Alternating the Administration of Ixazomib and Lenalidomide As Maintenance Therapy after Autologous Transplant for Multiple Myeloma

Autologous transplant (ASCT) can cause remissions in Multiple Myeloma (MM) patients (pts), but relapse remains a major problem. Currently, lenalidomide alone for as long as tolerated post ASCT is the standard maintenance utilized in the USA. Since the use of an alternating schedule of an Immunomodulatory drug (IMiD) with a proteasome inhibitor (PI) might decrease the emergence of resistant dominant clones, we designed a study to investigate treating with a regimen alternating IMiD lenalidomide with PI ixazomib post ASCT. We report here on the toxicity and efficacy of this all-oral maintenance regimen.

Thirty to 120 days after recovery from toxicity of ASCT, pts began study therapy. Treatment regimen consisted of alternating ixazomib 4mg po on days 1, 8 and 15 per each 28-day cycle for two consecutive cycles followed by lenalidomide 10mg po daily for two consecutive cycles until MM progression, intolerable toxicity or maximum of 24 cycles. Dose adjustment for toxicity occurred. Pts remained on anti-VZV and PJP prophylaxis throughout therapy and until 2 months after stopping therapy. Pts got bisphosphonate therapy. Pts also received DVT prophylaxis therapy as clinically indicated. The primary endpoint was toxicity. Secondary endpoints were ability to deliver planned therapy, initial response, overall progressive free and survival rates.

Thirty pts were enrolled and treated on the study with at least 1 cycle of therapy. Twenty-three pts were male (77%), 13% were members of minority groups. The median age was 60 years (range 44-70 years). Three pts (10%) were over 65 years old. Fourteen pts (47%) had high-risk cyclogenetic MM per IMWG, including 6 pts (20%) that had multiple high-risk changes. Pts started study therapy at a median 107.5 days post ASCT (range 53-120 days). Thirteen pts (43%) stopped therapy before completing 24 cycles for the following reasons: relapse (n=8), patient's decision (n=2), secondary cancer treatment (n=1) and elective surgery that was complicated by infections (n=2). No pts met stopping rules for toxicity in the first 4 months of therapy. There were no deaths due to study therapy. The most common AE grades (gr) 2-4 were: abnormal glucose (10%, 100% gr 2), lymphocyte decreased (70%, 37% gr 2, 33% gr 3), low phosphate (17%, 100% gr 2), WBC decreased (53%, 33% gr 2, 20% gr 3), Platelet (PLT) decreased (33%, 23.3% gr 2, 6.7% gr 3 and 3.3% gr 4), ANC decreased (60%, 30% gr 2, 23.3% gr 3, 6.7% gr 4). The following infectious episodes were also seen in 27 patients (90%): non-identified upper respiratory tract infection (URTI) (n=34), identified URTI (n=9, included metapneumovirus (n=1), rhinovirus (n=2), RSV (n=1), influenza A (n=1) parainfluenza (n=2), RSV and COVID-19 (n=1) and COVID-19 (n=1)), nonneutropenic fever (n=1), thrush (n=1), conjunctivitis (n=1), shingles (n=1), cellulitis (n=3 include one case of MRSA), giardia (n=1), strep pneumonia with sepsis (n=1), bacterial pneumonia (n=2), viral gastroenteritis (n=2), urine tract infection (n=1), bronchitis (n=2) and tinea of the skin (n=1). The most frequent gr 3-4 AEs were hematological, with decreased WBC in 20%, decreased PLT in 10% and decreased ANC in 30% of pts.

Twenty-four (80%) of the pts still had detectable MM disease after ASCT before starting study therapy. At completion of study therapy, 29.2% had progressed, 21% had stable disease, 4.2% were in PR, 29% in nCR, 8.3% in sCR and 8.3% in CR. Overall, 50% of patients converted to a deeper response (≥ PR).

Four pts have developed a secondary cancer, localized skin cancer (n=3) and metastatic lung cancer (n=1). Only 1 pt was still receiving study therapy when the secondary cancer developed.

Median follow-up is 3.95 years (range 3.18-6.7 years). Sixteen (53%) of the pts have relapsed. Eight pts (37%) have died including 6 pts with relapsed MM and 2 pts without relapse (metastatic lung cancer (n=1) and non-COVID infection (n=1). To date, 9 pts (30%) are alive in relapse and 13 pts (43%) are alive in remission.

Post ASCT, the all oral regimen of alternating ixazomib and lenalidomide is overall well tolerated and has high initial response rates. Hematological toxicity as expected was the most significant toxicity. Significant gastrointestinal and peripheral neuropathy toxicity were not seen. The most common infection was non-specified URTI. A larger randomized trial comparing the alternating oral med schedule of ixazomib and lenalidomide to single agent lenalidomide is warranted.

Holmberg:Takeda/Millennium: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Merck: Research Funding; Janssen: Research Funding; Up-to-Date: Patents & Royalties; Sanofi: Research Funding. Green:SpringWorks Therapeutics: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectar Biosciences: Research Funding; Legend Biotech: Consultancy; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Juno Therapeutics: Patents & Royalties, Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Neoleukin Theraeutics: Membership on an entity's Board of Directors or advisory committees; Janssen Biotech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cowan:Abbvie: Consultancy, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; Allogene: Consultancy; BMS: Consultancy, Research Funding; EUSA: Consultancy; GSK: Consultancy; Harpoon: Research Funding; Janssen: Consultancy, Research Funding; Nektar: Research Funding; Sanofi: Research Funding; Secura Bio: Consultancy.

Use of ixazomib post autologous transplant for maintenance therapy