Phase I Trial of Pomalidomide, Bortezomib, and Dexamethasone As Frontline Treatment of AL Amyloidosis

Background: Systemic light chain (AL) amyloidosis is a clonal plasma cell dyscrasia in which misfolded monoclonal light chains form insoluble extracellular fibrillar deposits with resultant organ injury. Renal and/or cardiac involvement is common. Clinical staging is based on cardiac involvement, with median survival of Methods: Key eligibility: 1) AL with organ involvement; patients (pts) with light chain deposition disease (LCDD) also potentially eligible; 2) ≤ 1 cycle of prior systemic therapy for AL, excluding high dose melphalan; 3) Measurable disease, defined as a difference between the involved (amyloidogenic) and uninvolved free light chains of ≥ 5 mg/dL; 4) 18+ yrs of age; 5) ECOG performance status 0-2; 6) Serum creatinine ≤ 2.5 mg/dL; 7) serum NT-proBNP 70 yrs. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, or physician discretion. The 1° endpoint was determination of maximally tolerated dosing (MTD) for POM/BTZ/DEX. Key 2° endpoints included hematologic and organ response rates, and overall survival (OS). Hematologic response (HR) was evaluated each cycle, organ response (OR) every 4th cycle (or end of treatment, if Results: Eighteen pts were enrolled: 17 AL, 1 LCDD. Median age 63.5 (range 49-76), Mayo original cardiac stage 1/2/3/unknown: 4/8/3/3. Enrollment into cohort 1/2/3/4/2b: 3/3/7/0/5. DLT was observed in cohorts 3 and 2b. The MTD was POM 3 mg/BTZ 1.0 mg/m2/DEX 20 mg (as all enrolled pts met criteria for baseline DEX dose reduction). The most common adverse events (AEs) of any severity were fatigue (n=15), diarrhea (n=8), constipation (n=8), anemia (n=12), and neutropenia (n=7). Table 1 summarizes Grade 2+ AEs. A median of 3 cycles was given (range 1-27). Eight pts have died, 4 of sudden death attributed to underlying cardiac AL while on protocol therapy. These four deaths (3 in pts with Mayo cardiac stage 2 disease, 1 with stage 3) occurred during therapy cycles 2, 2, 3, and 4. The HR rate was 50% (4 partial responses (PR), 3 very good partial responses (VGPR), 2 complete responses). Two of the 4 pts who died during therapy had had a HR (1 PR, 1 VGPR). Two pts had cardiac responses per consensus criteria (Gertz MA, et al, Am J Hematol 2005). Updated OR and OS data will be provided at the meeting. Two pts who failed to achieve ≥ PR with POM/BTZ/DEX subsequently responded after cyclophosphamide was substituted for POM. Four pts went on to autologous stem cell transplant (2 after VGPR, 2 after Discussion: POM/BTZ/DEX, while having light chain-lowering activity as frontline therapy for AL, was difficult to administer. DLTs were observed in 2 different treatment cohorts using doses of POM and/or BTZ and DEX below those typically used in frontline MM therapy. The spectrum of AEs was otherwise typical for these agents. The on-trial deaths, all attributed to cardiac AL, underscore the complexity of clinical research in pts with previously untreated AL. On-trial deaths were less common in POM/DEX trials for relapsed AL (Sanchorawala V, et al. Blood 2016; Palladini G, et al. Blood 2017). Thus, though the observed HR rate was similar to that for CyBorD (Palladini G, et al. Blood 2015), there are no current plans for a Phase 2 trial of POM/BTZ/DEX as frontline therapy for AL amyloidosis. Disclosures Zonder: Celgene: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Prothena: Consultancy; Takeda: Consultancy; Pharmacyclics: Other: Data Safety Monitoring Committee; Janssen: Consultancy. Kukreti: Celgene: Honoraria; Amgen: Honoraria. Burt: Celgene: Speakers Bureau. Pregja: Takeda: Consultancy, Honoraria; Pharmacyclics: Other: Data Safety Monitoring Committee ; Celgene: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Prothena: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy, Honoraria. Matous: Celgene: Speakers Bureau; Multiple Myeloma Advisory Committee: Membership on an entity9s Board of Directors or advisory committees.