Treatment of double-refractory multiple myeloma

In most publications on relapsed and refractory multiple myeloma, the term double-refractory refers to the loss of response to lenalidomide and proteasome inhibitors. The prognosis in the case of double-refractory multiple myeloma is poor. Usually, these are severely pretreated patients who have accumulated drug toxicity after 2 or more lines of therapy, with limited reserves of bone marrow hematopoiesis and often decompensated comorbidities. A partial solution to the problem was to use certain new drugs that have demonstrated activity as monotherapy or in combination with dexamethasone in this group of patients. This review is aimed to provide a critical review of recent clinical studies addressing this issue. According to the recent European Hematology Association and European Society for Medical Oncology (EHA-ESMO) 2021 guidelines for the diagnosis and treatment of double-refractory multiple myeloma, triple combinations should be considered, including monoclonal antibodies (elotuzumab (Elo), isatuximab (Isa), daratumumab (Dara)), dexamethasone and pomalidomide (Elo-Pd, Isa-Pd, Dara-Pd) or carfilzomib (Isa-Kd, Dara-Kd). In Russia, as of March 2021, the first two regimens were approved (Elo-Pd, Isa-Pd). Elotuzumab was tested in combination with pomalidomide in the randomized phase II ELOQUENT-3 trial (Elo-Pd vs. Pd; n = 177). Median progression-free survival was 10.3 months on Elo-Pd vs. 4.7 months on Pd (hazard ratio 0.54; 95 % confidence interval 0.34–0.86; р = 0.008). Elo-Pd superiority was observed in all subgroups, including patients with double-refractory MM, high-risk cytogenetic aberrations del17p, t(4;14), t(14;16), and increased serum LDH. The Isa-Pd triplet was approved in the randomized phase III ICARIA-MM study (Isa-Pd vs. Pd; n = 307). The median progression-free survival in this protocol was 11.5 months in the Isa-Pd group vs. 6.5 months in the Pd group (hazard ratio 0.596; 95 % confidence interval 0.44–0.81; р = 0.001). Isa-Pd triplet superiority was demonstrated in all unfavorable prognostic subgroups, including lenalidomide-refractory patients, patients with high-risk cytogenetics, and doublerefractory patients. New triplets with monoclonal antibodies represent an important option for the treatment of doublerefractory multiple myeloma.

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Final Overall Survival Analysis of the TOURMALINE-MM1 Phase III Trial of Ixazomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma

Journal of Clinical Oncology ◽

10.1200/jco.21.00972 ◽

2021 ◽

pp. JCO.21.00972

Author(s):

Paul G. Richardson ◽

Shaji K. Kumar ◽

Tamás Masszi ◽

Norbert Grzasko ◽

Nizar J. Bahlis ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

High Risk ◽

Progression Free Survival ◽

Staging System ◽

Phase Iii ◽

Free Survival ◽

Refractory Multiple Myeloma ◽

International Staging System ◽

Intent To Treat

PURPOSE The double-blind, placebo-controlled, phase III TOURMALINE-MM1 study demonstrated a statistically significant improvement in progression-free survival with ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) versus placebo-Rd in patients with relapsed or refractory multiple myeloma. We report the final analyses for overall survival (OS). PATIENTS AND METHODS Patients were randomly assigned to ixazomib-Rd (n = 360) or placebo-Rd (n = 362), stratified by number of prior therapies (1 v 2 or 3), previous proteasome inhibitor (PI) exposure (yes v no), and International Staging System disease stage (I or II v III). OS (intent-to-treat population) was a key secondary end point. RESULTS With a median follow-up of 85 months, median OS with ixazomib-Rd versus placebo-Rd was 53.6 versus 51.6 months (hazard ratio, 0.939; P = .495). Lower hazard ratios, indicating larger magnitude of OS benefit with ixazomib-Rd versus placebo-Rd, were seen in predefined subgroups: refractory to any (0.794) or last (0.742) treatment line; age > 65-75 years (0.757); International Staging System stage III (0.779); 2/3 prior therapies (0.845); high-risk cytogenetics (0.870); and high-risk cytogenetics and/or 1q21 amplification (0.862). Following ixazomib-Rd versus placebo-Rd, 71.7% versus 69.9% of patients received ≥ 1 anticancer therapy, of whom 24.7% versus 33.9% received daratumumab and 71.8% versus 76.9% received PIs (next-line therapy: 47.5% v 55.8%). Rates of new primary malignancies were similar with ixazomib-Rd (10.3%) and placebo-Rd (11.9%). There were no new or additional safety concerns. CONCLUSION Median OS values in both arms were the longest reported in phase III studies of Rd-based triplets in relapsed or refractory multiple myeloma at the time of this analysis; progression-free survival benefit with ixazomib-Rd versus placebo-Rd did not translate into a statistically significant OS benefit on intent-to-treat analysis. OS benefit was greater in subgroups with adverse prognostic factors. OS interpretation was confounded by imbalances in subsequent therapies received, especially PIs and daratumumab.

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OCEAN: a randomized Phase III study of melflufen + dexamethasone to treat relapsed refractory multiple myeloma

Future Oncology ◽

10.2217/fon-2020-0024 ◽

2020 ◽

Vol 16 (11) ◽

pp. 631-641 ◽

Cited By ~ 6

Author(s):

Fredrik Schjesvold ◽

Pawel Robak ◽

Ludek Pour ◽

Johan Aschan ◽

Pieter Sonneveld

Keyword(s):

Multiple Myeloma ◽

Overall Response Rate ◽

Progression Free Survival ◽

Phase Iii ◽

Open Label ◽

Free Survival ◽

Refractory Multiple Myeloma ◽

Duration Of Response ◽

Secondary Endpoints ◽

Phase Iii Study

Melflufen is a novel peptide–drug conjugate that rapidly delivers a cytotoxic payload into tumor cells. It has emerged as a potential new multiple myeloma treatment, particularly for late-stage forms of the disease. Here we describe the rationale and design of OCEAN (NCT03151811), a randomized, head-to-head, superiority, open-label, global, Phase III study evaluating the efficacy and safety of melflufen + dexamethasone versus pomalidomide + dexamethasone. Eligible patients with relapsed refractory multiple myeloma have received 2–4 previous treatments and are refractory to both lenalidomide and their last treatment. Patients are excluded if they have previously received pomalidomide. The primary endpoint is progression-free survival, and key secondary endpoints include overall response rate, duration of response and overall survival.

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Efficacy and Toxicity Profile of Ibrutinib Based Regimens for Refractory Multiple Myeloma: A Systematic Review

Blood ◽

10.1182/blood-2018-99-109986 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1948-1948

Author(s):

Faiza Jamil ◽

Madeeha Shafqat ◽

Ali Younas Khan ◽

Seren Durer ◽

Ceren Durer ◽

...

Keyword(s):

Multiple Myeloma ◽

Clinical Trials ◽

High Risk ◽

Respiratory Infections ◽

Progression Free Survival ◽

Toxicity Profile ◽

Free Survival ◽

Refractory Multiple Myeloma ◽

Muscle Spasms ◽

Combination Regimens

Abstract BACKGROUND: Despite recent advancements in treatment for multiple myeloma (MM) there is a constant need for newer therapies to tackle the complex issue of relapse and therapy after relapse for patients with MM. Ibrutinib is an oral inhibitor of Bruton tyrosine kinase (BTK), which is overexpressed in the plasma cells. We conducted a comprehensive literature search to analyze the efficacy, dosing and toxicity profile of ibrutinib in relapsed MM. METHODS: Database search using PubMed, EMBASE, Cochrane Library, Web of Science and Clinicaltrials.gov was performed on 06/05/18 (last update) . All clinical trials that used ibrutinib either as monotherapy or in combination regimens in the setting of relapsed and refractory multiple myeloma (RRMM) were included. RESULTS: A total of 388 articles were found on the initial search and after screening, three phase I and II clinical trials qualified for inclusion. Ibrutinib based regimen data (n=155 patients) was analyzed (Table 1). Majority (68%) of the patients were refractory to their previous line of therapy. Ibrutinib Monotherapy: Monotherapy (n=31) with a dose of 420 mg/d to 840 mg/d demonstrated a 0% ORR (overall response rate). A median PFS (progression-free survival) of 0.9 to 2.8 months was noticed with ibrutinib monotherapy. Most common hematological adverse events (HAE) noted were anemia (32%), thrombocytopenia (29%) and neutropenia (13%). All-grade gastrointestinal disturbances (GI) were observed in 90% of cases, fatigue and respiratory infections (RI), each in 39% and muscle spasms in 23% of cases. Ibrutinib + Dexamethasone: The addition of 40 mg dexamethasone to 560 mg/d (n=18) and 840 mg/d (n=43) ibrutinib showed an ORR of 6% and 5% and reported median PFS of 3.7 months and 4.6 months, respectively. Side effects included anemia (26%), thrombocytopenia (23%), and neutropenia (2%). GI toxicity was noted in 82% patients, fatigue in 46%, RI in 15% and muscle spasms reported in 15% patients. Ibrutinib + Carfilzomib: At 560 mg/d dose of ibrutinib, the addition of 27 mg/m2 (n=3) and 36 mg/m2 of carfilzomib (n=5) showed a response of 67% and 40%, respectively. The best response was elicited when 20 mg of dexamethasone was added to 36 mg/m2 of carfilzomib and ibrutinib at a dose of 840 mg/d (n=18; ORR: 71%) and 560 mg/d (n=17; ORR: 71%). The median duration of responses was 12.9 months. Minimal responses were observed in an additional 4 patients giving an overall clinical benefit rate of 76%. At a dose of 36 mg/m2 of carfilzomib, median PFS was reported as 8.1 and 6.4 months at 560 mg/d and 840 mg/d doses of ibrutinib, respectively. Most common HAE were anemia (35%), thrombocytopenia (28%) and neutropenia (9%). Eighty-six percent of patients developed GI disturbances while fatigue and muscle spasms were noted in 53% and 19%, respectively. RI were observed in 51% of patients. Ibrutinib + Bortezomib: The combination of ibrutinib given at 840 mg/d dose with a twice weekly dose of bortezomib 1.3 mg/m2 elicited a response in 46% (n=20) patients, and minimal responses in 4 (21%) patients. Most common GI disturbance was diarrhea (50%). Upper respiratory infections were noted in 30% cases while, asthenia and peripheral edema seen in 20% of cases. Bortezomib/IMiD Refractory Cohort: Patients refractory to prior bortezomib (n=27) showed an encouraging ORR of 73% that was durable for a median of 9.1 months when ibrutinib+carfilzomib+dexamethasone regimen was used. Similarly, another cohort (n=25) of double refractory patients treated with a combination of ibrutinib and dexamethasone demonstrated minimal response in 4 (16%) and disease stabilization in another 5 (20%) patients. High-Risk Cohort: In a population of high-risk cytogenetics (del 17p and/or t[4;14]; n=11) treated with 560 mg/dl to 840 mg/dl of ibrutinib, 36 mg/m2 of carfilzomib and (+/-) 20 mg of dexamethasone showed an ORR of 78%, response was durable for a median of 9.1 months, and achieved a median progression free survival (PFS) of 8.1 months . CONCLUSION: Ibrutinib has demonstrated a promising efficacy (70-80% of ORR in combination regimens) along with an acceptable toxicity profile in the heavily pre-treated and dual drug refractory MM patients. Larger prospective clinical trials are needed to further evaluate its efficacy. Disclosures No relevant conflicts of interest to declare.

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A phase 2, open-label, multicenter study of ixazomib plus lenalidomide and dexamethasone in adult Japanese patients with relapsed and/or refractory multiple myeloma

International Journal of Clinical Oncology ◽

10.1007/s10147-021-02030-7 ◽

2021 ◽

Author(s):

Shinsuke Iida ◽

Tohru Izumi ◽

Takuya Komeno ◽

Yasuhito Terui ◽

Takaaki Chou ◽

...

Keyword(s):

Multiple Myeloma ◽

Confidence Interval ◽

Overall Response Rate ◽

Response Rate ◽

Progression Free Survival ◽

Japanese Patients ◽

Open Label ◽

Free Survival ◽

Refractory Multiple Myeloma ◽

Good Partial Response

Abstract Background TOURMALINE-MM1 was a global study that demonstrated a significant improvement in progression-free survival with ixazomib plus lenalidomide and dexamethasone compared with placebo plus lenalidomide and dexamethasone, in patients with relapsed and/or refractory multiple myeloma. The current study was conducted to evaluate further the efficacy and safety of ixazomib plus lenalidomide and dexamethasone in Japanese patients. Methods This phase 2, open-label, single-arm, multicenter study enrolled patients aged ≥ 20 years with relapsed and/or refractory multiple myeloma at 16 sites in Japan. Patients refractory to lenalidomide or proteasome inhibitor-based therapy at any line were excluded. The primary endpoint was the rate of very good partial response or better in the response-evaluable analysis set. Secondary endpoints were progression-free survival, overall response rate, duration of response, time to progression, overall survival and safety. Results In total, 34 patients were enrolled. The rate of very good partial response or better was 50.0% (95% confidence interval 31.9–68.1) and the overall response rate was 84.4% (95% confidence interval 67.2–94.7). Median progression-free survival was 22.0 months (95% confidence interval 17.3–not evaluable) and median overall survival was not estimable. The safety profile of ixazomib plus lenalidomide and dexamethasone in this study was similar to that in the TOURMALINE-MM1 study. Conclusions The efficacy and safety of ixazomib plus lenalidomide and dexamethasone in Japanese patients with relapsed and/or refractory multiple myeloma are comparable with reported TOURMALINE-MM1 study results. Clinicaltrials.gov identifier NCT02917941; date of registration September 28, 2016.

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Bortezomib, Lenalidomide and Low-Dose Dexamethasone (VRD) Versus Lenalidomide and Low-Dose Dexamethasone (Ld) for Newly-Diagnosed Multiple Myeloma- a Randomized Phase III Study

Blood ◽

10.1182/blood.v130.suppl_1.906.906 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 906-906

Author(s):

Anjali Mookerjee ◽

Ritu Gupta ◽

Shivali Jasrotia ◽

Ranjit Sahoo ◽

Rakesh Kumar ◽

...

Keyword(s):

Multiple Myeloma ◽

Low Dose ◽

Progression Free Survival ◽

Response Rates ◽

Phase Iii ◽

Stage Iii ◽

Newly Diagnosed ◽

Free Survival ◽

Median Progression Free Survival ◽

Grade 3

Abstract Background: In this prospective study, we compared VRD with Ld as induction therapy for newly-diagnosed Multiple myeloma patients. The primary objective of this study is to compare the progression-free survival in the 2 arms. Methods: Between September 2014 and Oct 2016, 144 patients have been recruited and randomly assigned to receive 4 cycles of either Bortezomib 1.3 mg/m2 SC on days 1, 8, 15 and 22 with Lenalidomide 15mg/day from day 1 to 14 (Arm A) or Lenalidomide 25 mg/day from day 1 to 21 (Arm B). Patients in both arms received oral dexamethasone 40 mg on days 1,8,15 and 22. Both treatment regimens were 28-day cycles. All patients received 75 mg aspirin daily, acyclovir prophylaxis and monthly zoledronic acid. Response assessment was done at the end of the 4th cycle using the International Myeloma Working Group (IMWG) uniform response criteria. The study was approved by the Institute Ethics Committee (Ref IEC/NP-264/01-08-2014, RP-7/2014). Results: These are the results from an analysis of 143 patients (arm A-74, arm B-69). Baseline characteristics of patients were similar in both arms with respect to age, gender, ISS and DS stage, immunoglobulin subtype and serum LDH. Patients' median age is 56 years (range 31-70) in arm A and 52 years (range 28-69) in arm B. Gender M/F: Arm A 54/20 and 43/26 in arm B. ISS stage III 51 (68.9%) arm A vs 44 (63.8%) arm B. Serum LDH raised to >250 u/L was observed in 25 (44.6%) vs 31 (52.5%) in arms A and B, p=0.4. Revised staging including ISS and serum LDH at baseline: stage III 47 (81%) and 37 (65%) in arms A and B respectively. 14 (18.9%) and 19 (27.5%) of patients had light chain myeloma in arms A and B respectively. Overall response rates (sCR+CR+VGPR+PR) is 78.4% vs 73.9% in arms A and B respectively, p=0.6; sCR + CR 21 (28.4%) and 21 (30.4%) respectively, p=0.86. Median follow-up 17.1 months (range 1 to 33). Median overall survival (OS) is 30.2 months (95% CI 28.2 to 32.2) and 28.6 months (95%CI 26 to 31.3) in arms A and B respectively, p=0.3. Median progression-free survival (PFS) was 27.8 months (95%CI 25.4 to 30.2) and 28 months (95%CI 24.6 to 31.4) respectively, p=0.3. Estimated one-year OS is 88% vs 85% in arms A and B, and PFS 83% vs 72%, respectively. Grade 3 anemia occurred in one patient in arm B, and grade 3 deep vein thromboses in one patient in arm A. One patient in arm A developed grade 4 myelosuppression leading to therapy change at the end of the first cycle. Conclusion: In this analysis - response rates and median progression-free survival are similar in both arms. Disclosures No relevant conflicts of interest to declare.

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Improvement in Overall Survival With Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma

Journal of Clinical Oncology ◽

10.1200/jco.2017.76.5032 ◽

2018 ◽

Vol 36 (8) ◽

pp. 728-734 ◽

Cited By ~ 101

Author(s):

David S. Siegel ◽

Meletios A. Dimopoulos ◽

Heinz Ludwig ◽

Thierry Facon ◽

Hartmut Goldschmidt ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Progression Free Survival ◽

Hazard Ratio ◽

Rank Test ◽

Free Survival ◽

Refractory Multiple Myeloma ◽

Risk Of Death ◽

End Point ◽

Grade 3

Purpose In the ASPIRE study of carfilzomib, lenalidomide, and dexamethasone (KRd) versus lenalidomide plus dexamethasone (Rd) in patients with relapsed or refractory multiple myeloma, progression-free survival was significantly improved in the carfilzomib group (hazard ratio, 0.69; two-sided P < .001). This prespecified analysis reports final overall survival (OS) data and updated safety results. Patients and Methods Adults with relapsed multiple myeloma (one to three prior lines of therapy) were eligible and randomly assigned at a one-to-one ratio to receive KRd or Rd in 28-day cycles until withdrawal of consent, disease progression, or occurrence of unacceptable toxicity. After 18 cycles, all patients received Rd only. Progression-free survival was the primary end point; OS was a key secondary end point. OS was compared between treatment arms using a stratified log-rank test. Results Median OS was 48.3 months (95% CI, 42.4 to 52.8 months) for KRd versus 40.4 months (95% CI, 33.6 to 44.4 months) for Rd (hazard ratio, 0.79; 95% CI, 0.67 to 0.95; one-sided P = .0045). In patients receiving one prior line of therapy, median OS was 11.4 months longer for KRd versus Rd; it was 6.5 months longer for KRd versus Rd among patients receiving ≥ two prior lines of therapy. Rates of treatment discontinuation because of adverse events (AEs) were 19.9% (KRd) and 21.5% (Rd). Grade ≥ 3 AE rates were 87.0% (KRd) and 83.3% (Rd). Selected grade ≥ 3 AEs of interest (grouped terms; KRd v Rd) included acute renal failure (3.8% v 3.3%), cardiac failure (4.3% v 2.1%), ischemic heart disease (3.8% v 2.3%), hypertension (6.4% v 2.3%), hematopoietic thrombocytopenia (20.2% v 14.9%), and peripheral neuropathy (2.8% v 3.1%). Conclusion KRd demonstrated a statistically significant and clinically meaningful reduction in the risk of death versus Rd, improving survival by 7.9 months. The KRd efficacy advantage is most pronounced at first relapse.

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Isatuximab plus carfilzomib/dexamethasone versus carfilzomib/dexamethasone in patients with relapsed/refractory multiple myeloma: IKEMA Phase III study design

Future Oncology ◽

10.2217/fon-2019-0431 ◽

2020 ◽

Vol 16 (2) ◽

pp. 4347-4358 ◽

Cited By ~ 10

Author(s):

Philippe Moreau ◽

Meletios A Dimopoulos ◽

Kwee Yong ◽

Joseph Mikhael ◽

Marie-Laure Risse ◽

...

Keyword(s):

Multiple Myeloma ◽

Progression Free Survival ◽

Phase Iii ◽

Review Committee ◽

Clinical Trial Registration ◽

Free Survival ◽

Refractory Multiple Myeloma ◽

The Past ◽

Independent Review ◽

Phase Iii Study

Although the treatment of relapsed/refractory multiple myeloma has improved dramatically over the past decade, the disease remains incurable; therefore, additional therapies are needed. Novel combination therapies incorporating monoclonal antibodies have shown significant promise. Here we describe the design of a Phase III study (NCT03275285, IKEMA), which is evaluating isatuximab plus carfilzomib and low-dose dexamethasone, versus carfilzomib/dexamethasone in relapsed/refractory multiple myeloma. The primary end point is progression-free survival. Responses are being determined by an independent review committee using 2016 International Myeloma Working Group criteria, and safety will be assessed throughout. The first patient was recruited in November 2017, and the last patient was recruited in March 2019; 302 patients have been randomized, and the study is ongoing. Clinical trial registration: NCT03275285

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Real-World Outcomes With Generic Pomalidomide in Relapsed Refractory Multiple Myeloma—Experience From a Tertiary Care Cancer Center

JCO Global Oncology ◽

10.1200/go.20.00228 ◽

2021 ◽

pp. 361-367

Author(s):

Suresh Kumar Bondili ◽

Bhausaheb Bagal ◽

Abhinav Zawar ◽

Pradeep Ventrapati ◽

Jayashree Thorat ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Retrospective Analysis ◽

Tertiary Care ◽

Progression Free Survival ◽

Response Rates ◽

Cancer Center ◽

Free Survival ◽

Refractory Multiple Myeloma ◽

Median Progression Free Survival

PURPOSE The prognosis of relapsed and refractory multiple myeloma (RRMM) that is refractory to bortezomib and lenalidomide is very poor wherein the median survival is between 3 and 9 months. We did this retrospective analysis to study the pattern of utilization, tolerance, and outcomes with pomalidomide in these patients having RRMM. MATERIALS AND METHODS Retrospective analysis of all the patients who were treated with generic pomalidomide at Tata Memorial Centre, Mumbai, during the period of May 2017 to March 2019 was done. Patients with secretory disease and who had completed at least one cycle of pomalidomide were analyzed for response rates, toxicity, and survival outcomes. RESULTS A total of 81 patients received pomalidomide-based therapy during this study period, out of which 75 were included in the survival analysis. Forty-eight patients (59.3%) were refractory to both lenalidomide and bortezomib. Overall response rate was 58.7%. Five patients (6.7%) achieved complete response, very good partial response was seen in 13 patients (17.3%), and partial response was seen in 26 patients (34.7%). After a median follow-up of 11 months (range 2-27 months), median progression-free survival was 9.1 months (95% CI, 5.4 to 12.9 months). Median progression-free survival for patients who were refractory to both lenalidomide and bortezomib versus nonrefractory was 5.5 and 12.6 months, respectively, which was significant statistically ( P = .04, hazard ratio, 0.35, 95% CI, 0.28 to 0.97). The median overall survival was not reached. Important toxicities included anemia (28%), neutropenia (16%), pneumonia (16%), and venous thrombosis (5%). CONCLUSION Generic pomalidomide-based therapy is an effective option and is well tolerated in patients with RRMM. Higher response rates and longer survival seen in our study are possibly because of heterogeneity of the study population.

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Isatuximab for relapsed/refractory multiple myeloma: review of key subgroup analyses from the Phase III ICARIA-MM study

Future Oncology ◽

10.2217/fon-2021-0568 ◽

2021 ◽

Author(s):

Paul G Richardson ◽

Simon J Harrison ◽

Sara Bringhen ◽

Fredrik Schjesvold ◽

Kwee Yong ◽

...

Keyword(s):

Multiple Myeloma ◽

Progression Free Survival ◽

Response Rates ◽

Phase Iii ◽

Free Survival ◽

Treatment Need ◽

Disease Response ◽

Refractory Multiple Myeloma ◽

Subgroup Analyses ◽

Unmet Treatment Need

In the Phase III ICARIA-MM study (NCT02990338), the addition of the anti-CD38 monoclonal antibody isatuximab to pomalidomide and dexamethasone led to increased progression-free survival and improved response rates in patients with relapsed/refractory multiple myeloma. There is an unmet treatment need, particularly among patients with poor prognoses, including those with high-risk cytogenetics, those who have renal impairment, those who are elderly and those who are refractory to prior lines of treatment. In this review, the subgroup analyses from the ICARIA-MM study, representing subpopulations with poor prognostic factors, are discussed. Overall, the addition of isatuximab to pomalidomide and dexamethasone improved progression-free survival and disease response rates across different subgroups, regardless of prognostic factor.

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Perifosine Plus Bortezomib and Dexamethasone in Patients With Relapsed/Refractory Multiple Myeloma Previously Treated With Bortezomib: Results of a Multicenter Phase I/II Trial

Journal of Clinical Oncology ◽

10.1200/jco.2010.33.9788 ◽

2011 ◽

Vol 29 (32) ◽

pp. 4243-4249 ◽

Cited By ~ 92

Author(s):

Paul G. Richardson ◽

Jeff Wolf ◽

Andrzej Jakubowiak ◽

Jeff Zonder ◽

Sagar Lonial ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Progression Free Survival ◽

Phase Iii ◽

The Novel ◽

Phase Iii Trial ◽

Free Survival ◽

Refractory Multiple Myeloma ◽

Heavily Pretreated ◽

Previously Treated

Purpose Novel agents have improved patient outcome in relapsed or relapsed/refractory multiple myeloma (MM). Preclinical data show that the novel signal transduction modulator, perifosine, enhances the cytotoxicity of dexamethasone and bortezomib. Clinical data suggest that perifosine in combination with dexamethasone has activity in relapsed or relapsed/refractory MM. Patients and Methods In a phase I/II study, perifosine in combination with bortezomib with or without dexamethasone was prospectively evaluated in 84 patients with relapsed or relapsed/refractory MM. All were heavily pretreated and bortezomib exposed; 73% were refractory to bortezomib, and 51% were refractory to bortezomib and dexamethasone. The dose selected for the phase II study was perifosine 50 mg/d plus bortezomib 1.3 mg/m2, with the addition of low-dose dexamethasone at 20 mg if progression occurred on perifosine plus bortezomib alone. Results An overall response rate (ORR; defined as minimal response or better) of 41% was demonstrated with this combination in 73 evaluable patients, including an ORR of 65% in bortezomib-relapsed patients and 32% in bortezomib-refractory patients. Therapy was generally well tolerated; toxicities, including gastrointestinal adverse effects and fatigue, proved manageable. No treatment-related mortality was seen. Median progression-free survival was 6.4 months, with a median overall survival of 25 months (22.5 months in bortezomib-refractory patients). Conclusion Perifosine–bortezomib ± dexamethasone demonstrated encouraging activity in heavily pretreated bortezomib-exposed patients with advanced MM. A phase III trial is underway comparing perifosine–bortezomib plus dexamethasone with bortezomib–dexamethasone in patients with relapsed/refractory MM previously treated with bortezomib.

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