Iopofosine I-131 treatment in late line patients with relapsed/refractory multiple myeloma post anti-BCMA immunotherapy

doi:10.21203/rs.3.rs-1751276/v1

Over the past decade, significant improvements in survival outcomes have been experienced by multiple myeloma (MM) patients. However, MM remains an incurable disease and patients with triple-class refractory MM have limited treatment options and a dismal prognosis. Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) has transformed the treatment algorithm of relapsed/refractory MM (RRMM), with high overall response rates. Nevertheless, a significant proportion of patients ultimately relapse despite achieving deep remission and show poor outcomes with subsequent treatment post anti-BCMA immunotherapies.¹ Iopofosine I-131 (iopofosine) is a first-in-class phospholipid ether radio-conjugate that targets lipid raft microdomains on tumor cells and is internalized. Here we present seven cases of triple class refractory MM patients that relapsed or were refractory to anti-BCMA immunotherapy and treated with iopofosine plus low dose dexamethasone (LoDEX). Patient received a single fractionated cycle of 30mCi/m² of iopofosine (15 mg/m² dosed day 1 and day 15) and received LoDEX (40 mg/week for 12 weeks) with an optional second cycle of iopofosine approximately 60 days later. Six of the seven patients achieved the minimum required total administered dose of 60 millicuries (mCi) to be in the evaluable population and 50% achieved a partial response (PR) or better.

MM is the second most common hematologic malignancy and accounts for 10% of all hematologic cancers². The disease is characterized by the uncontrolled expansion of malignant plasma cells (PCs) in the bone marrow (BM) resulting in aberrantly high levels of monoclonal immunoglobulins that can be detected in the blood and/or urine. Although effective treatments, such as proteasome inhibitors (PI), immunomodulatory agents (IMiDs), monoclonal antibodies, and autologous hematopoietic stem cell transplantation (ASCT), has improved patient outcomes with improved response rates and progression free survival^2–5, the prognosis for patients with multi drug-class refractory MM remains poor with extremely low overall survival^6,7. BCMA, a transmembrane glycoprotein in the tumor necrosis factor receptor superfamily 17 (TNFRSF17) has recently been recognized as an important therapeutic target as a result of high expression on plasma cells (PC). BCMA antigen can be effectively targeted via CAR-T cells. Recent studies demonstrate significant clinical responses in RRMM patients despite having failed multiple prior treatments (including PI and IMiDs). Two BMCA directed commercially available CAR-T products have been approved and their use is expected to grow exponentially. Moreover, the first approved anti-BCMA antibody–drug conjugate also has shown significant clinical responses in patients who failed at least three prior lines of therapy, including an anti-CD38 antibody, a PI, and an IMiD. Other promising anti-BCMA-based immunotherapeutic macromolecules including bispecific T-cell engagers, bispecific molecules, bispecific or trispecific antibodies, as well as improved forms of next generation CAR T cells, also demonstrate high anti-MM activity in preclinical and even early clinical studies.^8–11 Despite the success noted in demonstrating anti-MM activities of these BCMA-targeting agents, disappointingly none are curative. There are no approved therapeutics for the growing pool of post BCMA-treatment patients, a group that is increasingly recognized to have aggressive clinical course and poor prognosis.¹ Indeed, there is an unmet need for effective novel therapies that have unique mechanism(s) of action for these patients.

Iopofosine (formerly known as CLR 131, I-131-CLR-1404) is a first-in-class phospholipid radio-conjugate composed of the radioisotope iodine-131 (I-131)covalently bound to a phospholipid ether (PLE) mimetic that has been engineered to target tumor cells. Iopofosine binds to the hyper-prevalent lipid rafts on the tumor cell surface. Lipid rafts are highly ordered microdomains predominately composed of cholesterol, sphingolipids and coalesce signaling molecules. Lipid rafts are highly abundant on tumor cells, conserved across tumor types, and represent a novel potential approach for targeted drug delivery. Iopofosine binds to the lipid rafts and kills tumor cells in a multimodal process. Upon binding to the lipid rafts, iopofosine is internalized, delivering of I-131 intracellularly and causing double stranded DNA breaks via the beta emission from I-131 resulting in apoptosis. Additionally, the PLE portion of the molecule inhibits AKT. In the first in human, Phase 1 study of iopofosine in combination with dexamethasone, the drug was shown to be safe and induced deep and durable responses in highly pretreated RRMM patients.

The CLOVER-1 study was designed to further explore the safety and efficacy profile of single bolus doses of 31.25 mCi/m² and a fractionated 30 mCi/m²dose (15 mCi/m² given day 1 and 15) to achieve a minimum total administered doses (TAD) of 60 mCi in patients with triple class refractory RRMM (failed prior treatment with IMiD, PI, and anti-CD38 monoclonal antibody). Iopofosine demonstrated an overall response rate of greater than 40% in these patients with more than 3 months of progression free survival in patients that exceed the minimum of 60 mCi TAD. Based upon the success in this population, we designed an expansion cohort to evaluate an even more challenging patient population specifically those that met the definition of triple class refractory and who have failed or are refractory to anti-BCMA therapies.

Study Design:

CLOVER-1 is a multicenter, open-label, Phase 2 study evaluating IV administration of iopofosine in patients with relapsed/refractory B-cell malignancies (including multiple myeloma (MM), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia (LPL/WM), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), diffuse large b-cell lymphoma (DLBCL), and central nervous system lymphoma (CNSL) who have failed prior standard therapy. The primary objective of the study is to determine the clinical benefit rate (CBR) following the infusion of iopofosine. Secondary objectives included determination of overall response rate, progression free survival, time to next treatment, overall survival, duration of response and toxicity profile. Iopofosine was provided by Cellectar Biosciences, Inc. for this study. The study (NCT02952508) was reviewed and approved by Institutional Review Board of each participating center. All patients signed informed consent prior to enrollment.

Patients:

Adult patients with progressing relapsed or refractory MM were eligible if they had measurable disease by either M protein of 0.5 g/dl, urine m-protein of >200 mg/24 hours, or serum free light chains (FLC) of 10 mg/dl or more. Subjects were required to have an, ECOG performance status 0-2, an estimated life expectancy of at least 6 months and adequate bone marrow, renal, hepatic, and coagulation function. MM patients were required to have received at least 3 prior lines of therapy including a PI, IMID, anti-CD38 antibody and must have been at least 100 days post transplant. Important exclusion criteria included; prior total or hemi-body irradiation or external beam radiation resulting in greater than 20% of total bone marrow receiving greater than 20 Grays, any anti-cancer therapy within two weeks of study drug infusion, clinically significant bleeding within six months, major surgery within 6 weeks, uncontrolled hypertension, cardiac arrhythmia, or peripheral vascular disease, HIV or viral hepatitis.

Treatment:

Treatment consisted of iopofosine infusions given over 15-30 minutes. Subjects received a fractionated dose of 30 mCi/m² iopofosine as 15 mCi/m² on Day 1, and 15 mCi/m² on Day 15 (±1 day). Subjects could receive an optional second cycle of iopofosine in the same split dose regimen, at the discretion of the investigator.

All MM subjects also receive concurrent low dose dexamethasone (40 mg by mouth weekly for up to 12 weeks), with the first dose of dexamethasone given within 24 hours prior to the iopofosine infusion and continued weekly thereafter. Adjustments in dexamethasone dose due to age or intolerance were allowed at the investigator’s discretion.

All subjects received thyroid protection, consisting of saturated potassium iodine; Lugol’s solution or potassium iodide tablets, starting 24 hours before iopofosine and extending for 14 after the final iopofosine dose in each cycle. This sequence was repeated in patients undergoing a second cycle of therapy.

Safety assessments:

We used version 4.03 of the Common Terminology Criteria for Adverse Events (CTCAE) for assessment of the toxicity profile.

Clinical response assessment:

To assess antitumor activity of iopofosine subjects were divided into two dosing groups, receiving either < 60 or ³ 60 mCi total administered dose of iopofoine. Due to significant variability of radiation infused by body surface area and thereby the absorbed dose, total administered dose provides a more accurate measure of the actual radiation received by the subjects. Response was evaluated using the International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma.¹²

Seven patients were enrolled to the 30 mCi/m² fractionated (15 mCi/m² dosed day 1 and 15) dosing cohort. Six of these patients received a total administered dose of ³ 60 mCi with a median total administered dose was 71.5 mCi for all patients.

Baseline characteristics are presented in Table 1. All patients were triple-class refractory (refractory to IMiDs, PI and anti-CD38 MoAb) and anti-BCMA immunotherapy (either CAR-T or anti-BCMA antibody drug conjugate) exposed and either relapsed or refractory to it. In this highly refractory patient population, the overall response rate (ORR) was 50% (3 of 6 of patients receiving ³ 60 mCi total administered dose). The ORR in all patients was 42.8%. Clinical benefit defined as a ³ minimal response (MR) was noted in 83.3% (5 of 6) of patients that received ³ 60 mCi total administered dose and 71.4% (5 of 7) in all patients. In patients receiving at least 60 mCi total administered dose 100% (6 of 6) achieved stable disease or better (Table 2). The one patient that received less than < 60 mCi (~43.8 mCi) total administered dose had progressive disease at the time of first assessment (three weeks post initial treatment). At the time of data cutoff, the median overall survival had not been reached, the mean overall survival was 9.1 months (2.6 – 22.4 months) in patients receiving ³ 60 mCi total administered dose. Median progression free survival was 3.0 months (2.2 – 5.0).

All patients experienced at least one adverse event (Table 3). The median total administered dose was 71.5 mCi and 72.86 mCi for all patients and the ³ 60mCi total administered dose group, respectively. There were no adverse events leading to dosing delays, dose reductions or treatment discontinuations. The most common grade 1-2 event was fatigue, and expectantly, the most common grade 3-4 adverse events were cytopenias (thrombocytopenia 5 [75%], neutropenia 4 [57%] of 7). There were no grade 5 adverse events. No patients experienced any grade adverse events of neuropathy, cardiopulmonary toxicity, renal or hepatic toxicities, ocular toxicities, or cytokine release syndrome or similarly related toxicities. No patients experienced any bleeding or infections associated with the thrombocytopenia or neutropenia, respectively.

Median time to maximum grade of all cytopenias was 36 days (0 – 64 days). Median time to resolution (grade 2 or less) of any cytopenia was 21 days (0 – 42 days) post reaching maximum grade. Among patients experiencing thrombocytopenia the median time to nadir was 36 days (29 – 50 days) and a median of 21 days (14 – 41 days) to resolution post nadir. Median time to maximum grade for patients having any grade neutropenia was 43 days (0 – 64 days) with a median of 7 days (7 – 28 days) to resolution post reaching maximum grade. No patients experience febrile neutropenia. The two patients experiencing grade 4 neutropenia received a single injection of growth factor support. All cytopenias resolved within the study period.

In CLOVER 1, a fractionated dosing regimen of iopofosine (15 mCi/m² on day 1 and day 15) achieving approximately 60 mCi total administered dose demonstrated clinically meaningful activity in MM patients that were quadruple class refractory including that to an anti-BCMA immunotherapy. While the ORR (³ PR) was achieved in 50% of these patients, all patients were noted to have some clinical benefit (³ SD). The depth and durability of single agent iopofosine in this heavily pre-treated, refractory population compares favorably with other treatments being utilized alone in similar patient population.^13, ^{24, 25, 27}

A limitation of this primary analysis is the small patient cohort and the short duration of follow-up. However, it was encouraging to observe clinical patient in highly refractory patient population especially those patients who had failed anti-BCMA therapy; a group of patients that represent an unmet clinical need with no known effective treatment. Continued patient enrollment in this cohort as well as a longer follow-up is needed.

In patients with MM, responses to treatment and survival outcomes diminish with the failure of each subsequent regimen.³At present, MM patients who are triple-class refractory (PI, IMiDs and anti-CD38 MoAb) and relapsed or refractory to anti-BCMA immunotherapies have no approved therapies. The increasing use of anti-CD38 monoclonal antibodies in combination with IMiDs and PIs in newly diagnosed patients is limiting later line options. Recent entrants such as nuclear export inhibitors, provide limited activity in heavily pretreated, multi-class refractory patients and were poorly tolerated clinical trials.²⁵ Several BCMA-directed therapies have been approved or are in clinical development, including chimeric antigen receptor T-cell (CAR-T) therapies, bi-specific antibodies and antibody drug conjugates.^13–17 CAR-T therapy studies have shown a high proportion of patients achieving response; however, several challenges make this option unsuitable for relapsed/refractory MM patients who are unfit for the conditioning regimens or with inadequate disease control.^16,18While the response rates for the CAR-Ts range from 70 – >90%, a high relapse rates (50% ) within first 12 months, continue to pose clinical challenge. In addition, tolerability remains a concern with high rates of cytokine release syndrome and neurotoxicity.^{26, 27} Another anti-BCMA immunotherapy alternative belantamab mafodotin (an anti-BCMA antibody drug conjugate utilizing the microtubule-targeting cytotoxin MMAF) was recently approved by FDA for treatment of relapsed or refractory MM patients who have received at least 4 prior therapies (including anti-CD38 antibodies, PIs and IMiDs). Belantamab mafodotin demonstrated ~30% ORR with a PFS of 2.9 months.^19,20,24 Similar to the CAR-T therapies, early relapse and resistance to belantamab remain a challenge leaving post anti-BCMA an area of unmet need in MM.¹ As increased utilization of the anti-BCMA immunotherapies is anticipated, this patient population is expected to increase. Thus, investigation and development of novel agents with new mechanism of action such as iopofosine is highly desirable.

Iopofosine is a first-in-class phospholipid ether radio-conjugate that offers the advantage of providing targeted radiotherapy as a novel mechanism of action in hematologic cancers. Our early results demonstrate encouraging anti-MM activity in the niche of highly refractory patients. Iopofosine is a potential treatment option that is applicable to a complicated and diverse relapsed or refractory multiple myeloma population with an anticipated and acceptable safety profile. Reversible myelosuppression was the primary toxicity, specifically grade 3–4 thrombocytopenia and neutropenia which were comparable with previous radiotherapies and consistent with some of the approved treatments for this patient population.²⁸ Importantly, there were no unanticipated adverse events such as an increase in infections or bleeding in these patients and the thrombocytopenia and neutropenia were self-limited. Cardiotoxicity, peripheral neuropathy, and hyperglycemia adverse events have been described with selected proteasome inhibitors and immunomodulatory drugs, and for some patients dose modification for substantial renal impairment is required, none of which have been seen with iopofosine.^20,21 Additionally, BCMA-targeted CAR-T therapies have reported a risk of cytokine release syndrome, neurotoxicity and with belantamab mafodotin as experienced significant ocular adverse events.^{14,16, 22} Treatment tolerability is an issue, as treatment discontinuation due adverse events lead to poorer clinical outcomes.²² Intriguingly, to date, none of these adverse events were observed with iopofosine. The novel mechanism of action, manageable safety profile and the limited number of treatments of iopofosine make it a potential candidate for use in combination treatment regimens. Ongoing (NCT02952508) and planned trials will investigate iopofosine combinations with new and standard-of-care treatments. In conclusion, iopofosine shows promising anti-myeloma activity in patients with heavily pretreated disease who are triple class refractory and refractory or relapsed to anti-BCMA immunotherapy.

Acknowledgements: This study was supported by Cellectar Biosciences and the National Institute of Health (SBIR grant HHSN261201500071C)

Authorship and conflict of interest:

All authors participated in trial design. Drs Callander, Chanan-Khan and Ailawadhi enrolled patients and collected data. All authors had access to the complete data set, and were involved in data interpretation, manuscript preparation and revisions, and approved the final version of this manuscript.

Competing Interests: Jarrod Longcor and Kate Oliver are full time employees of Cellectar. Drs Callander, Chanan-Khan and Ailawadhi report no conflicts of interest with this study.

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Table 1 – Baseline Characteristics for Patients Included in this Analysis
	All patients (n=7)	≥ 60 mCi total administered dose (n=6)
Median age (range)	63 (46-77)	68 (46-77)
Male: Female	5:2	5:1
Race
White or White European	6 (86%)	5 (83%)
Black or African-American	1 (14%)	1 (17%)
Median prior therapies (range)	9 (4-17)	9 (4-17)
<5 Prior lines	1 (14%)	1 (17%)
>5 Prior lines	6 (86%)	5 (83.3%)
Prior stem cell transplant (n)	7 (100%)	6 (100%)
ISS Disease Stage (at entry)
Stage I	2 (29%)	2 (33%)
Stage II	2 (29%)	2 (33%)
Stage III	2 (29%)	1 (17%)
Unknown	1 (14%)	1 (17%)
Cytogenetic Risk: Standard/High/Unknown	3 (43%)/3 (43%)/1 (14%)	3 (50%)/2 (33%)/1 (17%)
Triple Class Refractory¹	7 (100%)	6 (100%)
Prior anti-BCMA Immunotherapy
CAR-T	2 (29%)	2 (33%)
Antibody Drug Conjugate	5 (71%)	4 (67%)
Median Time from Last anti-BCMA Treatment	85 days (12 – 654)	97 days (12 – 654)

Triple class refractory = refractory to immunomodulatory agents, proteasome inhibitors, and anti-CD38 monoclonal antibodies anti-BCMA, B-cell maturation protein; CAR-T, Chimeric antigen receptor T-cell therapy

Table 2 – Summary of Efficacy Measures Included in this Analysis
Efficacy Measure	≥ 60 mCi total administered dose (n=6) n (%)
Overall response rate (PR or better)	3 (50)
Clinical benefit (MR or better)	5 (83.3)
Disease control (Stable disease or better)	6 (100)

MR, minimal response; PR, partial response

Table 3 – Treatment Emergent Adverse Events
Adverse Events Occurring in > 1 Patient (n=7)
System Organ Class Preferred Term	All Grades n (%)	Grade 1 - 2 n (%)	Grade 3 n (%)	Grade 4 n (%)
Anemia	4 (57)	1 (14)	3 (43)	0 (0)
Leukopenia	4 (57)	1 (14)	0 (0)	3 (43)
Lymphopenia	2 (29)	0 (0)	1 (14)	1 (14)
Neutropenia	4 (57)	0 (0)	2 (29)	2 (29)
Thombocytopenia	5 (71)	0 (0)	2 (29)	3 (43)
Diarrhea	2 (29)	2 (29)	0 (0)	0 (0)
Fatigue	4 (57)	4 (57)	0 (0)	0 (0)
Hypocalcaemia	2 (29)	2 (29)	0 (0)	0 (0)
Hypophosphataemia	2 (29)	1 (14)	1 (14)	0 (0)
Dyspnea	2 (29)	2 (29)	0 (0)	0 (0)

There is NO conflict of interest to disclose.

Iopofosine I-131 treatment in late line patients with relapsed/refractory multiple myeloma post anti-BCMA immunotherapy

Status:

Version 1

Abstract

Introduction

Methods

Results

Discussion

Declarations

References

Tables

Additional Declarations

Status:

Version 1