Response Criteria For Multiple Myeloma Research Articles

Phase I/II Study Evaluating the Safety and Efficacy of Venetoclax in Combination with Dexamethasone As Targeted Therapy for Patients with t(11;14) Relapsed/Refractory Multiple Myeloma

Phase I/II Study Evaluating the Safety and Efficacy of Venetoclax in Combination with Dexamethasone As Targeted Therapy for Patients with t(11;14) Relapsed/Refractory Multiple Myeloma

Efficacy and Safety of CAR-T Therapy with Safety Switch Targeting Bcma for Patients with Relapsed/Refractory Multiple Myeloma in a Phase 1 Clinical Study

Background: Encouraging results are seen from several early phase clinical trials on the cellular immunotherapy based on chimeric antigen receptor (CAR)-engineered T (CAR-T) targeting B cell maturation antigen (BCMA) for the treatment of relapsed/refractory (RR) multiple myeloma (MM). We developed an anti-BCMA CAR-T cell product manufactured via gamma-retrovirus-mediated transduction of activated T cells to express a second-generation CAR with the 4-1BB costimulatory domain along with a truncated epidermal growth factor receptor (tEGFR) as a safety switch. The preclinical study confirmed its high reactivity against MM cells. Methods: A phase 1 clinical trial (NCT03093168) has been launched to evaluate the safety and feasibility of this BCMA CAR-T cell product for treating RRMM. The enrolled RRMM patients had received at least 2 prior treatment regimens, including a proteasome inhibitor and an immunomodulatory agent, or are double-refractory, and have over 5% BCMA expression on plasma cells (Nine patient with extramedullary plasmacytoma does not express BCMA). Patients were subjected to a lymphodepleting regimen with Cy (300 mg/m2, d-5 to d-3) and Flu daily for 3 days (25 mg/m2, d-5 to d-3) prior to the CAR-T infusion (d0) at a dose of 9×106CAR+ cells/kg. The efficacy was assessed by the International Uniform Response Criteria for Multiple Myeloma, and the toxicity is graded by CTCAE 4.03. Results: As of March 1th, 2019, 46 patients had been infused with this intended dose of the autologous BCMA CAR-T cells, and 44 patients had reached at least 1 month of follow-up. As of this data cut-off, the overall response rate (ORR) for the 44 evaluable patients was 79.6%, including 2sCRs, 16CRs, 8VGPRs and 8PRs, and 16 patients reached MRD-negative response. The CAR-T cell expansion and persistence were consistently observed throughout these patients. The medianPFS is 15mon, and the median OS result has not been reached (49.16% progression-free survival, and 53.95% overall survival at 24 months). Among the 44 infused patients, 22.7% had grade 1-2 Cytokine release syndrome (CRS ) and 6.8% (3 patients) had grade 3 CRS. No grade 4 CRS reactions developed and all toxicities were fully reversible. Conclusions: Our result demonstrates the high potential of this single CAR-T infusion therapy for RRMM, including 2sCRs, 16CRs and ongoing clinical responses for more than 26 months, with manageable CRS to date. These initial data provide strong evidence to support the further development of this anti-myeloma cellular immunotherapy. Disclosures No relevant conflicts of interest to declare.

Single Arm, Prospective, Open-Label Phase II Trial to Evaluate the Efficacy of Isatuximab in Patients with Monoclonal Gammopathy of Renal Significance

Background: Monoclonal gammopathy of renal significance (MGRS) is a monoclonal B cell disorder, not meeting the definition of lymphoma or myeloma, that produces monoclonal proteins which deposit in the kidneys. Permanent renal damage can occur either as a consequence of direct deposition of toxic proteins or by an induced inflammatory response. Due to the low burden of the plasma cell clone, patients do not otherwise qualify for potentially toxic anti-plasma cell treatments and treatment is generally based on consensus opinion. To date there are no clinical trials exploring treatment options. Isatuximab is a chimeric mouse/human IgG1k monoclonal antibody which targets CD38 on both malignant and normal plasma cells and exhibits it antitumor effects primarily by antibody-dependent cellular toxicity. Isatuximab has recently been shown to be an active drug in the treatment of multiple myeloma, with improvements seen in hematologic and renal markers, and has been shown to have manageable toxicity. Given the efficacy of isatuximab in multiple myeloma, we propose a trial evaluating isatuximab monotherapy to treat the small plasma cell clone in MGRS with the hopes of maximizing response and minimizing toxicity. Study Design and Methods: The primary objective of this study is to evaluate efficacy of isatuximab monotherapy in patients with MGRS in order to establish a standard of care treatment for patients with this disease. Adult patients with proteinuria of at least 1 gram in 24 hours and a histopathological diagnosis of MGRS on renal biopsy in the last 24 months will be eligible for the trial. Patients will be excluded if their estimated GFR is below 30 mL/min, they have multiple myeloma, high risk smoldering myeloma, other B cell neoplasm meeting criteria for treatment, concurrent diabetic nephropathy, or require dialysis. Patients will be screened for B cell disorders with bone marrow biopsy and aspirate, serum protein electrophoresis (SPEP) with immunofixation (IFE), 24-hour urine protein electrophoresis (UPEP), free light chain (FLC) testing and screening PET/CT at time of enrollment. Enrolled patients will be administered isatuximab 20 mg/kg IV weekly for 4 weeks and then will receive the same dose every 2 weeks thereafter for a total of 6 months. Patients may be continued on treatment following completion of the 6 months at the discretion of the provider. To reduce the risk of infusion related reactions, patients will receive premedications with corticosteroids, diphenhydramine, H2 blockade and acetaminophen at least 60 minutes prior to infusion. Patients will have repeat SPEP + IFE, 24-hour UPEP + IFE and FLC testing every 4 weeks. There will be an optional repeat kidney biopsy 9-12 months following treatment initiation to assess pathologic response in the kidneys. Statistical Methods: The study will be comprised of 20 patients being treated with isatuximab over a span of 24-30 months. Ten patients will be initiated on the therapy for a period of 6 months. Interim analysis will be done after these patients have completed all the treatment cycles. If 4 out of 10 patients show response in form of improved/stable renal function, the study will proceed to include next 10 patients. If >50% of the first group of 10 patients show doubling of creatinine while on therapy, that would be considered as an indication to discontinue the therapy and the study due to drug toxicity. Endpoints: The primary endpoint will be efficacy as measured by renal response and hematologic response. Renal response will be measured by assessing the amount of proteinuria in a 24 hour urine sample. A sustained reduction in proteinuria by 30% from the patient's baseline amount of proteinuria with stable renal function (serum eGFR within 20% of baseline) will be considered a positive renal response. Hematologic response will be quantified per the 2016 International Myeloma Working Group (IMWG) uniform response criteria for multiple myeloma. An important secondary endpoint will be safety and will be analyzed from all patients who receive any study drug. Adverse events will be characterized and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Other endpoints include time to dialysis and rate of minimal residual disease (MRD) negativity. Disclosures Lentzsch: Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy. Bhutani:Sanofi: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Our trial will be evaluating the efficacy of targeting CD38 on plasma cells with isatuximab in patients with monoclonal gammopathy of renal significance (MGRS). We will evaluate the effects of this drug on 24 hour proteinuria and hematologic response.

A Bispecific CAR-T Cell Therapy Targeting Bcma and CD38 for Relapsed/Refractory Multiple Myeloma: Updated Results from a Phase 1 Dose-Climbing Trial

Background: Anti-B cell maturation antigen (BCMA) chimeric antigen receptor(CAR) T cell therapy has shown promising results from a series of clinical trials. But short progression-free survival (PFS) due to BCMA-negative or positive relapse is pretty much the agenda.Here we constructed a dual-target BM38 CAR incorporating the anti-CD38 and anti-BCMA single-chain variable fragment in tandem plus 4-1BB signaling and CD3 zeta domains and conducted the first-in-human clinical trial(ChiCTR1800018143) in patients with RRMM to evaluate the safety, efficacy and duration of BM38 T cells. Methods:Patients with relapsed or refractory multiple myeloma(RRMM), who had received at least 2 prior treatment regimens, including a proteasome inhibitor and an immunomodulatory agent, were enrolled in the phase 1 dose-climbing trial of the bispecific CAR-T cell therapy. Patients were subjected to a lymphodepleting regimen with Cy(250 mg/m2, d-5 to d-3) and Flu(25 mg/m2, d-5 to d-3) daily prior to the CAR-T infusion (d0). The dose gradients of infused CAR-T cells were 0.5, 1.0, 2.0, 3.0 and 4.0×106 cells/kg and at least 2 patients were involved at every dose level. The efficacy was assessed by the International Uniform Response Criteria for Multiple Myeloma (2016), and the toxicity was graded by CTCAE 5.0. Results: As of 31 July 2019, 16 pts consisting of 10(62.5%) with genetic abnormalities and 5(31.25%) with extramedullary lesions,had received BM38 CAR-T cells in the 5 dose-climbing cohorts. At a median follow-up of 36 weeks, no DLTs and no grade ≥ 3 neurotoxicities were observed. Cytokine release syndrome (CRS), mainly grade 1-2, was reported in 10 of 16 (62.5%) pts; 4 pts had grade ≥ 3 CRS that resolved by tocilizumab and supportive treatment. Almost all the pts were observed with hematological toxicities relieved in the first month after infusion.14(87.5%) pts achieved an overall response with 8(50%) sCR, 2(12.5%) VGPR and 4(25.00%) PR and 14(87.5%) reached bone marrow minimal residual disease(MRD)-negative status. The longest duration of sCR was over 51 weeks and 5(62.5%) of 8 patients had still maintained sCR and 2 transformed to VGPR and 1 to PR. The median duration of progression-free survival(PFS) had not been reached; PFS rates at 9 months was 75%. More encouragingly, 5(100%)extramedullary lesions were eliminated.Up to the observed day, the BM38 CAR-T cells still exist in the patients' peripheral blood by flow cytometry(FCM) and quantitative polymerase chain reaction(q-PCR). The peak time of CAR-T cells proliferation of sCR patients was about the 2nd week after infusion, which was earlier than other patients. 4.0 × 106 CAR T cells (pt11, 12 and 15) were selected for the optimal dose with superior response and acceptable toxicities and expansion cohort would be conducted. Conclusions:Our study demonstrates an improved efficacy with the bivalent BM38 CAR-T therapy for RRMM with a high ORR, especially a higher rate and a longer duration of sCR and effective elimination for extramedullary lesions. No neurotoxicity was observed. CRS and other toxicities were manageable. These initial data provide strong evidence to support the further development of the dual-target CAR-T therapy for RRMM. Clinical trial information: ChiCTR1800018143 Disclosures No relevant conflicts of interest to declare.

S826 IMPROVED EFFICACY AND SAFETY OF A DUAL‐TARGET CAR‐T CELL THERAPY TARGETING BCMA AND CD38 FOR RELAPSED/REFRACTORY MULTIPLE MYELOMA FROM A PHASE I STUDY

Background:Encouraging results are seen from several early phase clinical trials on the cellular immunotherapy for relapsed/refractory (RR) multiple myeloma (MM), including anti‐B cell maturation antigen (BCMA) CAR‐T cell therapy and anti‐CD38 daratumumab (DARA) monotherapy. We conducted an anti‐BCMA and anti‐CD38 dual‐target CAR‐T cell in order to avoid negative relapse of single‐target loss. Here we report a promising results on 12 patients about the efficacy and safety in the ongoing phase I study.Aims:1.To evaluate the safety of the anti‐BCMA and anti‐CD38 dual‐target CAR‐T cell in RRMM, including cytokine release syndrome (CRS), neurotoxicity and other adverse events. 2.To assess the efficacy of the anti‐BCMA and anti‐CD38 dual‐target CAR‐T cell in RRMM, including the overall response rate(ORR),duration of remission and Progression‐free survival(PFS). 3.To estimate the proliferation and persistence of the dual‐target CAR‐T cell in the blood of RRMM patients.Methods:A phase I clinical trial (ChiCTR1800018143) has been launched to evaluate the efficacy and safety of the dual‐target CAR‐T cell product for RRMM. The enrolled RRMM patients had received at least 2 prior treatment regimens, including a proteasome inhibitor and an immunomodulatory agent, or are double‐relapsed or relapse after autologous hematopoietic stem cell transplantation(ASCT). Patients were subjected to a lymphodepleting regimen with Cy(250 mg/m2,d‐5 to d‐3) and Flu(25 mg/m2,d‐5 to d‐3) daily prior to the CAR‐T infusion (d0).The median number of infused cells was 2.17(0.5∼4.0) × 106 CAR+ cells/kg. The median follow‐up times is 21.5(6∼33)weeks and 66.7%(8/12) are more than 5 months. The efficacy was assessed by the International Uniform Response Criteria for Multiple Myeloma(2016), and the toxicity was graded by CTCAE 5.0.Results:As of January 31, 2019, 12 patients consisting of 66.67%(8/12) with genetic abnormalities,16.7%(2/12) with ASCT and 16.7%(2/12) with extrandal disease, have been infused with thedual‐target CAR‐T cell product. The overall response rate(ORR) is 83.3%(10/12), including 5 sCR, 2 VGPR and 3 PR. the shortest duration of sCR is 8 weeks and the longest one is over 26 weeks and 60%(3/5) have still maintained sCR more than 2 month. More encouragingly, 60%(6/10) have still kept sustained remission and allextramedullary lesions have been eliminated.The 8‐week Progression‐free survival(PFS) is 0.90 and 12‐week PFS is 0.77. Up to now, the CAR‐T cells still exists in the patients’ peripheral blood by flow cytometry and q‐PCR. The peak time of CAR‐T cells proliferation of sCR patients is about the 2nd week after infusion, which is earlier than other patients. 83.3%(10/12) were observed with cytokine release syndrome (CRS) and severe CRS(≥ Grade 3) accounted for 33.33%(4/12). No neurotoxicity was observed. Almost all the patients were observed with hematological toxicities. 16.7%(2/12) of patients was observed with hepatotoxicity and one patient with nephrotoxicity, which were relieved after symptomatic treatment.Summary/Conclusion:Our study demonstrates an improved efficacy with dual‐target CAR‐T therapy targeting BCMA and CD38 for RRMM with a high ORR, especially a higher rate and a longer duration of sCR. CRS and hematological toxicities are observed but manageable. Other toxicity is rare. These initial data provide strong evidence to support the further development of the dual‐target CAR‐T therapy for RRMM.ChiCTR1800018143 image

Low Dose of Human scFv-Derived BCMA-Targeted CAR-T Cells Achieved Fast Response and High Complete Remission in Patients with Relapsed/Refractory Multiple Myeloma

▪Introduction: B Cell Mature Antigen (BCMA)-targeted chimeric antigen receptor T (CAR-T) cell therapy emerges as promising treatment for patients with relapse/refractory multiple myeloma (RRMM). Previous studies indicate patients who receive high-dose CAR-T cells may achieve better remission but have worse adverse events, like cytokine release syndrome (CRS). To solve this dilemma, we have developed novel autologous CAR-T therapeutics CT053 that are genetically modified T cells comprising an extracellular anti-BCMA human scFv and an intracellular 4-1BB costimulatory motif connected to a CD3-zeta T cell activation domain.Methods: A multi-center investigator-initiated clinical study is designed to evaluate CT053 in patients with RRMM who have failed in the prior treatment with ≥2 regimens, including a proteasome inhibitor, an immunomodulatory agent, and anti-CD38 monoclonal antibody. All patients have ≥50% BCMA expression on malignant cells. Patients are subjected to the lymphodepletion with 20-25 mg/m2 fludarabine and 300-500 mg/m2 cyclophosphamide daily for 2-4 days prior to receiving single-dose infusion of CT053 CAR-T cells. In case of progressive disease, patient may be dosed again on basis of investigators' evaluation of the disease status, BCMA expression and CAR-T persistence. Most enrolled patients received a single dose of 1.5 x 108 cells, except for 1 patient who received 0.5 x 108 cells and 1 patient who was infused with 1.8 x 108 cells. The primary outcome measure is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs) and CAR T related AEs. Additional outcome measures include clinical response assessed according to the IMWG Uniform Response Criteria for Multiple Myeloma, overall and progression-free survival, pharmacokinetics and pharmacodynamic of CT053.Results: The study was performed in compliance with the declaration of Helsinki. As of the data cut-off date (July 10th, 2018), 16 patients (median 55 [39 to 67] years old) with a median of 3.9 (0.4 to 16.7) years since MM diagnosis, were infused with CT053. Patients had a median of 4 prior different regimens (range 2 to 10), and 56% (9/16) patients received prior autologous or allogeneic stem cell transplant.Among 16 patients, no neurotoxicity and no dose-limiting toxicities (DLT) were observed. The most common grade≥3 CAR-T related AEs were 3 thrombocytopenia (19%), 3 leukopenia (19%), 2 anemia (13%), 2 neutropenia (13%), 2 fever (13%) (Figure 1A). CRS was reported in 3 patients, including 1 Grade 3, 1 Grade 2 and 1 Grade 1, who had rapid recovery after Tocilizumab administration.13/16 patients were eligible for initial evaluation of early clinical response with a median observation period of 8 (4 to 36) weeks. Overall response rate (ORR) in 13/13 patients was 100% post treatment. 12/13 patients (92%) quickly achieved partial response (4 PR), very good PR (6 VGPR), and complete response (2 CR) within 4 weeks post single-dose infusion (Figure 1B). 5/12 patients (42%) who were dosed at ≥1.5 x 108 CT053 CAR-T cells obtained CR at a median of 8 weeks post treatment. Durable responses from 4 weeks towards the data cut-off date were found in 12/13 patients (92%). One relapse from VGPR by the Week 12 was reported in a patient who had aggressive RRMM at enrollment and received the reduced dose of lymphodepletion regimen at 19 mg/m2 fludarabine and 192 mg/m2 cyclophosphamide for 2 days prior to CT053 infusion. Because positive BCMA expression on malignant cells was verified at relapse, the patient was re-dosed with CT053 at the Week 16 and subjected to the further evaluation.All patients had detectable CAR-T expansion from Day 3 post CT053 infusion. Expansion peaks were found on Day 7 (5/13), Day 14 (6/13) and Day 21 (2/13). 11/13 patients had notable persistence of CT053 CAR-T cells up to 4-6 months. The only relapsed patient had the lowest CAR-T expansion peak among 13 patients, indicating the potential correlation between CAR-T expansion and response outcome.Conclusions: Data from this early-stage clinical study showed the unparalleled safety and efficacy of CT053 CAR-T cells. Major AEs were transient, manageable, and reversible. 100% ORR in 13/13 evaluable patients were reported post single-dose infusion of 0.5~1.8 x 108 cells. 5/12 patients who were dosed at ≥1.5 x 108 CAR-T cells rapidly achieved durable CR at median of 8 weeks, suggesting CT053 could be developed as competitive therapeutics to treat patients with RRMM. DisclosuresRuan:CARsgen Therapeutics: Employment. Xiao:CARsgen Therapeutics: Employment, Equity Ownership. Wang:CARsgen Therapeutics: Employment, Equity Ownership. Li:CARsgen Therapeutics: Employment, Equity Ownership.

Durable Remission Achieved from Bcma-Directed CAR-T Therapy Against Relapsed or Refractory Multiple Myeloma

Background: Promising results are seen from several early phase clinical trials on the cellular immunotherapy based on chimeric antigen receptor (CAR)-engineered T (CAR-T) targeting B cell maturation antigen (BCMA) for the treatment of relapsed/refractory (RR) multiple myeloma (MM). We developed an anti-BCMA CAR-T cell product manufactured via gamma-retrovirus-mediated transduction of activated T cells to express a second-generation CAR with the 4-1BB costimulatory domain along with a truncated epidermal growth factor receptor (tEGFR) as a safety switch. The preclinical study confirmed its high reactivity against MM cells.Methods: We initiated a phase 1 clinical trial (NCT03093168) to evaluate the safety and feasibility of this BCMA CAR-T autologous cellular therapy for treating RRMM. The enrolled RRMM patients either had received at least 3 prior treatment regimens, including a proteasome inhibitor and an immunomodulatory agent, or were double-refractory, and have over 5% BCMA expression on plasma cells (One patient with extramedullary plasmacytoma does not express BCMA). Patients were subjected to a lymphodepleting regimen with Cy (300 mg/m2, d-5 to d-3) and Flu daily for 3 days (25 mg/m2, d-5 to d-3) prior to the CAR-T infusion (d0) at a dose of 9´106 CAR+ cells/kg. The efficacy was assessed by the International Uniform Response Criteria for Multiple Myeloma, and the toxicity was graded by CTCAE 4.03.Results: As of July 6th, 2018, 17patients had been infused with this intended dose of the autologous BCMA CAR-T cells, and 14 patients had reached at least 1 month of follow-up. As of this data cut-off, the most common non-haematologicalgrade 3 adverse events were pneumonia, hypophosphatemiaand hypocalcemia(two[14%] of 14patients), and fever, cytokine release syndrome,and neurotoxicities (one[7%]of 14patients).All toxicities were fully reversible. The overall response rate (ORR) for the 14 evaluable patients was 79%, including 3 sCRs, 4 CRs and 2 MRD-negative responses (2 VGPR). The CAR-T cell expansion and persistence were consistently observed throughout these patients.The durable remission was observed for two early enrolled patients, with the ongoing objective response (1 sCR and 1 VGPR) lasting more than 15 months.Conclusions: Our result demonstrates the high potential of this single CAR-T infusion therapy for RRMM, including 3 sCRs and ongoing durable clinical responses, with only mild and manageable CRS to date. These initial data provide strong evidence to support the further development of this anti-myeloma cellular immunotherapy. DisclosuresLiu:HRAIN Biotechnology: Employment. Fang:HRAIN Biotechnology: Employment. He:HRAIN Biotechnology: Employment. Xie:HRAIN Biotechnology: Employment. Chen:HRAIN Biotechnology: Employment. Wei:HRAIN Biotechnology: Employment. Tao:HRAIN Biotechnology: Employment. Wang:Immune Design: Equity Ownership; HRAIN Biotechnology: Consultancy, Equity Ownership.

T Cells Expressing Anti B-Cell Maturation Antigen Chimeric Antigen Receptors for Plasma Cell Malignancies

Introduction:Chimeric antigen receptor (CAR) modified T cells targeting B-cell maturation antigen (BCMA) have shown activity in a case series of patients with relapsed or refractory Multiple Myeloma (MM), but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported. We aimed to define the duration of disease, number of treatment lines, treatment course, extramedullary plasma cell tumor, hematopoietic stem cell transplantation, FISH abnormal gene number, risk (combined FISH and second-generation sequencing analysis) ,feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in patients with malignant plasma cell disease treated with BCMA-CAR T cells. This trial is registered with ChiCTR, number ChiCTR-OPC-16009113.Methods:Between March 10, 2017, and March 27, 2018, 28 patients (including 26 patients with relapsed or refractory MM, 1 patient with Plasma cell leukemia and 1 patient with POEMS) were enrolled and infused with BCMA-CAR T cells. The CAR-BCMA chimeric antigen receptor was encoded by the lentiviral vector and contained a murine anti-BCMA single-chain variable fragment, a CD8a hinge, the CD28 transmembrane regions and intracellular domain and CD3-ζ T-cell activation domain. Peripheral blood mononuclear cells were collected from the patient by leukapheresis, and whole peripheral blood mononuclear cells were cultured and transduced. Patients received a target dose of 5.4 ~ 25.0×106 anti-BCMA CAR T cells per kilogram of body weight after a conditioning chemotherapy regimen of cyclophosphamide and fludarabine. MM response assessment was conducted according to the International Uniform Response Criteria for MM. Cytokine-release syndrome (CRS) was graded as Lee DW et al. described (Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188-195.)Results: Twenty-six of 28 treated patients obtained remission. According to the expression rate of BCMA on the surface of plasma cells, all patients were divided into BCMA strong expression group (22 cases, BCMA expression rate ≥ 50%) and BCMA weak expression group (6 cases, BCMA expression rate <50%). The overall response rate for BCMA strong expression group was 87%, with 73% complete response. The overall response rate for the BCMA weak expression group was 100%, with 33% very good partial response or complete response (Figure a-d). The overall survival of the two groups was undefined (a strong group) and 206.5 days (a weak group) respectively (P=0.0468). The median disease-free survival of the two groups was 296 days (strong group, 20 responded cases) and 64 days (weak group,6 cases) respectively (P=0.0069) (Figure e, f). Patients with longer duration have shorter overall survival time. Patients with soft-tissue plasmacytomas have short disease-free survival (155 days vs. 327 days) (Figure g, h). All toxicities were fully reversible, with the most severe being grade 3 cytokine release syndrome that occurred in four of 28 patients. High peak blood CAR+ cell levels were associated with anti-MM responses. Blood CAR-BCMA T cells were predominantly highly differentiated CD8+ T cells after infusion.Conclusions: BCMA-CAR T cell therapy is feasible, safe, and mediates potent anti-tumor activity in relapsed/refractory Multiple Myeloma. All toxicities were reversible Our results should encourage additional development of CAR T-cell therapies for other plasma cell malignancies such as plasma cell leukemia and POEMS. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-Bcma CAR T Cell Therapy

Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-Bcma CAR T Cell Therapy

Addition of Bortezomib to High Dose Melphalan As Conditioning Regimen for Autologous Stem Cell Transplantation Improves the Response Rate in Newly Diagnosed Multiple Myeloma Patients

High-dose Melphalan (HDM) is the most commonly used conditioning regimen for autologous stem cell transplantation (ASCT) in newly diagnosed transplant-eligible Multiple Myeloma (MM) patients. Recent evidence suggests that the depth of response after induction therapy influences progression free survival (PFS) and, in most studies, overall survival (OS). Actually the effect of the inclusion of new drugs in the conditioning regimen for ASCT is still unknown. Phase I-II clinical study showed that the addition of Bortezomib (Bor) to HDM is safe and a promising conditioning regimen. Thus, in this study we analyzed a single center experience on the use of Bor in combination with HDM (Bor-HDM) as conditioning regimen before ASCT as frontline treatment in MM patients in order to evaluate the safety and the response rates of this combination regimen. We analyzed a total cohort of 48 newly diagnosed MM patients (25 females and 23 males; median age 60 years, range 42-70) admitted consecutively to our Bone Marrow Transplantation Center from 2008 to 2014. Regarding prognostic stratification, 25% of patients were classified as stage III according to International Staging System (ISS), and 12% exhibited high-risk cytogenetic features (defined by presence of del(17p) and/or t(4;14) and/or t(14;16)). All patients with the exception of three underwent to 3-drugs Bor-based induction therapy including Bor (median cumulative dose: 28.9 mg/m2), Thalidomide and Dexamethasone (VTD). After induction therapy and stem cell collection 28 out of 48 patients were treated with Bor-HDM, whereas 20 patients with HDM alone as conditioning regimen before ASCT. HDM was administered on day -2 (median dose: 200 mg/m2), and a single-dose Bortezomib at the dosage of 1.3 mg/m2 was administered on day -1 in the Bor-HDM group. Stem cells were reinfused on day 0 (median number of CD34+ infused: 3.3x106/Kg, range 1.86-6x106/Kg). Responses were evaluated at day 100 after ASCT, and definitions of response were used according to the International Myeloma Working Group (IMWG) Uniform Response Criteria for MM. Quantitative variables were compared by non-parametric Kruskal-Wallis and Mann-Whitney tests as appropriate and categorical variables were analyzed by Chi-square and Fisher’s exact test. pvalue of <0.05 was considered significant.Any significant difference was not observed between Bor-HDM group vs HDM group, regarding age at diagnosis (p=0.77), sex (p=0.24), cumulative induction dose of Bortezomib (p=0.42), dose of Melphalan used for conditioning (p=0.16) and the median number of CD34+ cells infused (p=0.12). Distribution of ISS stage was similar in the two groups (p=0.14), as well as that of high-risk cytogenetic (p=0.14). Moreover the response rates after the induction therapy was not statistically different in the two groups of patients analyzed (sCR + CR: 19% in Bor-HDM group vs 26% in HDM group; VGPR: 33% vs 48%; PR: 48% vs 26%, p=0.22). Any significant difference on hematopoietic recovery rates was not observed in Bor-HDM as compared to HDM alone with a mean time to neutrophil recovery of 12 days (range 9-18) and to platelet recovery of 12 days (range 9-21) in both groups. Bor-HDM conditioning was well tolerated, without increase of neuropathy occurrence.Then we analyzed the response rate after ASCT, showing that the overall response rate (ORR) was significantly higher in Bor-HDM group as compared to HDM (sCR+CR: 56% in Bor-HDM vs 17% in HDM; VGPR 30% vs 28%; PR: 15% vs 56%, p=0.0072) with a higher number of "good quality" response (sCR + CR + VGPR: 86% vs 45%; p=0.0075). The number of sCR was also significantly higher in Bor-HDM as compared to HDM alone (23% vs 0%, p=0.067). Moreover an improvement of the response rate after ABMT was seen more frequently in the Bor-HDM group as compared to the HDM group (p=0.0063). We then observed that the number of patients that underwent tandem ASCT was higher in the HDM group (66% vs 41%), even not reaching a statistical significance. In conclusion, this retrospective analysis suggests that BOR-HDM is safe as conditioning regimen with a higher response rate after ASCT as compared to the standard HDM regimen giving the rational design for randomized studies needed to assess whether this conditioning regimen is superior to HDM alone. DisclosuresGiuliani:Celgene: Research Funding; Janssen: Research Funding.

Potential pitfalls of serum free light chain analysis to assess treatment response for multiple myeloma.

Response to treatment in patients with a plasma cell disorder is typically measured by evaluating the bone marrow and myeloma markers, including monoclonal protein spike and immunofixation (IFE) in blood and urine, and serum free light chains (sFLCs). Stringent complete response criteria for Multiple Myeloma (MM) patients require a normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. We performed a retrospective chart review to further evaluate these criteria. A total of 142 patient charts were analysed. Of these, 17 patients were found to have an abnormal sFLC ratio, but no other evidence of disease, including normal flow cytometry and normal fluorescence insitu hybridization (FISH) analysis on highly selected plasma cells. In all patients, the abnormal sFLC ratio was caused by abnormalities in the serum kappa light chains. These results suggest that current definitions may need to be revised to take aberrancies related to abnormal immune recovery into account.

Effect of Expression of Multidrug Resistance Genes on Efficacy the Treatment of Multiple Myeloma By Proteasome Inhibitor

Background: Increased expression of efflux protein, such as P-glycoprotein, multidrug resistance protein, lung resistance protein, breast cancer resistance protein are a major reason for resistance to existing or previously effective therapy multiple myeloma (MM). Effect of the expression of genes of multidrug resistance (MDR) - MDR1, MRP1, LRP, and BCRP on the efficacy of therapy with proteasome inhibitor is currently not well understood.Aim: Determination of mRNA expression of genes responsible for the development of drug resistance, such as MDR1, MRP1, LRP, BCRP in bone marrow aspirates in patients with newly diagnosed and refractory / relapsed MM before start bortezomib-containing chemotherapy programs.Materials and methods: We studied bone marrow aspirates of 29 patients (12 men and 17 women) aged 48 to 77 years (median 60 years) with stage 3 MM by classification Durie-Salmon. 14 of studied patients made a group of newly diagnosed MM. 15 patients made a clinically refractory / relapsed group MM. The bone marrow in this group of patients was studied after treatment with alkylating agents at the time of registration of resistance to the given therapy. In the future, all patients were treated by bortezomib - containing chemtheapy regimens. mRNA expression studied genes was determined by semi-quantitative polymerase chain reaction reverse transcription.Results: In both groups of patients had comparable expression of all studied MDR`s genes. In the group of newly diagnose patients the MDR 1 mRNA expression was detected in 93% (13/14) of the samples, the mRNA of the gene MRP 1 was detected in 79% (11/14). The BCRP mRNA expression was detected in 100% of the investigated samples. The expression of mRNA of the gene LRP was identified in 71% of the studied cases (10/14). In the group of patients after treatment with alkylating agents the expression of mRNA of MDR1 was detected in 87% (13/15) of samples, MRP 1 was detected in 93% (14/15), BCRP was in 100% of cases, and the LRP mRNA was detected in 13/15 (87%) of the samples.Treatment efficacy was assessed by Iinternational Unified Response Criteria for multiple myeloma after the 6 cycles of treatment. Evaluation of treatment efficacy in patients previously non-treated with chemotherapy as well as in the group of clinical resistance patients showed comparable results by the number of objective response rate (57% and 60% respectively).Conclusions: The expression of MDR genes does not determine the resistance of tumor cells to bortezomib. The proteasome inhibitor bortezomib can overcome the MDR gene activity, attaching it to alkylating drugs increases the sensitivity to them of resistant tumor cells. DisclosuresGolenkov:Novartis: Consultancy.

Descriptive Analysis of Bortezomib Use in Multiple Myeloma in Four Adult University Teaching Hospitals in Quebec, Canada

Background: Bortezomib, a reversible inhibitor of the 26S proteasome widely used in the treatment of multiple myeloma, is now being used in various other indications. Pharmacy directors gave the Therapeutic Drug Management Program (TDMP - www.pgtm.qc.ca) the mandate to evaluate bortezomib use in four University Hospitals in Quebec, Canada.Objectives: Describe bortezomib use for all indications in our hospitals and review its utilisation in the treatment of multiple myeloma.Methods: A review of pharmacy databases was performed to identify patients who receivedbortezomib between June1st 2012 and May 31st 2013. The pharmaceutical and medical records of every patient who received bortezomib were reviewed to assess the treatment, pathology and adverse events.Results: Two hundred and thirty two bortezomib regimens were administered to 227 different patients during the study period. Median age was 68. The most frequent indication (55%) was first-line treatment of multiple myeloma (n=128) followed by treatment of relapsed/refractory disease (31%) (n=73). Various other indications, including amyloidosis (n=17), lymphoplasmacytic lymphoma (n=12) and mantle cell lymphoma (n=2), represented 13% of the population.At the time of data analysis, 35% of patients were still treated with bortezomib, 25% had finished their planned treatment and 34% had discontinued treatment because of adverse events or disease progression. Fifteen patients (6%) died during the study period.Among the 45 patients eligible for autologous stem cell transplant (ASCT), the main regimen used was the association of bortezomib and dexamethasone (VelDex) (n=27), primarily using subcutaneous bortezomib (n=24) at 1.3 mg/m2 (n=30). Median treatment duration was four cycles. Twenty-eight patients have undergone ASCT and only two progressed.The association of bortezomib, melphalan and prednisone (VMP) (54.2%) followed by VelDex (29%) and the association of cyclophosphamide, bortezomib and dexamethasone (CyborD) (16.8%) were the regimens used in the population (n=83) not eligible to ASCT. Response rate using international uniform response criteria for multiple myeloma was 47.9% excluding patients still receiving treatment at the time of data collection.Seventy three patients received bortezomib for relapsed/refractory myeloma. Of these patients, thirty two (43.8%) discontinued therapy, nineteen due to disease progression, eight for the occurrence of side effects and five for other reasons. The initial dose was variable, from 1.0 to 1.6 mg/m2, and close to half of this patient population received CYBorD (49.4%), followed by VelDex (30.2%) and VMP protocols (15%). The number of cycles for patients who completed treatment (4 to 9) as well as the median exposure time (57 to 223 days) was also highly variable.Respectively 8.5% and 10.9% of the population treated with bortezomib for multiple myeloma were hospitalized (n=17) or had to discontinue treatment (n=22) because of adverse events (mostly hematologic toxicity, peripheral neuropathy or gastro-intestinal toxicity).Conclusions: Bortezomib is widely used in the treatment of multiple myeloma. Treatment algorithms should be developed and implemented to optimize the use of bortezomib, particularly in the relapsed/refractory setting. Standard regimens should also be implemented in each center. The utilisation of pre-printed orders for the prescription of chemotherapy regimens promotes uniform prescription. A review of the literature should be performed and recommendations should be made for the use of bortezomib in off-label indications like amyloidosis and lymphoplasmacytic lymphoma. DisclosuresOff Label Use: bortezomib use in amyloidosis and lymphoplasmacitic lymphoma. Lemieux-Blanchard:celgene: Membership on an entity's Board of Directors or advisory committees; Amgen and Janssen: Other: preceptorship. Bérard:Janssen: Honoraria. Sebag:Janssen: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Novartis: Honoraria.

Unmeasurable Serum M-Protein Multiple Myeloma Benefit Less from Bortezomib Than Measurable Myeloma

Background: According to international uniform response criteria for multiple myeloma(MM), unmeasurable disease is defined as serum M-protein level of less than 1 g/dl and urine M-protein level less than 200 mg/d. The anti-tumor activity of bortezomib partly depended on degradation of misfolded or unfolded proteins through ubiquitin-proteasome pathway. We postulate that bortezomib may not able to induce sufficient apoptosis in unmeasurable serum M-protein myeloma comparing with measurable group. The goal of this study is to determine whether the level of serumM-protein expression act as a validated surrogate marker to predict the prognosis in the bortezomib-based therapy.Materials and Methods: Between 2004 and 2013, a retrospective study was carried out of 630 patients with new diagnosis MM (NDMM) excluding light chain MM, who underwent bortezomib-based therapy or thalidomide-based therapy and for whom had complete data on clinical characteristics, molecular cytogenetics variety, treatment and overall survival (OS) time. According to the level of M-protein, they were devided into two groups: unmeasurable (serum M-protein<1g/dl) and measurable (serum M-protein>1g/dl) M-protein MM.Results: 1) 92 patients were defined asunmeasurable M-protein MM and were 14.60% of the 630 cases cohort. 2) Compared with measurable M-protein MM, unmeasurable M-protein MM were characterized by younger age(54.89 vs.58.85, p<0.001), lower frequency of IgG and IgA M-protein type (IgG, 14.13% vs. 68.96%; IgA, 21.74% vs. 30.86%; p<0.001), higher incidence of IgD M-protein type (IgD, 36.96% vs. 0.19%; p<0.001), lower frequency of kappa light chain involved (kappa, 26.09% vs. 53.72% p<0.001), higher level of albumin (44.44 vs.32.34, p<0.001) and higher median of LDH (265.29 vs.168.99, p<0.001), higher incidence of renal dysfunction (33.70% vs 16.54%, p<0.001 ) and less advanced ISS stage (Ⅰ, 34.09% vs. 17.30%; Ⅱ, 21.69% vs. 42.54%; Ⅲ, 44.32% vs.40.16%; p<0.001). In addition, unmeasurable M-protein patients had higher incidence of del(17p) ( 15.49% vs. 5.45%; p=0.001) and t(11;14) ( 35.85% vs. 13.99%; p<0.001). However, the incidence of del(13q), 1q21 gains and t(4;14), t(14;16) had no statistically significance (p>0.05). 3) Furthermore, we analyzed OS in these two groups with thalidomide-based or bortezomib-based chemotherapy. In thalidomide-based therapy, the median OS of unmeasurable and measurable M-protein MM were 32.0 (95% CI: 14.3-49.7) and 40.0 (95% CI: 34.3-45.7) months respectively (p=0.124).In bortezomib-based group, the median OS of unmeasurable and measurable M-protein MM were 29.5 (95% CI: 15.4-43.6) and 58.0 (95% CI: 46.1-70.0) months respectively. The unmeasurable M-protein MM had a remarkably shorter OS (P=0.034). Secondly, patients were stratified according to level of M-protein (unmeasurable and measurable), then compared according to treatment. In unmeasurable M-protein MM, the median OS of bortezomib group and thalidomide groupwere 29.5 (95% CI: 15.4-43.6) and 32.0 (95% CI: 14.3-49.7) months respectively(p=0.498). In measurable M-protein MM with bortezomib and thalidomide-based chemotherapy, the median OS were 58.0 (95% CI: 46.1-70.0) and 40.0 (95% CI: 34.3-45.7) months respectively (p=0.004).Conclusion: In conclusion, unmeasurable serum M-protein myeloma had shorter OS than measurable group, especially in the bortezomib-based therapy. In unmeasurable group, the difference of OS was not significant between thalidomide-based and bortezomib-based therapy. Our findings suggested that the level of serum M-protein was capable of predicting different survival groups to bortezomib and unmeasurable myeloma might benefit less than measurable group from bortezomib. DisclosuresNo relevant conflicts of interest to declare.

Predictors Of Survival Outcomes In Phase I Relapsed Or Refractory Multiple Myeloma Patients

ObjectivesCategorization of response criteria for multiple myeloma (MM) is based on magnitude of change in serum and urine paraprotein values and normalization of free light chain ratio (rFLC). However, the association between improvements in these surrogate markers and patient outcomes is not validated in the phase I setting. Early measures of response would be beneficial for patients and agents to identify those likely to have prolonged disease-free intervals and to validate agent activity for rapid movement to subsequent development. MethodsWe identified 31 trials that met enrollment criteria of phase I, relapsed or refractory disease, and non-transplant study population. Clinical and demographic data collected included age, sex, race, ECOG performance status (PS) at entry, myeloma subtype and isotype, prior therapy, cytogenetics at study entry, date of progression, and date of expiration. Patients with t(4;14), del13, del17p, t(14;16), or t(14;20) were considered to have non-standard risk cytogenetics. Evaluation of the relationship between progression free survival (PFS) and change in plasma cell activity by the rFLC and magnitude of response in serum/urine paraprotein per IMWG criteria was performed. Landmark analyses occurred at cycle 2 and 4, 8, and 12 months. Progression free survival (PFS) at 12 months was the primary outcome of interest. ResultsAmong 87 patients; 47 (54%) were female; 56 (64%) white, 29 (33%) black; 27 (31%) non-standard risk cytogenetics; ECOG PS 1 in 73 (84%); and median prior lines 5 (1-11). Eighty were evaluable for paraprotein changes, 71 for rFLC. Normalization of rFLC at 4 months conferred a PFS advantage (11.3 v 2.8 months, p = 0.038) (Table 1). Normalization of rFLC by 12 months was found to predict PFS (6.1 vs. 2.8 months, p = 0.015) and a longer OS (45 vs. 17.4 months, p = 0.002). Magnitude of response in paraprotein was found to predict and correlate linearly with PFS at all time landmarks (r2 = 0.769 to 0.952). Analysis of PFS by IMWG criteria and by quartiles of 50% changes were both linear (p < 0.001) (Figure 1). [Display omitted] ConclusionThese findings suggest that normalization of the rFLC and magnitude of paraprotein response are viable surrogate disease endpoints in phase I clinical trials of novel agents and combinations. The use of current IMWG criteria in the phase I setting is valuable, but the addition of time of response and alterations of response boundaries should be further evaluated in the setting of improved treatments. Disclosures:Kaufman:Onyx: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Millenium: Consultancy; Merck: Research Funding. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy.

Normalization of free light chain kappa/lambda ratio is a robust prognostic indicator of favorable outcome in patients with multiple myeloma

To clarify the impact of serum free light chain (sFLC) ratio normalization in patients with multiple myeloma (MM) treated with novel agents. Treatment response in 126 consecutive patients over 7 years was assessed by IMWG criteria and sFLC assay. Thirty-four patients (27%) showed complete response (CR), 37 (29%) very good partial response (VGPR), 39 (31%) partial response (PR), and 16 (13%) stable disease (SD) or less at a median follow-up of 28 months. Fifty-two patients (41%) with sFLC ratio normalization showed superior progression-free survival (PFS) and overall survival (OS) compared to those who did not (3-yr OS, 94% vs. 48%; P < 0.001). This favorable effect of sFLC ratio normalization occurred irrespective of high (>1000 mg/dL) or low (<100 mg/dL) baseline sFLC. Rates of normal sFLC ratio were as follows: CR, 69%; VGPR, 64%; PR, 16%; and SD or less, 0%. OS was significantly superior in patients with than without normal sFCL ratio in respective response groups. Although various factors (advanced age >70, high LDH, ISS stage 3) showed negative prognostic impacts on PFS and OS on univariate analysis, normal sFLC ratio and achievement of CR emerged as the strongest prognostic predictors for longer OS in MM patients on multivariate analysis. This study demonstrated the significance of obtaining normal sFLC ratio independent of other clinical variables. Analysis of sFLC ratio could identify the favorable group of patients as well as immunofixation test and support the inclusion of sFLC ratio as part of the response criteria for MM.

Propylene Glycol-Free Melphalan Induces Higher Remission Rates in Multiple Myeloma Patients Undergoing Autologous Transplantation

Abstract 4551 Background:In a recent phase IIa open-label, randomized, cross-over design study, we evaluated the pharmacokinetics of Propylene Glycol-Free Melphalan (PG-free Mel) HCL and Alkeran in multiple myeloma patients undergoing transplantation. In this study, we have shown through statistical tests of the geometric means of AUC that PG-free Mel was bioequivalent to Alkeran, and provided marginally higher blood drug levels. Hypothesis:Because this new formulation is associated with marginally higher blood drug levels and because melphalan is associated with a linear dose-response curve, we speculated that patients treated on study would have a better multiple myeloma response compared to matched controls. Goal:To assess day +100 multiple myeloma responses from the study patients (n=24) receiving PG-free Mel conditioning in combination with Alkeran. Responses were assessed based on International Uniform Response Criteria for Multiple Myeloma. Comparison was made to a matched cohort of patients who received conventional melphalan. Methods:We compared the study patient responses to matched controls (n=24) treated exclusively with Alkeran or generic melphalan conditioning within the same time frame in a case-control study design. The controls were matched to study population based on disease stage, age, and pre-transplant response. Results:The study population and the control cohort were well matched in terms of age, gender, disease stage, and pre-transplant response. However, the study population had more patients with high-risk cytogenetics (10 vs 3). Overall response (CR, VGPR, and PR) was higher in the study population (22 vs 19). While no patient on the study progressed within 100 days of transplant, 3 patients in the matched cohort progressed within 100 days. The median duration of follow up of surviving patients was 650 days in the study cohort and 409 days in the matched control cohort. Twenty three study patients and 22 patients in the matched control cohort were reported alive. On the other hand, 7 study patients and 8 patients in the matched cohort progressed during follow up. Conclusion:Compared to matched controls, PG-free Mel, as part of the melphalan conditioning regimen, resulted in higher remission rates and less disease progression at day 100 post autologous transplant for multiple myeloma. Disclosures:Off Label Use: Propylene glycol free melphalan for high-dose therapy and autologous transplant for multiple myeloma.

Re-infused lymphocyte dose does not influence disease control following upfront autologous stem cell transplantation for multiple myeloma

Re-infused lymphocyte dose does not influence disease control following upfront autologous stem cell transplantation for multiple myeloma

Historical perspective and advances in the treatment of multiple myeloma

Corticosteroids and melphalan were used for decades to treat multiple myeloma. Combination chemotherapy has been extensively studied with similar overall survival rates to melphalan and prednisone. In the last decade, the development of new agents has progressed significantly. Thalidomide and its newer derivatives lenalidomide, bortezomib, and pegylated liposomal doxorubicin have drastically revolutionized treatment approaches. As a result, numerous clinical trials have yielded exciting treatment strategies resulting in therapeutic advances, and improved responses and overall survival of patients. This review summarizes the international uniform response criteria for multiple myeloma and gives a historical perspective on previous therapies with updates on the newest available treatments.

Historical perspective and advances in the treatment of multiple myeloma

Corticosteroids and melphalan were used for decades to treat multiple myeloma. Combination chemotherapy has been extensively studied with similar overall survival rates to melphalan and prednisone. In the last decade, the development of new agents has progressed significantly. Thalidomide and its newer derivatives lenalidomide, bortezomib, and pegylated liposomal doxorubicin have drastically revolutionized treatment approaches. As a result, numerous clinical trials have yielded exciting treatment strategies resulting in therapeutic advances, and improved responses and overall survival of patients. This review summarizes the international uniform response criteria for multiple myeloma and gives a historical perspective on previous therapies with updates on the newest available treatments.