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Subject will receive Ruxolitinib Oral Tablet \[Jakafi\] at 15mg BID, and Methylprednisolone at 40mg QOD until disease progression. Lenalidomide at 10mg QD will be added to the treatment (Ruxolitinib, Methylprednisolone) once disease progression was confirmed.

Ruxolitinib Oral Tablet \[Jakafi\] at 5mg, 10mg or 15mg BID, Lenalidomide Oral at 5mg or 10mg QD and Methylprednisolone Oral at 40mg QOD. (Dose varies during dose escalation portion of the study)

Ruxolitinib will be administered on days 1-28 of the treatment cycle.

Ruxolitinib Oral Tablet [Jakafi]

Lenalidomide will be administered on Days 1-21 of the treatment cycle.

Methyl-prednisolone will be administered on Days 1-28 of the treatment cycle.

Andrea Limon

Matthew Brobeck

This is a phase 1, multicenter, open-label study evaluating the safety and efficacy of ruxolitinib, steroids and lenalidomide among MM patients who currently show progressive disease using BCMA to test progression.

In recent years, new and more effective drugs have become available for the treatment of multiple myeloma (MM), resulting in a dramatic increase in median overall survival (OS).1 Therapeutic options have expanded to include immune-based approaches such as daratumumab and elotuzumab.2 The clinical course of MM is highly variable, and relapsing/refractory (RR)MM more so, with periods of response followed by periods of relapse. Improvements in predicting and determining individual patient outcome would allow for more effective and timely treatment interventions.

Over the last several years, we have identified a new serum biomarker, B cell maturation antigen (BCMA), for monitoring patients with MM. Changes in serum (s)BCMA quickly identify changes in the clinical status of MM and it is also a promising new prognostic marker. Specifically, we demonstrated that compared to healthy donors, patients with MM showed elevated levels of sBCMA.3 These levels were positively correlated with the proportion of plasma cells in bone marrow biopsies and changes in monoclonal (M)-protein and serum free light chain (SFLC) levels and indicated a patient's current clinical status.3 Importantly, sBCMA levels were also independent of renal function and maintained independent significance when tested against other known prognostic markers for MM including age, serum β-2-microglobulin, hemoglobin, and presence of bone disease. Furthermore, we demonstrated that increases in sBCMA by \> 25% from start of any new therapy predicted a markedly shorter progression free survival (PFS) and occurred much more quickly than those observed with standard biomarkers to monitor the course of MM including M-protein and SFLC levels.

To further validate sBCMA as a disease status biomarker for MM, we have incorporated monitoring of sBCMA for all patients participating in several ongoing clinical trials. Specifically, patients participating in a Phase 1 study of ruxolitinib, methylprednisolone and lenalidomide for RRMM patients, were monitored weekly for sBCMA and standard MM markers during their first treatment cycle and monthly thereafter. We determined the safety and efficacy of this novel, all oral combination consisting of the Janus kinase 1/2 inhibitor ruxolitinib in combination with lenalidomide and methylprednisolone.5 Successive cohorts of participants (3 participants per cohort) were given the following doses of drugs, all oral (PO): Dose Level 0: ruxolitinib 5 mg twice a day (BID), methylprednisolone 40 mg every other day (QOD) and lenalidomide 5 mg daily (QD) on days 1-21 of a 28-day cycle; Dose Level 1: ruxolitinib 10 mg BID, methylprednisolone 40 mg QOD, and lenalidomide 5 mg QD on days 1 21 of a 28-day cycle; Dose Level 2: ruxolitinib 15 mg BID, methylprednisolone 40 mg QOD, and lenalidomide 5 mg QD on days 1 21 of a 28-day cycle), and Dose Level 3: ruxolitinib 15 mg BID, methylprednisolone 40 mg QOD and lenalidomide 10 mg QD on days 1 21 of a 28-day cycle. Dose Level 3 was the maximum administered dose.

Data analysis on the first 28 patients treated with this triple combination demonstrated promising safety and efficacy profiles.5 Specifically, the clinical benefit rate (CBR) and overall response rate (ORR)7 were 46% and 38%, respectively.5 No dose-limiting toxicities occurred. Grade 3 or grade 4 adverse events (AEs) included anemia (18%), thrombocytopenia (14%), and lymphopenia (14%). Most common serious AEs (SAE) included sepsis (11%) and pneumonia (11%). Notably, all 12 responding patients were refractory to lenalidomide and steroids.

To date, we have enrolled a total of 49 patients. Forty are evaluable for safety and efficacy.8 The CBR and ORR were 47% and 37%, respectively. Responses included 1 complete response (CR), 4 very good partial responses (VGPR), 10 partial responses (PR), and 4 minimal responses (MR), and 16 and 5 patient showed stable disease (SD) and progressive disease (PD), respectively. Notably, all 19 patients achieving \> MR were refractory to lenalidomide (i.e., progressed while on or within 8 weeks of receiving the last dosage of this drug). PFS for all evaluable patients was 4.0 months with the median follow-up time of 3.0 months (range, 0.2 13.3). The median follow-up time for the responding patients was 5.4 months (0.9 13.3) with the duration of response (DOR) of 5.0 months. This all oral regimen was well tolerated, and reversible Grade 3/4 cytopenias occurred in only a small minority of patients.

We analyzed sBCMA levels for these patients and demonstrated that its baseline levels predicted PFS and increases of \> 25% occurred more rapidly than those observed with M protein or SFLC and predicted for a much shorter PFS.9 Specifically, serum BCMA was a faster predictor than International Myeloma Working Group (IMWG) criteria of disease progression for 67% of the MM patients showing disease progression, and no patient showed progression more rapidly using IMWG criteria than sBCMA.

Furthermore, an expansion of the ongoing Phase 1 study is evaluating the combination of ruxolitinib 15 mg BID and methylprednisolone 40 mg QOD continuously without lenalidomide in this same patient population. Subjects are enrolled and treated with this two-drug combination until disease progression. Twenty-nine patients were enrolled in the doublet combination, and the ORR and CBR were both 45% (2 VGPR, 11 PR, 0 MR). Per study design, once disease progression occurred as determined using IMWG criteria, lenalidomide at 10 mg PO daily on days 1 21 of a 28-day cycle was added to the regimen. To date, 19 subjects have been enrolled in this portion of the study and 17 patients have completed at least 2 full cycles of lenalidomide-containing therapy. Ten patients have responded (3 PR and 7 MR) while 4 patients exhibited SD and 5 patients had PD.

These results show that the combination of ruxolitinib and steroids is active for treating RRMM and that the addition of lenalidomide upon disease progression will overcome disease progression in many patients. These results provide the basis for the current trial which will use monitoring of sBCMA levels and IMWG criteria to more quickly allow addition of lenalidomide to patients failing the two-drug combination.

Therefore, in this pilot study involving patients with RRMM initially treated with ruxolitinib and methylprednisolone, we specifically propose to use changes in sBCMA levels (\> 25% increase from its nadir level) or conventional indicators of disease progression per IMWG criteria (changes in M-protein and SFLC levels), whichever occurs first, to determine when to add lenalidomide to patients failing the doublet combination of ruxolitinib and methylprednisolone.

This is a pilot, multicenter, open-label study evaluating the utility of using increases in serum BCMA \> 25% versus IMWG criteria to determine disease progression among patients with RRMM treated with ruxolitinib and methylprednisolone to determine when to add lenalidomide to the regimen. Subjects that were treated with ruxolitinib with methylprednisolone and showed disease progression will have lenalidomide added to their regimen. PD is defined by either change in sBCMA (≥ 25% increase from nadir) or by standard IMWG criteria, whichever occurs first. PD will be confirmed by two consecutive tests.

Pilot Study Using Changes in Serum BCMA to Determine Disease Progression in Multiple Myeloma

Treatment of Patients With Relapsed/Refractory Multiple Myeloma With Ruxolitinib, Methylprednisolone and Lenalidomide: Using Changes in Serum B-Cell Maturation Antigen (BCMA) or International Multiple Working Group (IMWG) Criteria to Determine Disease Progression in Order to Add Lenalidomide to Those Failing the Ruxolitinib/Methylprednisolone Combination

* To establish the utility of using an increase in sBCMA levels \> 25% or IMWG criteria for disease progression to direct this therapeutic approach, TTP will be measured, where TTP is defined as a number of days between the start of treatment (cycle 1 day 1) and PD. PD is defined by either change in sBCMA (≥25% increase from its nadir levels) or by standard IMWG criteria (using sM-protein and SFLC assessments), whichever occurs first. PD will be confirmed by two consecutive tests.
* Duration of response 1 (DOR1), defined as the time from the first response to progressive disease as determined by either changes in sBCMA or IMWG criteria (whichever occurs first) while patients are on ruxolitinib and methylprednisolone treatment
* Duration of response 2 (DOR2), defined as the time from the first response to progressive disease as determined by standard IMWG criteria while patients on ruxolitinib, lenalidomide and methylprednisolone treatment

• Occurrence of adverse events throughout the study, graded via Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 criteria

* Efficacy of treatment will be assessed by the overall response rate (ORR; ORR = CR + VGPR + PR) and clinical benefit rate (CBR; CBR = CR + VGPR + PR + MR) of the doublet and triplet combinations
* PFS1 as defined based on the length of time that patient was receiving therapy consisting of ruxolitinib with steroids until PD or death from any cause as determined by either an increase in sBCMA of ≥25% from its nadir or using IMWG criteria
* PFS2 as defined based on the length of time that patient was receiving ruxolitinib, lenalidomide and steroid therapy to the time they reached disease progression as determined by the standard IMWG criteria or death from any cause
* PFS from start of study treatment to disease progression as determined by the standard IMWG criteria or death from any cause including receiving treatment with ruxolitinib, lenalidomide and steroid

Incyte Corporation

Oncotherapeutics

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Pilot Study Using Changes in Serum BCMA to Determine Disease Progression in Multiple Myeloma	NCT06209606	Multiple Myelom...	Ruxolitinib Ora... Lenalidomide Methylprednisol...	18 Years -	Oncotherapeutics
Pilot Study Using Changes in Serum BCMA to Determine Disease Progression in Multiple Myeloma	NCT06209606	Multiple Myelom...	Ruxolitinib Ora... Lenalidomide Methylprednisol...	18 Years -	Oncotherapeutics

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