Low-dose dexamethasone and thalidomide with higher frequency zoledronic acid (dtZ) for newly diagnosed multiple myeloma

18506 Background: Although dexamethasone (Dex), thalidomide (Thal) and zoledronic acid (Zol) have frequently been combined for the treatment of multiple myeloma (MM), the ideal dosing schedule is unknown. We previously reported that lower doses of Dex and Thal can be effectively combined with high-frequency dosing of Zol (Haematologica 2005). Methods: This “dtZ” regimen - which comprises weekly Dex 20 mg OM for 4 days, Thal 50 mg ON, and 3-weekly Zol 4 mg - resulted in an impressive response rate (RR) of 61.6% and near complete remission (nCR)/complete remission (CR) rate of 7.7% in 26 patients with relapsed/refractory MM. Results: In this present study, we treated 22 newly diagnosed MM patients with “dtZ” and report an even more impressive RR of 100.0% and nCR/CR rate of 20–35%. The median time to response was 1.8 months and median time to maximum response was 2.2 months. The median time to progression (TTP) has not been achieved yet. As expected, low-dose Dex/Thal resulted in lower (18.1%) grade 3 or 4 toxicities. These were all infections; which lead to further dose-reduction of Dex. There were no thromboembolic events, despite the fact that aspirin was not routinely given. Of particular interest, 3- weekly Zol was not associated with any significant decrease in renal function, and none of our patients developed osteonecrosis of the jaw (ONJ). In fact, at the time of writing of this abstract, more than 1,000 doses of Zol had been administered in a 3-weekly fashion to these as well as other patients, and only 1 patient developed ONJ. This patient who had already received greater than 20 doses of Zol healed uneventfully after receiving appropriate outpatient dental treatment, and subsequently received another 8 doses of Zol with no recurrence of ONJ. Conclusion: In conclusion, the Zol-based “dtZ” regimen is potentially a highly-effective and safe frontline regimen for MM. Using Zol every 3 weeks with lower doses of Dex and Thal does not appear to increase the rate or severity of nephrotoxicity or ONJ. Although we do not know exactly why every patient responded to “dtZ”, we speculate that this could be due to a critical balance that has been achieved between the anti-MM, anti-osteoclastic and immunostimulatory effects of the individual drugs of the combination. No significant financial relationships to disclose.

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A Phase I/II Trial of Bortezomib, Low Dose Intravenous Melphalan and Dexamethasone for Patients with Relapsed Multiple Myeloma.

Blood ◽

10.1182/blood.v108.11.3542.3542 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3542-3542 ◽

Cited By ~ 6

Author(s):

Rakesh Popat ◽

Catherine Williams ◽

Mark Cook ◽

Charles Craddock ◽

Supratik Basu ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Median Time ◽

Low Dose ◽

Overall Response Rate ◽

Response Rate ◽

Chemotherapeutic Agents ◽

Time To Progression ◽

Overall Response ◽

Grade 3

Abstract Background: Bortezomib is an effective treatment for patients with relapsed multiple myeloma with an overall response rate (MR+PR+CR) of 46% and time to progression of 6.2 months (APEX study). We and others have previously demonstrated potent in-vitro synergy with chemotherapeutic agents such as melphalan and it is likely that this will translate into improved responses in the clinical setting. Methods: This was a multi-centre, non-randomised Phase I/II clinical trial for patients with relapsed multiple myeloma. Bortezomib 1.3mg/m2 was given on Days 1,4,8 and 11 of a 28 day cycle, and intravenous melphalan on Day 2 for a maximum of 8 cycles. In the Phase I component melphalan was given at 2.5, 5,7.5 and 10mg/m2 in a dose escalation scheme and the maximum tolerated dose (MTD) of 7.5mg/m2 was taken forward to an expanded Phase II component. Dexamethasone 20mg on the day of and the day after each dose of bortezomib was permitted for progressive or stable disease after 2 or 4 cycles respectively. Responses were classified by EBMT criteria. Results: To date 39 patients have been enrolled (median age 61years [range 40–77]) with a median of 3 lines of prior therapy [range 1–5] of which 26 (67%) have had one previous autologous stem cell procedure and 4 (10%) have had two. 23 (59%) have had prior exposure to thalidomide and 4 (10%) to bortezomib. 36 have now completed at least 1 cycle and are therefore evaluable for response. The overall response rate (CR+PR+MR) across all treatment levels was 75% rising to 81% (CR 11%; nCR 3%; VGPR 8%; PR 39%; MR 19%) with the addition of dexamethasone in 13 cases for suboptimal response. Rapid responses were seen with the median time to response being 1 month [range 1–6]. The median time to progression is 10.1 months and the median overall survival has not yet been reached at a median follow-up of 7.4 months. Of the patients that have had disease progression 7 (35%) had responses of longer duration than their previous therapy. The MTD was defined by unacceptable delays in administering treatment due to myelosuppresion. The toxicities have been acceptable with 13 SAEs reported of which 8 were hospitalisation due to infection. The most common grade 3–4 adverse events were: thrombocytopenia (53%), infections (25%), neutropenia (17%) and neuropathy (17%). Three grade 3 cardiac events were seen (myocardial infarction, atrial fibrillation and cardiac failure) and GCSF was administered to 13 patients as treatment and prophylaxis of grade 4 neutropenia. 13 patients were withdrawn from the study due to toxicity of which 7 were for neuropathy and 3 for delayed haematological recovery. Of note, 11 patients (28%) had pre-existing grade 1 neuropathy prior to starting therapy. Summary: The combination of bortezomib, low dose intravenous melphalan and dexamethasone appears to be highly effective in patients with relapsed multiple myeloma where a response rate of 81% is seen with 14% achieving nCR/CR. The toxicity profile associated is predictable, manageable and predominantly haematological. Recruitment is ongoing to a total of 53 patients.

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Bortezomib, Low Dose Intravenous Melphalan and Dexamethasone for Patients with Relapsed Multiple Myeloma: Final Results of a Phase I/II Clinical Trial.

Blood ◽

10.1182/blood.v110.11.2713.2713 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2713-2713

Author(s):

Rakesh Popat ◽

Catherine Williams ◽

Mark Cook ◽

Charles Craddock ◽

Supratik Basu ◽

...

Keyword(s):

Clinical Trial ◽

Multiple Myeloma ◽

Phase I ◽

Median Time ◽

Low Dose ◽

Overall Response Rate ◽

Response Rate ◽

Time To Progression ◽

Overall Response ◽

Grade 3

Abstract Background: Bortezomib is an effective treatment for patients with relapsed multiple myeloma with an overall response rate (≥PR) of 43% and time to progression of 6.2 months (APEX study). We and others have previously demonstrated potent in-vitro synergy with chemotherapeutic agents such as melphalan and it is likely that this will translate into improved responses in the clinical setting. Methods: This was a multi-centre, non-randomised Phase I/II clinical trial for patients with relapsed multiple myeloma. Bortezomib 1.3mg/m2 was given on Days 1,4,8 and 11 of a 28 day cycle, and intravenous melphalan on Day 2 for a maximum of 8 cycles. In the Phase I component melphalan was given at 2.5, 5,7.5 and 10mg/m2 in a dose escalation scheme and the maximum tolerated dose (MTD) of 7.5mg/m2 was taken forward to an expanded Phase II component. Dexamethasone 20mg on the day of and the day after each dose of bortezomib was permitted for progressive or stable disease after 2 or 4 cycles respectively. Responses were defined by EBMT criteria. Results: 53 patients were enrolled (median age 61years [range 40–77]) with a median of 3 lines of prior therapy [range 1–5] of which 26 (67%) have had one previous autologous stem cell procedure and 4 (10%) have had two. 23 (59%) have had prior exposure to thalidomide and 4 (10%) to bortezomib. The overall response rate (≥PR) across all treatment levels (n=52) was 65% rising to 69% (CR 19%; nCR 4%; VGPR 6%; PR 40%; MR 15%) with the addition of dexamethasone in 27 cases for suboptimal response. Of the 32 patients treated at the MTD the overall response rate (≥PR) was 78% (CR 28%; nCR 6%; VGPR 6%; PR 38%; MR 9%). Rapid responses were seen with the median time to response being 1 month [range 1–6]. The median time to progression was 10 months and the median overall survival has not yet been reached at a median follow-up of 17 months. Of the patients that have had disease progression 7 (35%) had responses of longer duration than their previous therapy. The MTD was defined by unacceptable delays in administering treatment due to myelosuppresion. The toxicities have been acceptable with 13 SAEs reported of which 8 were hospitalisation due to infection. The most common grade 3–4 adverse events were: thrombocytopenia (53%), infections (25%), neutropenia (17%) and neuropathy (17%). Three grade 3 cardiac events were seen (myocardial infarction, atrial fibrillation and cardiac failure) and GCSF was administered to 13 patients as treatment and prophylaxis of grade 4 neutropenia. 19 patients were withdrawn from the study due to toxicity of which 7 were for neuropathy and 3 for delayed haematological recovery. Of note, 11 patients (28%) had pre-existing grade 1 neuropathy prior to starting therapy. Summary: The combination of bortezomib, low dose intravenous melphalan and dexamethasone appears to be highly effective in patients with relapsed multiple myeloma with a response rate (≥PR) at the MTD of 78% including 34% nCR/CR. The toxicity profile is predominantly haematological.

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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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Evaluation of Single Agent Lenalidomide in Patients with Newly Diagnosed Multiple Myeloma (NDMM).

Blood ◽

10.1182/blood.v114.22.3868.3868 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3868-3868

Author(s):

Rachid Baz ◽

Mohamad Hussein ◽

Daniel J. Lebovic ◽

Elizabeth Finley-Oliver ◽

Mehul P Patel ◽

...

Keyword(s):

Multiple Myeloma ◽

Median Time ◽

Light Chain ◽

Single Agent ◽

Immunomodulatory Activity ◽

High Dose ◽

Newly Diagnosed ◽

Antitumor Effects ◽

Grade 3

Abstract Abstract 3868 Poster Board III-804 Introduction Lenalidomide (Len) is an immunomodulatory drug with antitumor effects mediated through activation of T and NK cells as well as modulation of tumor cytokine environment. Currently Len is approved in combination with dexamethasone (dex) for treatment of patients with relapsed myeloma. Interestingly, in NDMM, higher 1 and 2 year survival rates were observed when the dose of dex was reduced compared to standard high dose dexamethasone and Len (Rajkumar et al. 2008). The immune suppressive effects of dex can antagonize Len immunomodulatory activity and may explain this observation. To our knowledge, Len has not been evaluated as a single agent in NDMM. Patients and methods Records of patients with newly diagnosed symptomatic multiple myeloma treated with single agent Len at H. Lee Moffitt Cancer Center and Roswell Park Cancer Institute were reviewed (after IRB approval at both institutions). Data was collected on disease characteristics, demographics and treatment outcomes. Responses assessed as per the IMWG criteria. Results From March 2007 to July of 2009, 18 patients with NDMM have been treated with Len alone. The median age was 70 years (range 46-84), and 12/18 were males. Heavy chain was IgG in 12 and IgA in 4 patients with 2 patients with light chain myeloma. The involved light chain was kappa in half the patients. Clinical stage of patients included stage IIIA (n=13), IIA (n=4) and IA (n=1) using the DS system whereas as per the ISS system 10, 6 and 2 has stages I, II and III respectively. Cytogenetics were not available on most patients (11); and 4 of 7 patients with available cytogenetics had deletion 13q identified by FISH. The median b2m was 2.8 mg/L (range 2.1-10.7) with >3.5mg/L in 7/18 patients. All except one patient (with a creatinine clearance of 49 ml/min) were started on Len 25 mg daily for 21 days of a 28 days cycle. As of August 1st 2009, 3 patients are inevaluable for response due to short follow up. Among the remainder 15 patients, 3 achieved a CR (1 stringent CR), 2 VGPR, 3 PR, 4 had MR with SD in additional 3 patients. Thus MR or better response was noted in 80% of patients. The median time to first response was 55 days (range 28-98) and median time to best response was 73 days (range 31-591). After a median follow up of 7 months (range 1-26), 1 patient died of progressive disease (despite the addition of dexamethasone and subsequent bortezomib therapy), 4 patients required the addition of dexamethasone. Len was generally well tolerated and no grade 4 hematologic toxicity were noted, 1 patient had grade 3 neutropenia, 1 patients grade 3 anemia and 2 patient grade 3 thrombocytopenia. Four patients had Len dose reduced. Conclusion Single agent Len appears to be an effective therapy in newly diagnosed myeloma patients (MR and better in 80% of patients) and should be evaluated in a prospective fashion in an attempt to decrease corticosteroid toxicity in a group of vulnerable patients and potentially enhance the immunomodulatory activity of Len. Our experience suggests that single agent Len can be effectively employed as an initial step in sequencing anti-myeloma regimen(s) for treatment of NDMM. Disclosures: Baz: celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: lenalidomide as a single agent in newly diagnosed myeloma. Hussein:Celgene: Employment.

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Elotuzumab In Combination with Lenalidomide and Low-Dose Dexamethasone In Patients with Relapsed/Refractory Multiple Myeloma: Interim Results of a Phase 1 Study

Blood ◽

10.1182/blood.v116.21.1936.1936 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1936-1936 ◽

Cited By ~ 1

Author(s):

Sagar Lonial ◽

Ravi Vij ◽

Jean-Luc Harousseau ◽

Thierry Facon ◽

Philippe Moreau ◽

...

Keyword(s):

Multiple Myeloma ◽

Disease Progression ◽

Median Time ◽

Research Funding ◽

Low Dose ◽

Nk Cell ◽

Phase 1 ◽

Maximum Tolerated Dose ◽

Phase 1 Study ◽

Grade 3

Abstract Abstract 1936 Background: Elotuzumab is a humanized monoclonal IgG1 antibody targeting CS1, which is highly and uniformly expressed on multiple myeloma (MM) cells, and important to myeloma cell survival. Elotuzumab exerts significant antitumor activity against primary myeloma cells via NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC), regardless of sensitivity or resistance to conventional therapies. In preclinical studies, the activity of elotuzumab is independently enhanced by lenalidomide and dexamethasone. We present the results of an ongoing phase 1 study evaluating the maximum tolerated dose (MTD), safety, clinical response, and pharmacokinetics of elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed/refractory MM. Methods: Entry criteria included patients who had measurable disease, had experienced at least 1 relapse, and had not received lenalidomide for at least 6 weeks before the first dose of elotuzumab. The study enrolled 3 escalating dose cohorts of elotuzumab (5, 10, and 20 mg/kg IV), administered on days 1, 8, 15, and 22 of a 28-day cycle in the first 2 cycles, and then days 1 and 15 of each subsequent cycle, along with lenalidomide 25 mg PO daily on days 1 to 21 and dexamethasone 40 mg PO weekly. At each dose level, dose-limiting toxicities (DLTs) were assessed during cycle 1 and clinical responses were evaluated with International Myeloma Working Group (IMWG) criteria during each cycle. The first 5 patients received up to 6 cycles of therapy before a protocol amendment allowed subsequent patients to be treated until disease progression. Results: Twenty-nine patients with advanced MM (median stage III) who had received a median of 3 prior MM therapies, including bortezomib (69%), thalidomide (59%), or lenalidomide (21%), were enrolled. Of these, 28 received elotuzumab; 3 patients each were treated with 5 and 10 mg/kg and 22 with 20 mg/kg. Patients received a median of 8.5 treatment cycles and 20.5 doses of elotuzumab. Sixteen patients have permanently discontinued study treatment. No DLTs were observed up to 20 mg/kg during the escalation phase and hence no MTD was established. The most frequent grade 3/4 toxicities were neutropenia (36%) and thrombocytopenia (21%); 2 patients experienced 3 serious infusion-related reactions (1 patient with a grade 4 hypersensitivity reaction and 1 with 2 grade 3 stridor events) during the first treatment cycle. Objective responses (partial response or better) were obtained in 82% (23/28) of treated patients and 96% (21/22) of lenalidomide-naïve patients. ORRs were also high in patients who had received prior thalidomide 94% (15/16) or whose disease was refractory to the most recent therapy 82% (9/11). The median time to response was 7 weeks. The proportion of patients without disease progression (Kaplan-Meier estimate) at 16 months is 53% for total patients and 66% for patients in the 20 mg/kg elotuzumab cohort, who are being treated until disease progression. The median time to progression was not reached. Conclusions: The combination of elotuzumab, lenalidomide, and low-dose dexamethasone was generally well tolerated and showed encouraging overall response rates in patients with relapsed/refractory MM who had received multiple prior therapies. A larger phase 2 study is ongoing to confirm the rate and durability of the responses observed in this phase 1 trial. Disclosures: Lonial: Millennium, Celgene, Bristol-Myers Squibb, Novartis, Onyx: Advisory Board, Consultancy; Millennium, Celgene, Novartis, Onyx, Bristol-Myers Squibb: Research Funding. Vij:Bristol-Myers Squibb: Honoraria; Celgene: Research Funding; Celgene, Bristol-Myers Squibb: Speakers Bureau. Harousseau:Bristol-Myers Squibb, Celgene, Janssen-Cilag, Novartis, Onyx: Honoraria; Celgene, Janssen-Cilag: Speakers Bureau. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Moreau:Celgene, Facet Biotech, Bristol-Myers Squibb: Honoraria. Leleu:Janssen-Cilag, Celgene, Chugai Pharmaceutical, Roche, Amgen, Novartis, Leo Pharma: Consultancy, Honoraria, Research Funding. Kaufman:Celgene, Millennium: Consultancy; Celgene, Merck: Research Funding. Westland:Facet Biotech: Employment. Tsao:Facet Biotech: Employment. Singhal:Facet Biotech: Employment. Jagannath:Millennium, Takeda Pharmaceutical Company, Janssen-Cilag: Honoraria.

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High Response and Complete Remission Rates in Relapsed/Refractory Multiple Myeloma Treated with Bortezomib, Thalidomide, Dexamethasone and Zoledronic Acid (VTD-Z) Combination Therapy.

Blood ◽

10.1182/blood.v106.11.5127.5127 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5127-5127

Author(s):

Gerrard Teoh ◽

Daryl Tan ◽

William Hwang ◽

Liang Piu Koh ◽

Charles Chuah ◽

...

Keyword(s):

Multiple Myeloma ◽

Zoledronic Acid ◽

Complete Remission ◽

Single Agent ◽

Cytotoxic Agents ◽

Refractory Multiple Myeloma ◽

Vein Thrombosis ◽

Grade 3 ◽

Weekly Cycles ◽

Deep Vein

Abstract Purpose: Bortezomib (VELCADETM) is a novel proteasome inhibitor that has shown tremendous clinical efficacy either as a single agent or in combination with other cytotoxic agents in relapsed/refractory multiple myeloma (MM). In this study, we combined bortezomib (V) with thalidomide (Thal), dexamethasone (Dex) and zoledronic acid (Zol) to determine the efficacy and toxicity of this regimen (VTD-Z) in patients with relapsed/refractory MM. Methods: Patients were treated for 2 to 11 three-weekly cycles of VTD-Z comprising: V 1.3 mg/m2 on days 1, 4, 8 and 11; Thal 50 mg ON; Dex 20 mg OM on days 1 to 4, 8 to 11, 15 to 18; and Zol 4 mg on day 1. Patients did not receive any prophylaxis for venous thrombosis. Response was graded according to Bladès criteria. Results: Twelve patients (2 males, 10 females; median age 63.3 years) with relapsed/refractory MM were studied. Complex karyotypes were present in all (10 out of 10) patients who had karyotype studies performed at the time of diagnosis. Four patients had deletion chromosome 13 (del(13)). The overall response rate (RR) was 91.7% (11 out of 12), of which 50.0% (6) achieved complete remission (CR), 25.0% (3) achieved near-CRs (nCR), 16.7% (3) were partial responders (PR). There were no minimal responders (MR) and 1 (8.3%) non-responder (NR). Two patients who achieved CR had del(13). Transient grade 3 thrombocytopenia was the only severe adverse event and this was observed in 4 (33.3%) patients. Grade 2 peripheral neuropathy was observed in 4 (25.0%) of patients. None of the patients developed deep vein thrombosis or pulmonary embolism. The single NR was the only death that occurred during the period of study. Conclusions: Our study demonstrates that the VTD-Z regimen is exceptionally effective and safe in patients with relapsed/refractory MM. The high CR/near-CR rates (total of 75.0%), attained after relatively few cycles of VTD-Z, suggest that these three drugs could be at least additive, if not, even synergistic. Longer term follow-up will be required to determine the durability of these responses.

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Safety and efficacy of bone-modifying agents among multiple myeloma patients: A retrospective cohort study

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155221996039 ◽

2021 ◽

pp. 107815522199603

Author(s):

Christina Billias ◽

Megan Langer ◽

Sorana Ursu ◽

Rebecca Schorr

Keyword(s):

Multiple Myeloma ◽

Cohort Study ◽

Zoledronic Acid ◽

Retrospective Cohort Study ◽

Retrospective Cohort ◽

Osteonecrosis Of The Jaw ◽

Safety And Efficacy ◽

Modifying Agent ◽

Skeletal Related Events ◽

Agent Group

Objective To determine the incidence of skeletal-related events among multiple myeloma patients who received chemotherapy without a bone-modifying agent (zoledronic acid and denosumab) versus those who received chemotherapy with a bone-modifying agent. The secondary objective was to determine the incidence of skeletal-related events in patients without any prior history of skeletal-related events and who were treated with zoledronic acid every four weeks versus those who received zoledronic acid at an extended interval of every twelve weeks. Additional secondary objectives included the incidence of nephrotoxicity, hypocalcemia and osteonecrosis of the jaw in all patients. Methods This institutional review board-approved, retrospective cohort study included patients 18 to 89 years old with a diagnosis of multiple myeloma, who were being treated with chemotherapy between July 1, 2016 and October 31, 2019. Safety and efficacy were assessed through analysis of pertinent data collected: patient demographics, baseline skeletal-related events, development of new skeletal-related events, number and type of bone-modifying agent doses administered, and drug-related toxicities such as nephrotoxicity, hypocalcemia, and osteonecrosis of the jaw. Results A total of 73 patients were included. New skeletal-related events occurred in 12 patients (27%) in the chemotherapy without a bone-modifying agent group and in 5 patients (17%) in the chemotherapy with a bone-modifying agent group (OR = 0.56, 95% CI [0.172–1.8]; P = 0.32). The incidence of skeletal-related events was similar among patients receiving zoledronic acid every four weeks versus every twelve weeks in patients without a prior skeletal-related event (N = 0 vs. N = 2 respectively; P = 0.47). There were no statistically significant differences observed in each of the three secondary safety endpoints: incidence of hypocalcemia, nephrotoxicity and osteonecrosis of the jaw. Conclusion Multiple myeloma patients receiving chemotherapy without a bone-modifying agent had higher rates of skeletal-related events compared to those being treated with chemotherapy and a bonemodifying agent. Our results highlight the benefit of utilizing bonemodifying agents for the prevention of skeletal-related events in all multiple myeloma patients being treated with chemotherapy.

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Three Drug Regimens for Newly Diagnosed Multiple Myeloma Transplant-Ineligible Elderly Patients - a Systematic Review

Blood ◽

10.1182/blood-2019-132095 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5574-5574

Author(s):

Abdul Aziz Siddiqui ◽

Kazi Najamus-saqib Khan ◽

Arafat Ali Farooqui ◽

Muhammad Saad Farooqi ◽

Muhammad Junaid Tariq ◽

...

Keyword(s):

Multiple Myeloma ◽

Elderly Patients ◽

Phase Ii ◽

Low Dose ◽

Phase Ii Trial ◽

Alkylating Agents ◽

Phase Iii ◽

Newly Diagnosed ◽

Great Efficacy ◽

Drug Regimens

Introduction: Patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for autologous stem cell transplant (ASCT) tend to have comorbidities and/or advanced age that make this subset of patients difficult to manage with current drug regimens. Methods: A comprehensive literature search of PubMed, Embase, Clinicaltrials.gov and Web of Science was performed from inception and completed on 07/17/2019. Studies focusing on efficacy and tolerability of 3-drug regimens in patients with NDMM were included for the review. Results: Out of 3579 studies, a total of 10 (08 phase II and 03 phase III) clinical trials in last ten years (2010-2019) using 3-drug regimens in NDMM elderly pts (893M/807F) ineligible for ASCT (determined by investigators) were selected. A total of 1703/1740 NDMM pts were evaluated. Proteasome inhibitors (PIs) such as carfilzomib (C), bortezomib (V) and ixazomib (I) showed promising results in elderly transplant-ineligible NDMM pts. CLARION trial (phase III, n=955) compared two PIs (C and V) with melphalan (M) and prednisone. There was no statistically significant difference in progression-free survival (PFS) between two groups (median: 22.3 vs 22.1 months; HR: 0.91; 95% CI, 0.75-1.10, p = 0.159) as well as overall survival (OS) (HR: 1.08; 95% CI: 0.82-1.43). Difference in the least square means of the HR-QoL (Health related- quality of life) was 4.99 (p<.0001) favoring C-group. M may not be an ideal drug to combine with carfilzomib in this setting given more AEs.(Facon et al 2019). V as 3-drug regimen in combination with lenalidomide (L) in 242 pts achieved statistically significant prolonged PFS (median 43 mo) and OS (median 75 mo) with great efficacy and acceptable risk-benefit profile. (Durie et al 2017; phase III). Multinational phase II trial (n=70) by Dimopoulos et al (2019) evaluated I, with different fixed doses of cyclophosphamide (Cy). Median duration was 19 cycles, indicating the long-term tolerability of regimen. With favorable toxicity profile and maintained QoL scores, trial concluded that this therapy is tolerable in elderly transplant-ineligible NDMM pts. Tuchman et al (2017) in phase II trial (n=14) investigated (V-Cy-d) and achieved ORR of 64%, with ≥VGPR of 57%. Low dose V showed great efficacy with M yielding ORR of 86% and VGPR or better of 49% in phase II trial (n=101) that also evaluated Cy as 3-drug combination but results were more productive with M with longer PFS and OS which reduced when impact of frailty was examined on outcomes. Since toxicity was higher with M, trial suggested that 2-drug combination should be preferred in elderly frail patients. (Larocca et al 2015). Efficacy was quite promising when Bringhen et al (2014) trialed C with Cy-d; 87% OS and 76% PFS at 1 y in phase II trial (n=58) with much favorable safety profile. Monoclonal antibodies (mAb) such as elotuzumab (E) and pembrolizumab (Pe) are also tested in elderly. First study conducted on NDMM pts using humanized mAb; E, in phase II trial (n=40) by Takezako et al (2017) attained primary endpoint of the study (ORR) of (88%) and VGPR or better of 45% in Japanese pts with tolerable toxicities in elderly. No subjects on this study experienced severe peripheral neuropathy. KEYNOTE-185; a phase III multinational trial by Usmani et al (2019) evaluated Pe with Ld in 151 pts. FDA halted this study due to unfavorable benefit-risk profile; 19 deaths, 6 due to disease progression (PD), and 13 due to treatment-related AEs. Median PFS and median OS were not reached in either group. Immunomodulators such as L achieved one of the longest PFS reported in a trial of transplant ineligible patients (35 mo) by using LVd regimen in phase II multicenter trial (n=50). (O'Donnell et al 2018) Alkylating agents like bendamustine (ben) and M have been tested in different novel regimens. Decreasing intensity and increasing duration of ben resulted in better outcomes in phase II trial (n=59) by Berdeja et al (2016) and can be given as first line treatment. Ben yielded great results with low dose dexa as compared to high dose achieving 92% ORR. Original regimen was effective but relatively more toxic. Incidence of herpes and neuropathy decreased dramatically with the treatment modifications. Conclusion: Three-drug regimens having PIs, mABs, immunomodulators and alkylating agents have shown desirable results in NDMM transplant (ASCT)-ineligible elderly patients and are likely the emerging standard of care for NDMM. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

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Safety and Efficacy of Four Drug Versus Three Drug Regimens Among Patients with Newly Diagnosed Multiple Myeloma: A Systematic Review and Meta-Analysis

Blood ◽

10.1182/blood-2020-143379 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 3-3

Author(s):

Saad Ullah Malik ◽

Nazma Hanif ◽

Priyanka Kumari ◽

Khadija Noor Sami ◽

Chase Warner ◽

...

Keyword(s):

Multiple Myeloma ◽

Clinical Trials ◽

Adverse Events ◽

Randomized Clinical Trials ◽

Standard Of Care ◽

Drug Regimen ◽

P Value ◽

Newly Diagnosed ◽

Drug Regimens ◽

Grade 3

Introduction: During recent years there has been a boom in the availability of treatments for multiple myeloma (MM). Based on the status of disease (newly diagnosed or relapsed/refractory), several regimens have successfully improved progression free survival (PFS) and overall survival (OS) in these two types of patients. Triple drug regimen is considered the current standard of care for newly diagnosed MM patients. However, with the advent of four drug regimens, some studies demonstrated a significant improvement in PFS and OS compared to standard of care where as others showed marginal to no difference. Also, it remains unclear whether the benefits of using four drug regimen outweigh the risks. Thus, the aim of our meta-analysis was to compare the efficacy and safety of four drug versus three drug regimens among newly diagnosed multiple myeloma patients. Methods: We built a PICO based search strategy using keywords like "multiple myeloma", "randomized clinical trials" and ran literature search on PubMed, Embase, Wiley Cochrane Library, Web of Science and ClinicalTrials.gov ranging from the date of inception till 16th July, 2020. A pre-validated data extraction sheet was used to extract data on PFS, OS and ≥Grade 3 hematologic adverse events at the longest follow-up. We included only randomized clinical trials (RCTs) comparing four versus three drug regimen in newly diagnosed MM patients. We excluded studies other than RCTs, studies conducted on relapsed refractory MM patients or other plasma cell dyscrasias. A generic variance weighted random effects model (DerSimonian and Laird) was used to derive hazard ratio estimates along with their 95% confidence intervals (CIs) for PFS and OS. Risk ratio along with its 95% CIs was estimated for Grade ≥3 hematologic adverse events. Heterogeneity was assessed with Cochrane Q -statistic and was quantified with I2 test (I2 >50% was consistent with a high degree of heterogeneity). A pre-specified sensitivity analysis was also performed for risk of adverse events. Cochrane Collaboration's tool was used to assess the quality of included RCTs and GRADE was used to rate the quality of evidence. Results: Initial search retrieved 7622 titles. After duplicate removal, 4880 articles were left. Following initial screening, 58 articles were considered for full text review. Of these only 3 studies (n=2277) met inclusion criteria. Four drug regimens included daratumumab, bortezomib, melphalan-prednisone (D-VMP), daratumumab, bortezomib, thalidomide-dexamethasone (D-VTd) and bortezomib and melphalan prednisone and thalidomide (VMPT-VT) respectively. Whereas, three drug regimens were bortezomib, melphalan-prednisone (VMP), bortezomib, thalidomide-dexamethasone (VTd) and bortezomib, melphalan and prednisone (VMP) respectively. There was a significant improvement in PFS when 4 vs 3 drug regimens were compared in patients with newly diagnosed MM (HR: 0.53, 95% CI: 0.46-0.62, p-value:<0.001, I2: 0%). Also, OS improved significantly in four drug regimen group (HR: 0.62, 95% CI: 0.51-0.76, p-value:<0.001, I2: 3.5%). There was no statistically significant difference in any grade ≥3 hematologic adverse events when 4 vs 3 drug regimens were compared (RR: 1.26, 95% CI: 0.93-1.73, p-value:0.14, I2: 93%). Sensitivity analysis after removing D-VTd regimen from any grade ≥3 hematologic adverse events revealed similar results (RR: 1.05, 95% CI: 0.97-1.13, p-value:0.23, I2: 23%) confirming the robustness of analysis. When each hematologic adverse event was looked at separately, there was no difference between 4 vs 3 drug regimen in rates of anemia (RR: 0.99, 95% CI: 0.76-1.28, p-value:0.92, I2: 0%), neutropenia (RR: 1.39, 95% CI: 1.00-1.94, p-value:0.05, I2: 85%) and thrombocytopenia (RR: 1.13, 95% CI: 0.92-1.39, p-value:0.24, I2: 33%). There was low risk of bias and strength of evidence was of moderate. Conclusion: Using four drug regimens, compared to three drug regimens, significantly improves PFS and OS among newly diagnosed multiple myeloma patients without any difference in the risk of ≥3 grade hematologic adverse events. Further randomized clinical trials are required to establish four drug regimen as standard of care for patients with newly diagnosed multiple myeloma. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

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Whole-Body Low-Dose Multidetector-Row CT in Multiple Myeloma: Guidance in Performing, Observing, and Interpreting the Imaging Findings

Life ◽

10.3390/life11121320 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1320

Author(s):

Antonio Pierro ◽

Alessandro Posa ◽

Costanzo Astore ◽

Mariacarmela Sciandra ◽

Alessandro Tanzilli ◽

...

Keyword(s):

Multiple Myeloma ◽

Low Dose ◽

Plasma Cells ◽

Traditional Approach ◽

Response To Treatment ◽

Whole Body ◽

Newly Diagnosed ◽

Low Dose Ct ◽

Lytic Lesions ◽

Total Body

Multiple myeloma is a hematological malignancy of plasma cells usually detected due to various bone abnormalities on imaging and rare extraosseous abnormalities. The traditional approach for disease detection was based on plain radiographs, showing typical lytic lesions. Still, this technique has many limitations in terms of diagnosis and assessment of response to treatment. The new approach to assess osteolytic lesions in patients newly diagnosed with multiple myeloma is based on total-body low-dose CT. The purpose of this paper is to suggest a guide for radiologists in performing and evaluating a total-body low-dose CT in patients with multiple myeloma, both newly-diagnosed and in follow-up (pre and post treatment).

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