time, I would like to turn the call over to Monique Kosse of Lifesci Advisors. Please go ahead.

Thank you, operator, and good morning, everyone. Thank you for participating in today's KOL call discussing the data presented earlier today at ASCO. Before we begin, I would like to remind everyone that comments and various remarks about future expectations, plans and prospects constitute forward-looking statements. Cellectar cautions that these forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially from those indicated. Cellectar encourages you to review the company's filings with the Securities and Exchange Commission, including, without limitation, the company's Form 10-K, which identifies specific factors that may cause actual results or events to differ materially from those described in the forward-looking statements. As a reminder, this conference call is being recorded and will be available for audio rebroadcast on Cellectar's website, www.cellectar.com. I would like to note that for some participants dialed in by phone and also viewing the presentation on the web, there may be a slight delay between the audio and video. For those listening and viewing by the webcast, the audio and video should be synced and you will not notice any delay. Finally, we would like to note the content of this conference call contains time-sensitive information that is accurate only as of the date of the live broadcast June 4, 2021. Except as required by law, Cellectar undertakes no obligation to revise or update any statements to reflect events or circumstances after the date of this conference call. With that, I would like to now turn the call over to Jim Caruso, President and CEO of Cellectar. Jim?

Good morning, everyone, and welcome to the Cellectar Biosciences WM ASCO poster and clinical data discussion. On behalf of the team, I thank you for participating in today's call. Joining me are members of the Cellectar Biosciences management team, Dr. John Friend, our Chief Medical Officer; and Jarrod Longcor, our Chief Business Officer. We are also very pleased to have key thought leader and the global lead investigator of our Pivotal Waldenstrom’s CLOVER-WaM study, Dr. Sikander Ailawadhi. Today, Dr. Ailawadhi will review clinical data from our poster presented at the 2021 American Society of Clinical Oncology Annual Meeting or ASCO, this in-depth data presented from the Phase IIA study further substantiates a compelling CLR 131 product profile for the treatment of relapsed/refractory Waldenstrom's. Following Dr. Ailawadhi review, Dr. John Friend will close with an overview of our WM Global pivotal study. After our prepared remarks, we will then open the call for a question-and-answer session. Before I turn the call over to Dr. Ailawadhi, please forward to Slide 3, and and let me provide a brief overview of how we constructed our CLR 131 franchise. Our objective is to establish multiple pathways to value creation in order to mitigate risk to identifying cost-efficient and higher probability of success, clinical development opportunities. CLR 131 is unique. And that it provides development pathways for both hematologic malignancies as well as solid tumors. One of these programs is Waldenstrom's. The data released today and to be discussed on this call is impressive, especially given a highly challenging patient population with limited approved treatment options. In terms of multiple myeloma, the data in highly refractory patients is also strong. Overall response rates in triple class refractory, quad, penta refractory and high-risk patients range from 40% to 62%, which provides optionality for future development considerations. For our adult hematology program, we have a clear registration pathway in WM. And in the ongoing Phase IIA cohort, we continue to enrich our highly refractory multiple myeloma patient data set to strengthen CLR-131's Compendia profile and to enhance registration pathway options. The Phase I head and neck study in collaboration with the University of Wisconsin Madison is part of a prestigious SPORE grant, which initiated patient enrollment in the back end of 2020. We are highly encouraged by the University's pace of patient enrollment through the first half of 2021. Our pediatric program represents potential for yet another accelerated regulatory pathway. As you can see, we are evaluating a variety of pediatric CNS tumors, high-grade gliomas, neuroblastomas and multiple pediatric soft tissue sarcomas. As you may recall, CLR 131 has demonstrated the capacity to cross the blood-brain barrier, which may make it particularly effective for the treatment of brain tumors and metastasis. CLR 131 has been granted 4 pediatric orphan drug designations and 4 rare pediatric drug designations, which under certain circumstances, makes the company eligible for pediatric vouchers. We look forward to providing future updates on all of our clinical programming. Now it is my great pleasure to turn the call over to Dr. Ailawadhi. Sikander, please go ahead.

Thanks a lot, Jim. I really appreciate this opportunity to share this exciting information with everybody on the call and look forward to our discussion. So with that, I'm actually calling in, so I'm going to request to go to Slide 5, which is where I'll briefly talk about an overview about Waldenstrom's. Now clinicians and investigators like myself who focus on this disease, we obviously see a lot of these cases, but in general, Waldenstrom's is an ultra-orphan disease with a global incidence of just about around 6,000-or-so patients per year. We have about 1,900-or-so newly diagnosed patients in the U.S. every year. As a result of the global aging population, the annual incidence actually has been growing at a rate of approximately 30% with the global prevalence as of 2019 of approximately 60,000 patients suffering from Waldenstrom's. The average age for Waldenstrom’s diagnosis is about 70 years, but as we mentioned, with the aging population, the numbers do keep increasing the prevalence. Waldenstrom’s macroglobulinemia, also for the sake of simplicity you referred to as WM is an incurable disease and inevitably, all patients' disease will progress. It is also characterized by serum monoclonal immunoglobulin M or IgM and a clonal lymphoplasmacytic cell infiltrating the bone marrow. It is basically this clonal lymphoplasmacytic cell, which produces the IgM protein, which is the marker of the disease. Although WM shares some characteristics of both multiple myeloma and non-Hodgkin's lymphoma, researchers over the past decade-or-so have uncovered many unique features that are shifting the treatment paradigm for WM. Currently, first-line therapy is rituximab combinations, also called chemoimmunotherapy, which results in a median 3.5 years of progression-free survival or PFS. Now rituximab administered as a 1-2 hour IV infusion once weekly for anywhere from 4 to 8 weeks is the way it is typically used by itself. In second line, ibrutinib, an oral medication is given daily until progression or serious adverse events and is the only approved drug for monotherapy and actually also in combination with rituximab and achieves a median progression-free survival of 2 years in about close to 70% of those patients eligible for ibrutinib. I should also point that ibrutinib is approved for the use in Waldenstrom, irrespective of line of therapy, so can be used as a frontline treatment as well, but the characteristics of the PFS response rate, et cetera, remain quite similar to the later line therapy data. But despite all of this, despite this being the only FDA approved treatment, there are a number of key challenges with ibrutinib, including its lack of efficacy in certain Waldenstrom genotypes. Some side effects, which can frequently be serious, but importantly, are very chronic and can be affecting the patient's quality of life. And the fact that patients relapsed shortly upon discontinuation, resulting in no meaningful treatment-free remission. And actually to that list, I can also add the fact that all the ibrutinib based clinical trials in Waldenstrom have shown a nearly 0% complete response rate. So we know that while ibrutinib will provide some disease stabilization and responses, it is more of an inhibitor in the sense that it does not eliminate the disease and does not give deep responses. Thus, the natural history of the disease may not be very meaningfully changed in the absence or after stopping the ibrutinib. And finally, many patients are not eligible to receive ibrutinib due to concomitant diseases or comorbidities, which can sometimes overlap with the side effect profile of ibrutinib. Also, patients discontinue its use early in treatment due to adverse events, such as ventricular arrhythmias can happen, atrial fibrillation or a risk of bleeding or bruising, but I also mentioned the chronic side effects that can be low-grade, but can be much more of an impact on quality of life like diarrhea, fatigue, headaches, rash, et cetera. So there clearly exists a need for a new treatment option, a different mechanism of action in Waldenstrom that provides treatment-free intervals and improves the safety and plus, like I said, meaningfully changes the natural history of disease by providing deeper and meaningful responses with limited treatment duration. And that option could very well be CLR 131. Slide 6, please. So I'll talk a little bit about Waldenstrom and the frequently targeted pathways. We mentioned that in the past decade saw a lot of has been understood about the genomics of Waldenstrom. So the Waldenstrom molecular landscape has been transformed, thanks to the recent research linking Waldenstrom to two frequently mutated genes called MYD88 and it is also called MYD88 or has been called MYD88, I'm used to calling it MYD88 and the CXCR4. The MYD88 L265P mutation has been identified to be present in anywhere from 67% to 90%, I would say closer to 90% of patients with Waldenstrom and often aligns with extent of bone marrow involvement. Mutation of the MYD88 results in a higher level of activation of the Bruton's tyrosine kinase, or BTK, which stimulates higher proliferation compared to unmutated cells. Also for CXCR4 with over 40 different mutations in the coatings region affecting up to 40% of the patients. The key mutations are either frameshift mutations or nonsense mutations and result in providing a survival signal to the cancer cells. So the CXCR4 mutations have been shown to be associated with higher bone marrow involvement, delayed response, lower rates of deep responses and shorter treatment-free survival. Waldenstrom’s patients who are MYD88 wild-type lack mutations in the MYD88 and have a disease course that is marked by increased risk of disease transformation and shorter overall survival. Moreover, and as expected, these patients show little activity to BTK inhibitors, such as ibrutinib. So what we're thinking is that the MYD88 wild-type where the MYD88 mutation is not present in those 10% to 30-ish percent of patients, ibrutinib may provide much less benefit or nearly none. Patients that are MYD88 mutated and CXCR4 mutated have lower responses in those with the nonsense mutation platform worse than those with the frameshift mutations. Slide 7, please. So in Waldenstrom's, there are some treatment prognostic indicators that we use. In 2003, Bob Kyle from Mayo define a series of prognostic indicators for determining when a patient with Waldenstrom should be treated. These indicators, which are shown on the slide here, continue to be utilized today, both in clinical practice and in clinical trials. The choice of therapy for Waldenstrom patients is guided by the patient's clinical profile, taking into account their medical history, demographics, clinical signs and symptoms of the disease, the genomic features and also drug availability. In general, physicians will initiate treatment upon progression of disease as evidenced by increasing the IgM or signs or symptoms associated with Waldenstrom's, such as lymphadenopathy, anemia or in rare cases, hyperviscosity syndrome. Most treatment guidelines recommend first-line therapy with alkylators like bendamustine, cyclophosphamide and/or proteasome inhibitors like bortezomib, carfilzomib, both in combination with rituximab, but also the availability of BTK inhibitors like ibrutinib in combination with rituximab. Many patients inevitably experienced relapse after this initial therapy and require further treatment. Second-line therapy may include agents of a different class of drugs as monotherapy or in combination. So frequently, you can imagine if something was used in the first-line that would not come back in the second line -- depending on chemoimmunotherapy, protease inhibitors, BTK inhibitors, et cetera. And we would go back and forth. Slide 8, please. So as we mentioned, with all of this data so far, Waldenstrom does clearly have an unmet medical need. There remains significant unmet need in the treatment because as demonstrated in the graphs on this slide, patients with a dual wild-type genotype for MYD88 and CXCR4 performed the worst when a median -- with a median time to progression of approximately just about 4 months. This clearly demonstrates the need for a new treatment that works across all genotypes, whether that means second line or later or beyond. Additionally, when the patients are stratified based upon risk profile, it has again seen that there is clear need for new therapies that can treat high-risk patients because this is where we mentioned the median time to progression of 1.9 years and intermediate risk patients. Beyond these, there is also a need for treatments that provide patients with a meaningful period of treatment-free survival or remission, improved adverse event profile and therapies that have the potential to result in complete responses. So as I've kind of summarized with these few sentences that we're looking for mode of action where we can provide deep meaningful responses to patients, treatment-free intervals and treatments that can overcome these genomic profile nuances so that we have currently, certain drugs that work on certain of these subgroups, but hopefully, we are coming to the point that we have treatment options that can overcome these subgroup types. Slide 9, please. So talking now more about CLR 131 so unlike other treatments, CLR 131 is a targeted treatment, taking advantage of the hypermetabolic activity of cancer cells, CLR 131 binds to specialized regions on the cell surface that allow it's to enter and be deposited next to the nucleus. In the case of CLR 131, this allows the active part of the drug, the radioactive iodine-131 to more efficiently create DNA brakes and kill the tumor cells. Unlike BTK inhibitors or some other therapies, this means that CLR 131 is disease-modifying as defined by tumor cell lysis rather than just slowing the tumor proliferation. So in other words, I'd said more of an eliminator rather than just an inhibitor. This results in patients experiencing extended periods of treatment-free remission as the number of Waldenstrom cells have been reduced or, in some cases, even eliminated. Furthermore, the mechanism of action of CLR 131 is independent of the genotypes we discussed in the previous slide, meaning that CLR 131 has the potential to work in all genotype subgroups. Finally, CLR 131 has demonstrated the ability to cross the blood-brain barrier, targeting both primary tumor sites as well as metastatic tissue, including micrometastases. The top image on this slide is taken from a 13-year-old patient with metastatic ependymoma, who was enrolled and dosed with CLR 131 in the ongoing pediatric clinical study. And the arrows clearly demonstrate the selective uptake of CLR 131 in tumors compared to the normal brains, [ brain tumor ]. Similarly, in an old patient with non-small cell lung cancer, the selective uptake of CLR 131 in the lung based tumor is highlighted by the yellow arrow. Next slide, please. This slide talks about the CLR 131 Phase IIB -- Phase II B-cell malignancies Waldenstrom’s study design. The 6 patients presented in the poster were from a Phase II dose-finding study enrolled in the study, which enrolled multiple myeloma and various non-Hodgkin's lymphoma subtypes, including Waldenstrom. The overall study schema and design is presented here. In general, Waldenstrom’s patients were required to have measurable disease by IgM or defined extramedullary disease, received at least 1 prior therapy or were ineligible to receive standard therapy and required new treatment to be enrolled. Patients received up to 4 20-minute infusions of CLR 131 over 180-day period. The objectives of this study are to evaluate the safety and efficacy of CLR 131, including clinical benefit rate, overall response rate, PFS or progression-free survival and duration of response. Next slide, please. Slide 11 is showing our CLR 131 Waldenstrom patient baseline characteristics. The demographics for the 6 highly refractory Waldenstrom patients enrolled are presented here in this slide. The median age was 69 years and had received a median of 2 prior lines of therapy. The majority of patients were also high-risk with 5 of the 6 being refractory to rituximab combinations and all 6 patients either refractory to ibrutinib or were ineligible for treatment with ibrutinib. Only 1 of the 6 patients had responded to their prior line of therapy. So you can imagine while we're talking about a median 2 lines of prior therapy, we are talking about a highly refractory group of patients. One patient was followed by 5 extramedullary manifestations of this disease with the remaining patients being followed by IgM. Patients had a median bone marrow involvement of 65%, so a high tumor burden. And for those tracked by IgM, the median IgM concentration was nearly 4,000 milligram per deciliter, again, meaning that there was high disease burden and significant disease presence. Next slide, please. Slide 12 talks about CLR 131 Phase II Waldenstrom best response by patient for these patients we are talking about, the 6 of them. To date, in this highly refractory mixed genotype population, CLR 131 has achieved a 100% overall response rate with an 83.3% major response rate and a 16.7% complete response rate. Now focusing on the MYD88 wild type patients, of which there were 3 highlighted in green, the major response rate was 100% including the complete response rate patient represented by the bar at the bottom of the figure. Importantly, patients with MYD88 mutations and CXCR4 mutations or whom had not been genotyped, also responded well to treatment, with 2 achieving a major response and a final patient still under observation and continuing to see further reductions in IgM level. So I want to take a minute again to go back to this data, which, for me, as a Waldenstrom treating physician, I mean, we get excited when we shared this data with patients when we talk to them about the clinical trial, we're talking about an 100% overall response rate and a nearly 17% complete response rate and about 83% major response rates. So these numbers are very exciting to me, and I can say that also to patients. Next slide, please. This is talking about the kinetics of the response. The CLR 131 Phase II Waldenstrom, rapid reduction in the IgM. The median IgM reduction for all patients was to 74% with the median time to initial response being 22 days from the initial infusion, again, a fast early response. The average IgM reduction in the MYD88 wild type patients, including the 2 with dual MYD88 and CXCR4 wild-type was an impressive 75%. In patients that were refractory to at least 2 prior treatments, the IgM reduction was 72%. Again, time to major response was approximately 6 weeks, so relatively short. Next slide, please. This slide is talking about the CLR 131 Phase II Waldenstrom PFS or progression-free survival. On Slide 14, the PFS of -- as we say, is presented and the median PFS for both the MYD88 wild-type patients as well as the high-risk subgroup of patients was not reached after 18 months. This is highly relevant as researchers of Dana-Farber reported a PFS of approximately 4 months in MYD88 wild-type patients treated with ibrutinib. For patients treated with CLR 131 that were refractory to at least 2 drugs, the median PFS was 10 months. Next slide, please. As discussed previously, the median time to initial response was only 22 days after the first infusion and the median time to major response as defined by at least a 50% reduction in IgM was 44 days. The treatment-free remission is the time from the last CLR 131 infusion to progression of disease, death or initiation of new treatment, and the median treatment-free remission is 1.1 year and ongoing. The median duration of response has not been reached with 100% of the MYD88 wild-type and high-risk patients exceeding 8.5 months. Next slide, please. Over here, we talk about the safety and the treatment-emergent adverse events. Now as expected, the most frequently reported treatment-emergent adverse event are cytopenias, in particular, thrombocytopenia and neutropenia. And I should point out that this profile is something we've presented before in the clinical trials or previous presentations from the study. So to me, the important thing is that there is no other side effect that is emerging and something that is expected, and we are aware of, so we can plan and kind of prepare for it and also manage the patient appropriately. Irrespective of the type of the cytopenia, they were very predictable, as I mentioned, showing consistent timing to patients starting to experience cytopenias, timing to the [indiscernible] and the recovery. Similar to cytopenias observed in other heme diseases, they were considered manageable in the patients with Waldenstrom with some patients receiving either growth factor support or platelet transfusions. Importantly, CLR 131 has not experienced any significant off-target effects like cardiotoxicity, changes in liver enzymes, renal or neurological issues, keratopathy, peripheral neuropathy, et cetera. And these are very important to keep in mind because, again, the side effect profile, these other factors that I'm mentioning, they are frequently issues for which either patients have to be taken off-treatment from other agents or cannot be started on treatment because they have these ongoing symptoms from comorbidities. Next slide, please. So in conclusion, as presented today, CLR 131 represents a unique and differentiated mechanism of action that appears to provide a meaningful benefit to all patients with Waldenstrom. This includes patients from all genotypes, risk profiles and multi drug refractory patients. Compared to ibrutinib, which showed a major response rate of 71% in patients who are -- who were single drug refractory, only rituximab and it showed 0% for dual wild-type patients as monotherapy. CLR 131 showed an 83.3% major response rate in rituximab refractory patients, a 100% major response rate in dual wild-type patients and an 83.3% response rate in multidrug refractory patients. Other classes of drugs, including BTK inhibitors, have been tested as a treatment in naive or second-line patients and had responses ranging from 0% to 83%. CLR 131 demonstrated a 74% IgM reduction in a more refractory patient population with a robust major response rate of about 83%. Importantly, the median duration of response treatment-free survival, PFS and OS have not been reached, all of which has been achieved with up to 4 infusions of approximately 20 minutes over 180 days. So in my mind, extremely exciting data. And with that, I would like to turn it over to John Friend, the Chief Medical Officer at Cellectar.

Thank you, Dr. Ailawadhi. The study schema for the registrational trial is presented here on Slide 19. We launched the study, CLOVER-WaM, a global open-label single-arm pivotal study, evaluating the efficacy and safety of CLR 131 in 50 Waldenstrom patients who have received at least 2 previous lines of therapy, including those patients who have failed or had a suboptimal response to ibrutinib or other Bruton's tyrosine kinase inhibitors or BTKi. Patients will receive 2 cycles of CLR 131 with cycle 1 consisting of a 20-minute infusion on day 1 and day 15, followed by cycle 2, consisting of another 20-minute infusion on day 57 and 71. The primary endpoint of the study is major response rates as defined by a 50% reduction in IgM from baseline with key secondary endpoints being treatment-free survival, duration of response and overall response, again, which is defined by a minor response or better. As you can imagine, based on the data presented today by Dr. Ailawadhi, we will seek to enroll similar patients as presented here, and our expectation is that they will respond in a similar manner based on the mechanism of action and mechanism of delivery. In addition to the patients with every potential genotype being eligible for the study and because of CLR-131's unique ability to cross the blood-brain barrier, we also look to include patients with CNS manifestations of Waldenstrom, also known as Bing–Neel syndrome. Slide 20. CLR 131 is our lead phospholipid drug conjugate, or PDC, iodine-131 is covalently bound to the cancer targeting moiety, known as a PLE or phospholipid ether. The PLE is a long-chain fatty acid [indiscernible] that targets highly abundant and stabilized micro domain present on cancer cell membrane called lipid rafts. We know that these domains harbor various receptors, including FGFR3, which is a tyrosine kinase receptor. The figures on the right demonstrate a very nice overlap of lipid rafts, seen in green and FGFR3 present in red. FGFR3 is overexpressed in 100% of Waldenstrom cells, a 50% of multiple myeloma cells and 30% of other non-Hodgkin's lymphoma cells. This expression closely mimics the clinical data we've observed to date with overall response rates of 100% in Waldenstrom, between 40% and 62% response rate in refractory multiple myeloma and 30% in refractory other NHL populations, including DLBCL. The patients presented here represent some of the most challenging WM patients to be evaluated in a clinical trial setting. Given that CLR 131 demonstrated 100% overall response rate and 83.3% major response rate and meaningful treatment-free remission and duration of response. We are highly encouraged. When comparing this to other data sets, CLR 131 is outperforming first and second-generation BTKi and BCL-2 inhibitors, like venetoclax, despite being evaluated in later line and more refractory patient population. Additionally, in comparison to third-generation BTKis, for example, LOXO-305, CLR 131 outperforms this agent as well. LOXO-305 showed in a recent publication that in 19 Waldenstrom patients, they've achieved a major response rate of 47%. And in those patients that had received a BTKI in the past, this major response rate actually dropped to 38%. As you've heard Dr. Ailawadhi state, CLR 131 was effective across all genotypes, including patients with MYD88 wild type. BTKis, in general, are not used by many Waldenstrom treating physicians because of their poor response rates. In the ibrutinib and zanubrutinib monotherapy clinical studies, overall response rates of 0% and 11% were observed in this genotype. Unlike other therapies in the space, CLR 131 monotherapy has the potential to be the first approved disease-modifying therapeutic for Waldenstrom. With a patient-friendly dosing paradigm of 4 20-minute infusions over approximately 71 days and then no longer requiring therapy for their disease or better said an extended treatment-free remission in excess of now 1 year, are several key drivers in our novel and attractive target product profile. The safety profile, again, reflects the targeted delivery of CLR 131 to cancer cells that coalesce in the bone marrow. As expected, transitory and highly reproducible cytopenias are observed without observing those off-target effects that Dr. Ailawadhi had mentioned before, including liver, kidney and cardiac toxicity. The ongoing pivotal trial, again, was launched in December, and we are looking forward to sharing this data in mid-2022. I will now turn the call over to the operator to take questions.

[Operator Instructions] Our first question is from Kevin DeGeeter with Oppenheimer.

Thank you, Dr. Ailawadhi, for actually a very nice presentation. I guess my first question is as follows. Is -- when you think about your second to third line, Waldenstrom's patients, and what therapy is appropriate. Is it really sort of genotype that drives your decision, with a lot of discussion of genotype here today? Or is it still primarily that stratification into low intermediate and high-risk that it was most informative as to driving or informing what treatment is appropriate for the patient?

Kevin, thanks a lot for that question. And you're probably hitting the [Audio Gap] with that question because -- so if it's okay, rather than directly getting to how we select the treatment, I'll just bring up a certain nuance that we have to keep in mind. At the moment, when Waldenstrom is diagnosed, right from get-go, the MYD88 is tested very frequently, even in the community, right from get-go. The CXCR4 is not tested as frequently. If you go to Dana-Farber, you got to [indiscernible], you go to MD Anderson, both the tests will be done right from get-go. We don't keep repeating them, but that becomes a very important part and parcel of the patients kind of diagnoses. With that in mind, one of the things to keep -- consider is that while these genomic tests are done, we don't have a very standardized way of either running the test or evaluating the test. And let's say it goes to LabCorp or whoever, and the report comes saying, the patient has MYD88 positive, so that is very supportive of their diagnosis of Waldenstrom. As I said, CXCR4 in the community is not yet done. So hypothetically, we are putting patients on treatment, let's say, with ibrutinib, let's say, with rituximab, whatever, where they may be CXCR4 mutated, they may not eventually derive benefit or they may have been tested for MYD88, but the testing technique may be kind of subpar. And now there is a MYD88 wild-type patient who's getting that treatment because the testing was not appropriately done. So with that in mind, yes, by all means, we do test all academic centers would test. And while it is not a given that everybody who is MYD88 wild-type or MYD88 or CXCR4 mutated, well, they should never ever get X, Y or Z drug, but those algorithms exist. And believe it or not, patients are the ones who actually come in armed with this information saying, "hey, I've tested MYD88 or I've been told I'm MYD88 wild-type, and my doctors told me about a group, why should I get it?" And frankly, our answer to them is well, you're right, you're best likely to respond to the treatment, but at some point, we run out of treatment options. I have maybe 5 or 6 clinical trials open for Waldenstrom, but frankly, majority of those 1,900 newly diagnosed patients we talk about, they don't frequently get access to all those trials. So that's where the importance comes. That yes, we should test these genomics. They should inform our decisions. They are not 100%, but they are very, very informative if they're done right. And that same information exists for second line, third line and [ so on ].

That's extremely helpful. And then I think as we look at this data, there would seem to be an argument for use of 131 prior to BTK, particularly in the double wild types, but kind of -- and perhaps other populations as well. Can you just talk to us a little bit how you think about sequencing therapies? And I guess sort of informing that. Do the majority of your patients who are treated on the second line, are they also sort of treated in third line. How do we think about sequencing here? Because if you have better genotype coverage and the opportunity for deeper response, if it seems that there's an opportunity to go into an earlier population and 1 being evaluated and the CLOVER-WaM study.

Sure. So again, excellent question, and you're hitting on the process of how drug development is frankly done, right? We started a population where we think that we might get the biggest benefit or the options are more limited, but if we do get that clear signal, which, in this case, we are getting, it makes perfect sense to try and bring it sooner to try and do something earlier lines of therapy. Now I cannot say that everybody who wakes up with the diagnose of Waldenstrom frontline therapy should get drug A or drug B or drug Z. That's where the kind of the art of treating the patient or tailoring the treatment to the right patient comes in. But if I was to look at an option like CLR 131, well, we're talking about a patient population that's a median age of 68 years, right? So as patients grow older, bone marrow reserves may keep decreasing, I would rather use a treatment where I can get a fixed duration of therapy early on when the marrow may be able to -- may be in a healthier state and get a predictable side effect profile and get a response and move on, that doesn't mean that everybody frontline should get this treatment, but I would seriously think that especially in patients who have those -- the MYD88 wild-type, the CXCR4 mutated, well, I really don't need to waste their time and their body and their health with a drug like ibrutinib because I know the benefit is going to be very limited. Will there be an isolated case over there, which may derive benefit, yes, but do I need to plan my treatment for that isolated situation, probably not. I would rather go with something that is a more definitive treatment. And frankly, something that I've brought up a few times now on the slide when I was presenting, was that the frustrating part of treating Waldenstrom is that we don't get a deep response in general. So we -- you have to keep the patient on treatment. We haven't talked about that, but throwing the fact that even with an insurance setup, the patient is paying about $1,000 out of pocket every month with Medicare coverage. So that's where we get stuck with patients. I mean those patients which were ineligible, at least one of them was one who just could not afford the drug. And this is despite insurance. I mean, as a doctor, what am I supposed to do. And if I was to draw some comparison from, let's say, the CLL world, when we talk to patients about fixed duration versus indefinite therapy, the patients undoubtedly and overwhelmingly favor fixed duration therapy because that's what they -- is meaningful to them, and that's what's just much more conducive.

No, that's extremely helpful. And then just lastly for me, then I'll get back into the queue. With regard to, I guess, particularly the MYD wild-type patients. Among these 6 patients reported today. Any notable clinical features or patient features that you think may also contribute to what are -- appear to be unusually strong responses? Or is it -- it was really the only variable you identify the treatment here, 131?

So I think, Kevin, with a small number of patients, it is very hard to come up with a marker. And I'm assuming you're getting to the point of: a, can we identify who might benefit from this more and then what is the prevalence of that marker in the general population for Waldenstrom’s just to kind of get an idea of, hey, who could this drug benefit? If that's the way of thinking about it, what I've seen in treating all these patients, and I've had a lot of experience with CLR, especially in Waldenstrom, I have seen benefit across age groups across whether it is -- so I've had patients in their 50s. I've had patients in their 70s with variable bone marrow involvement, and you see a big disease burden. We've also seen benefit of patients who were IgM followed or who had just tumors to follow like a lymphoma, traditional lymphoma because Waldenstrom can do that. And on top of that, now we are saying that across genomic subtypes, there was benefit. So within this group of patients that is presented here and just with Waldenstrom patients that are treated with CLR 131, we've seen benefit across clinical, genomic, demographics subgroups. So I don't really think that there is a marker of response. And in fact, in my mind, that is an advantage or that's the way I like to have rather than I know the whole field in oncology is shifting towards that personalized medicine. But frankly, if we talk about Waldenstrom, it's to our advantage and to our benefit to patients that we may have a drug which could benefit patients across different subgroups because if we start breaking down the Waldenstrom patients only saying, well, this is the only group that's going to benefit, or that's the only group, we're talking about very small numbers because it's an ultra-rare disease.

Our next question is from Jonathan Aschoff with ROTH Capital Partners.

Dr. Ailawadhi. I was wondering, how broadly do you think CLR 131 will actually be utilized commercially outside LPL/WM, if approved?

You said outside of WM/LPL?

Yes.

So I guess it depends absolutely on what the indication is. I mean if I guess the way I...

Specific model for myeloma ?

Specific model. Okay. Good to know. So again, I've treated a lot of patients with myeloma with CLR 131. I think how it would be utilized would be absolutely dependent on how the approval comes. The drug ever gets approved, where it gets approved, in what indication and in what line of therapy. So I think that would drive it. The way I can probably answer it is, if you're thinking about the logistics of using CLR 131 with radioisotope, who would use it, who would not use it. So think about it this way that we have patients with multiple myeloma, where we, let's say, the patient is progressing, and we have to give them BDT pace, [ DSAT ], et cetera, which is a hospital-based treatment, but for that matter, we transplant these patients where they are supposed to go to the hospital, get [indiscernible], et cetera. So I think with myeloma, we are a little bit more attuned to treating the patient in the hospital or in an institution setting for different regimens or options. So I would think if the drug is available, we will figure out the logistics of giving it because those logistics exist, especially in a disease like myeloma, but I would say that eventually, how it gets used, will have to depend a lot on how it comes to market or what the [ labor ] thinks.

Well do you believe that it has already made a decent case for itself in multiple drug-resistant myeloma?

So frankly, I -- again, we're, at the moment, limiting ourselves to this poster in this presentation. And I would actually partly defer to the Cellectar team just to see how they want to -- how much they would like to discuss outside of Waldenstrom, outside of the data being presented. But all I can say is that I have presented data at ASH for multiple myeloma with CLR. This was from previous presentations in 2019. And before that posters, I have seen several responses in highly refractory, multidrug resistant, multiple myeloma. But beyond that, I don't think I want to make a kind of a statement beyond that. There is data that we presented, and we've seen impressive responses.

Yes. Thank you, Sikander, and Jonathan, thanks for that question. It's a fair question. And I'm in agreement with Sikander. We want to stay focused on WM. But having said that, just as an aside, we continue: one, we're obviously very bullish on later line treatment of multiple myeloma with CLR 131. The data, to your point, has been very impressive even in quad, penta refractory and triple class refractory, quite frankly, and beyond. So I think it's fair to say that we continue to enrich that patient population. So we have an ongoing Phase II, I guess, a portion of it, in which we continue to target and enroll highly refractory multiple myeloma patients, and so we continue to enrich that data set to maintain optionality relative to our clinical development or registration pathway plays as well as, as you mentioned, upon approval in WM with a very robust data set in multiple myeloma. Does that allow for potential Compendia listing and third-party reimbursement which I think is also on the table and fair.