Tag: Multiple Myeloma

SUMMARY: The FDA on November 6, 2018 approved EMPLICITI® (Elotuzumab) in combination with POMALYST® (Pomalidomide) and Dexamethasone for the treatment of adult patients with Multiple Myeloma who have received at least two prior therapies, including REVLIMID® (Lenalidomide) and a Proteasome Inhibitor. Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 30,770 new cases will be diagnosed in 2018 and 12,770 patients are expected to die of the disease. Multiple Myeloma (MM) in 2018 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). Despite the introduction of novel therapies for the treatment of Multiple Myeloma, many patients still face poor outcomes in the Relapsed/Refractory setting.

EMPLICITI® is a immunostimulatory monoclonal antibody that binds to the Signal Lymphocyte Activation Molecule – SLAMF7 protein (CS1, CD319), which is highly expressed on Myeloma cells and also expressed on Natural Killer (NK) lymphocytes in the immune system. By virtue of its dual mechanism of action, it targets and destroys Myeloma cells and also enhances the activation of Natural Killer cells. The FDA in November 2015, approved EMPLICITI® for use in combination with REVLIMID® and Dexamethasone for the treatment of patients with Multiple Myeloma who received one to three prior therapies, based on the ELOQUENT-2 trial.

ELOQUENT-3 is a multicenter, randomized, open label, phase II trial in which 117 patients with Relapsed/Refractory Multiple Myeloma were randomly assigned, in a 1:1 ratio, to receive EMPLICITI® plus POMALYST® and Dexamethasone (N=60) – EMPLICITI® group or POMALYST® and Dexamethasone (N= 57) – control group. Treatment was administered in 28-day cycles. Patients in the EMPLICITI® group received EMPLICITI® 10 mg/kg IV days 1, 8, 15, and 22 during cycles 1 and 2 and 20 mg/kg on day 1 of each cycle thereafter. POMALYST® was given at 4 mg orally on days 1 thru 21 of each cycle along with Dexamethasone 40 mg weekly for patients 75 years of age or less or 20 mg for those more than 75 years of age. Treatment was continued until disease progression or unacceptable toxicity. Eligible patients had received 2 or more prior lines of therapy and prophylaxis against thromboembolism was required for all patients. The median age of patients was 67 years. Prior treatments included VELCADE®- Bortezomib (100%), REVLIMID® (99%), KYPROLIS® – Carfilzomib (21%), NINLARO® – Ixazomib (6%), and DARZALEX® – Daratumumab (3%). Close to 55% of patients had undergone Stem Cell transplantation and most patients were refractory to REVLIMID® (87%), a Proteosome Inhibitor (80%), or both (70%). The Primary end point was Progression Free Survival (PFS). The Secondary endpoints included Overall Response Rate (ORR), Complete Response (CR), Stringent Complete Response, Very Good Partial Response and Partial Response Rates.

After a minimum follow up period of 9.1 months, the median PFS was 10.3 months in the EMPLICITI® group and 4.7 months in the control group (HR=0.54; P=0.008), which suggested a 46% reduction in the risk of disease progression. The PFS of EMPLICITI® was consistently observed across all predefined patient subgroups. The Overall Response Rate was 53% in the EMPLICITI® group as compared with 26% in the control group, suggesting a doubling in the Response Rates in the EMPLICITI® group (P=0.0029) with Very Good Partial Responses or better seen in 20% of those in the EMPLICITI® group. The Overall Survival data were immature at the time of the analysis. However, a trend favoring the EMPLICITI® group was observed (HR for death=0.62).

The incidence of serious adverse events was 53% in the EMPLICITI® group and 55% in the control group and the most common treatment-related adverse events in the EMPLICITI® and control groups were neutropenia (18% versus 20%), hyperglycemia (18% versus 11%) and anemia (10% versus 15%), respectively. Adverse events that led to discontinuation of treatment occurred in 18% of the patients in the EMPLICITI® group and in 24% of the patients in the control group.

It was concluded that among patients with Multiple Myeloma who had progressed on REVLIMID® and a Proteosome Inhibitor, EMPLICITI® combined with POMALYST® and Dexamethasone significantly decreased the risk of progression or death and also doubled the Response Rate, compared to POMALYST® plus Dexamethasone alone. Elotuzumab plus Pomalidomide and Dexamethasone for Multiple Myeloma. Dimopoulos MA, Dytfeld D, Grosicki S, et al. N Engl J Med 2018;379:1811-1822

SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 30,770 new cases will be diagnosed in 2018 and 12,770 patients are expected to die of the disease. Multiple Myeloma (MM) in 2018 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). Multiple Myeloma evolves from a precursor stage called Monoclonal Gammopathy of Undetermined Significance (MGUS) to MM. Smoldering Multiple Myeloma (SMM) is an intermediate stage in this process of disease evolution.

Monoclonal gammopathies are often diagnosed by electrophoretic examination of the serum and urine proteins. They include Serum Protein ElectroPhoresis (SPEP), Serum Protein Immunofixation electrophoresis (SIFE), Urine Protein ElectroPhoresis (UPEP), Urine Protein Immunofixation electrophoresis (UIFE), and Bone Marrow evaluation. In addition, quantitative assessment of Serum Free Light Chains has been recommended for diagnosis and monitoring of neoplastic monoclonal gammopathies.

The Y-shaped Immunoglobulins are heterodimeric proteins composed of two heavy (H) and two light (L) chains. The two different types of light chains include Kappa and Lambda, which are distinctive in their amino acid sequence, with normally twice as many Kappa light chains. Malignancy can affect both types of light chains and in Multiple Myeloma. The relevant light chain production can increase, but the increase is more often in the Kappa light chains. Immunoglobulin light chains are produced in excess of the corresponding heavy chains and the excess free light chains can be quantified in serum and can also be detected in the urine, as they, by virtue of their size, are freely filtered through the glomerulus (Bence Jones protein). Excess amounts of free monoclonal light chains in patients with monoclonal gammopathy can produce nephropathy due to precipitation of these proteins in renal tubules.

Serum free Kappa and Lambda light chains are normally present in a ratio of about 0.26 to 1.65 and this ratio is increased in patients with Kappa light chain monoclonal gammopathy and decreased in patients with Lambda chain producing monoclonal gammopathies. Even though alteration in the serum K/L ratio is an important diagnostic criterion for plasma cell neoplasms, there is a high rate of positive results in patients receiving tertiary care, with abnormal K/L ratio noted in 36% of patients and about 90% of these are Kappa light chain dominant.

The serum K/L ratio is however less frequently abnormal and stays normal in patients with Lambda chain lesions even when an abnormal Lambda immunoglobulin is detected in the urine. These variabilities can result in the less-common Lambda chain-associated lesions going undiagnosed. There is a high false negative rate for Lambda dominant K/L ratio in Lambda chain associated monoclonal gammopathy (89% for MGUS, 60% for SMM and 51% for MM). It is estimated that the overall excess false negative K/L ratio rate for Lambda chain lesions, compared to Kappa chain lesions, is approximately 30%. The high false negative rate for the Lambda dominant K/L ratio, in patients with Lambda chain neoplastic monoclonal gammopathies, may be due to under-detection of Lambda light chains, Lambda chains are not produced in as much excess as are Kappa chains resulting in lower rates of Lambda dominant K/L ratio in patient with Lambda light chain neoplastic monoclonal gammopathy, and overproduction of polyclonal Kappa light chains in Lambda chain monoclonal gammopathies, as is usually noted in patients receiving tertiary care.

This study was undertaken by comparing the results of Serum and Urine Protein Electrophoreses with the results of Serum Free Light Chain Assay (SFLCA), to ascertain if the levels of overproduction of the Kappa and Lambda light chain types and their detection rates are different in patients with neoplastic monoclonal gammopathies. The authors performed a retrospective review of SPEP/SIFE, UPEP/UIFE, and SFLCA results from January 2010 through September 2017 from a total of 482 patients. Among these patients, 175 patients had a diagnosis of Neoplastic Monoclonal Gammopathy (MGUS, SMM or MM). , and evaluable results were available to address the questions of this study. Patients with Lymphomas and CLL were excluded.

The authors noted that the serum K/L ratios were appropriately abnormal more often in Kappa light chain disease. In contrast, in those with Lambda light chain disease, the K/L ratios were normal in about 25% of patients but free homogenous Lambda light chains were detectable in urine.

It was concluded that the serum Kappa/Lambda ratio in patients with Lambda light chain disease can be normal in a 25% of patients with Neoplastic Monoclonal Gammopathy and can be missed if not further evaluated with UPEP/UIFE. The authors comment that UPEP/UIFE is under- utilized and the study results question the medical necessity and clinical usefulness of the serum free light chain assay. Serum Free Light Chains in Neoplastic Monoclonal Gammopathies: Relative Under-Detection of Lambda Dominant Kappa/Lambda Ratio, and Underproduction of Free Lambda Light Chains, as Compared to Kappa Light Chains, in Patients With Neoplastic Monoclonal Gammopathies. Lee WS and Singh G. J Clin Med Res. 2018;10:562-569.

SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 30,770 new cases will be diagnosed in 2018 and 12,770 patients are expected to die of the disease. Multiple Myeloma in 2018 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). ASCO recently issued a clinical practice guideline update on the role of Bone-Modifying Agents (BMA) in Multiple Myeloma following a systematic literature review of 35 relevant studies by an expert panel. In the updated guidelines, ASCO has recommended expanding the use of bisphosphonates to include all patients being treated for active Multiple Myeloma. The previous guidelines recommended BMAs only for patients with lytic disease. The new recommendation was based on results from the phase III MRC Myeloma IX Trial, which demonstrated the benefit of bisphosphonate therapy in patients with newly diagnosed multiple myeloma who did not have lytic bone disease.

Indications to initiate a BMA – Key Recommendations

Patients with lytic disease on plain radiographs or other imaging studies

For patients with Multiple Myeloma who, on plain radiograph(s) or other imaging studies (MRI or CT scan), have lytic destruction of the bone or compression fracture of the spine from osteopenia, AREDIA® (Pamidronate) 90 mg IV over at least 2 hours or ZOMETA® (Zoledronic acid) 4 mg IV over at least 15 minutes every 3 to 4 weeks is recommended. Alternative treatment includes the use of XGEVA® (Denosumab), a monoclonal antibody that targets Receptor Activator of Nuclear factor Kappa-B Ligand (RANKL).

Patients with solitary plasmacytoma or smoldering (asymptomatic) or indolent myeloma

Starting bisphosphonates in patients with Solitary Plasmacytoma or Smoldering (asymptomatic) or indolent Myeloma is not recommended.

Adjunct to pain control in patients with pain as a result of osteolytic disease and those receiving other interventions for fractures or impending fractures

AREDIA® or ZOMETA® IV is recommended for patients with pain as a result of osteolytic disease and as an adjunctive treatment of patients receiving radiation therapy, analgesics, or surgical intervention to stabilize fractures or impending fractures. XGEVA® is an additional option.

Patients with myeloma with normal plain radiograph or osteopenia in bone mineral density measurements

The Expert Panel supports starting intravenous bisphosphonates in patients with Multiple Myeloma with osteopenia (osteoporosis), but no radiographic evidence of lytic bone disease.

Patients with monoclonal gammopathy of undetermined significance

Starting bisphosphonates in patients with Monoclonal Gammopathy of Undetermined Significance is not recommended, unless osteopenia/osteoporosis exists.

Dosing and selection of BMAs

As a result of increased concerns over renal adverse events, Guidelines recommend that patients with preexisting mild to moderate renal impairment (estimated Creatinine Clearance, 30-60 mL/min) should receive a reduced dosage of ZOMETA®. No changes in infusion time or interval are required. ZOMETA® has not been studied in patients with severe renal impairment and is not recommended for use in these patients. Recent data that compare XGEVA® with ZOMETA® has demonstrated fewer adverse events related to renal toxicity with XGEVA®, and this may be preferred in patients with compromised renal function. AREDIA® 90 mg administered over 4-6 hours is recommended for patients with extensive bone disease and existing severe renal impairment (serum creatinine level more than 3.0 mg/dL (265 µmol/L or an estimated Creatinine Clearance of less than 30 mL/min. Although no dosing guidelines are available for patients with preexisting renal impairment, the Expert Panel recommends that clinicians consider reducing the initial AREDIA® dose in that setting. Infusion times less than 2 hours with AREDIA® or less than 15 minutes with ZOMETA® should be avoided.

Duration of therapy

The Expert Panel suggests that bone-targeting treatment continue for a period of up to 2 years. Less frequent dosing has been evaluated and should be considered in patients with responsive or stable disease. In patients who do not have active Myeloma and are on maintenance therapy, the physician may consider a 3-month interval of bisphosphonate administration. There are no data to support a more precise recommendation for the duration of bisphosphonate therapy in this group of patients. For those patients for whom bisphosphonates were withdrawn after 2 years, the drug should be resumed upon relapse with new-onset Skeletal Related Events. XGEVA® should not be stopped abruptly, given its reversible mechanism of action.

Monitoring

The Expert Panel recommends that serum creatinine should be monitored before each dose of AREDIA® or ZOMETA®, in accordance with FDA-approved labeling. XGEVA® does not require monitoring of renal function. In patients who develop renal deterioration without an apparent cause during bisphosphonate therapy, ZOMETA® or AREDIA® should be withheld. Bisphosphonate therapy can be resumed at the same dosage as that before treatment interruption, when serum creatinine returns to within 10% of the baseline level. XGEVA® requires no dose modification. Serum Calcium should be monitored regularly, and serum Vitamin D levels should be evaluated intermittently. Hypocalcemia is an adverse effect of all bone resorptive agents and is more pronounced with XGEVA®. Patients should be Calcium and Vitamin D repleted. The Expert Panel also recommends intermittent evaluation (every 3-6 months) of all patients receiving AREDIA® or ZOMETA® therapy for the presence of albuminuria, on a spot urine sample. In patients who experience unexplained albuminuria, a 24-hour urine collection should be obtained to assess for more than 500 mg/24 hours of urinary albumin, and discontinuation of the drug is advised until renal problems are resolved. These patients should be reassessed every 3-4 weeks with a 24-hour urine collection for total protein and Urine Protein ElectroPhoresis, and AREDIA® should be reinstituted over a longer infusion time (4 hours or more) and at doses not to exceed 90 mg every 4 weeks, when renal function returns to baseline. The Expert Panel supports the use of screening urinalysis for proteinuria, but underscores that a 24-hour urine collection for the determination of total protein and electrophoresis is required if the test is positive. Although no similar guidelines are available for ZOMETA®, some Expert Panel members recommend that ZOMETA® be reinstituted over a longer infusion time (30 minutes or more).

Biochemical markers

Use of the biochemical markers of bone metabolism to monitor bone-modifying therapy use, is not suggested for routine care.

Osteonecrosis of the jaw

OsteoNecrosis of the Jaw (ONJ) is an uncommon but potentially serious complication of IV bisphosphonates and XGEVA®. The Expert Panel agrees with the recommendations described in the revised FDA label for ZOMETA® and AREDIA®, Dear Doctor letters, a white paper, and various position papers or statements. All patients should receive a comprehensive dental examination and appropriate preventive dentistry before bone-modifying therapy. Active oral infections should be treated, and sites that are at high risk for infection should be eliminated. While on therapy, patients should maintain excellent oral hygiene and avoid invasive dental procedures, if possible. Continuation of a bone-targeting agent in the setting of ONJ has to be individualized and dependent on a risk-benefit ratio and the severity of bone disease.

Role of bone-modifying agents in multiple myeloma: American Society of Clinical Oncology clinical practice guideline update. Anderson K, Ismaila N, Flynn PJ, et al. J Clin Oncol. 2018;36:812-818.

SUMMARY: The FDA on May 7, 2018 approved DARZALEX® (Daratumumab) in combination with VELCADE® (Bortezomib), a proteasome inhibitor, Melphalan, an alkylating agent and Prednisone VMP regimen), for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for Autologous Stem Cell Transplant (ASCT). Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 30,770 new cases will be diagnosed in 2018 and 12,770 patients are expected to die of the disease. Multiple Myeloma in 2018 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). With a record number of regulatory approvals for myeloma treatment over the past 12 years, the median survival for patients with myeloma is over 10 years.

The incidence of multiple myeloma increases with age and the median age of patients diagnosed with multiple myeloma is approximately 70 yrs. Elderly patients with myeloma in the US are often treated with a combination of REVLIMID® (Lenalidomide) and Dexamethasone, whereas Melphalan, Prednisone, and Thalidomide (MPT) and VELCADE® (Bortezomib), Melphalan and Prednisone (VMP) are the most widely used regimens outside the US. These regimens are associated with a PFS of 18-24 months and an OS of 4-5 years. For patients with newly diagnosed multiple myeloma who are ineligible for ASCT, treatment with VMP regimen has been a standard effective regimen, based on the VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone) trial. 

DARZALEX® (Daratumumab) is a human IgG1 antibody that targets CD38, a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. DARZALEX® exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Dependent Cytotoxicity (CDC) and direct Apoptosis. Additionally, DARZALEX® may have a role in immunomodulation, by depleting CD38-positive regulator immune suppressor cells, and thereby expanding T cells, in patients responding to therapy. In previously treated patients with myeloma, DARZALEX® in combination with REVLIMID® and Dexamethasone (POLLUX trial) as well as in combination with VELCADE® and Dexamethasone (CASTOR trial), induced higher Response Rates and significantly prolonged PFS, reducing the risk of disease progression or death by over 60% in previously treated myeloma patients.

ALCYONE is a multicenter, randomized, open-label, active-controlled, phase III trial in which DARZALEX® given along with VELCADE®, Melphalan and Prednisone (VMP regimen) was compared with VMP alone (control group), in patients with newly diagnosed multiple myeloma, who were ineligible for Autologous Stem Cell Transplantation (ASCT). Of the 706 enrolled patients, 350 were assigned to the DARZALEX® group and 356 to the control group. The median age was 71 yrs. All the patients received up to nine 6 week cycles of VELCADE® 1.3 mg/m2 SQ, twice weekly on weeks 1, 2, 4, and 5 of cycle 1 and once weekly on weeks 1, 2, 4, and 5 of cycles 2-9), Melphalan 9 mg/m2 orally, once daily on days 1-4 of each cycle, and Prednisone 60 mg/m2 once daily on days 1-4 of each cycle. In the study group, patients received DARZALEX® 16 mg/kg IV administered with Dexamethasone 20 mg oral or IV (to manage infusion reactions), once weekly for a total of 6 doses, every 3 weeks for a total of 16 doses and every 4 weeks thereafter until disease progression or unacceptable toxicity. The Primary end point was PFS. Secondary end points included Overall Response Rate, rates of Very Good Partial Response, Complete Response rate, Minimal Residual Disease negativity and Overall Survival.

At a median follow up of 16.5 months in a prespecified interim analysis, the 18-month PFS was 71.6% in the DARZALEX® group and 50.2% in the control group (HR=0.50; P<0.001). This meant a 50% reduction in the risk of disease progression or death when DARZALEX® was added to VMP regimen. The median PFS for DARZALEX® plus VMP had not yet been reached, compared to a median PFS of 18.1 months for patients who received VMP alone. The Overall Response Rate was 90.9% in the DARZALEX® group, as compared with 73.9% in the control group (P<0.001), and the rate of Complete Response or better (including stringent Complete Response) was 42.6%, versus 24.4% (P<0.001). In the DARZALEX® group, 22.3% of the patients were negative for Minimal Residual Disease (at a threshold of 1 tumor cell per 105 white cells), as compared with 6.2% of those in the control group (P<0.001). The most common adverse events were cytopenias noted in both treatment groups, and with the exception of infections (23% versus 15%), combining DARZALEX® with VMP regimen did not increase overall toxicities. DARZALEX® associated infusion-related reactions occurred in 28% of the patients.

It was concluded that DARZALEX® is the first monoclonal antibody approved for newly diagnosed multiple myeloma patients who are not eligible for a Autologous Stem Cell Transplant, and in combination with VMP regimen significantly improved Progression Free Survival and Response Rates. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. Mateos MV, Dimopoulos MA, Cavo M, et al. for the ALCYONE Trial Investigators. N Engl J Med 2018; 378:518-528

SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 30,770 new cases will be diagnosed in 2018 and 12,770 patients are expected to die of the disease. Multiple Myeloma in 2018 remains an incurable disease. The therapeutic goal therefore is to improve Overall Survival (OS) in the relapsed setting.

KYPROLIS® (Carfilzomib) is a second generation selective, epoxyketone proteasome inhibitor and unlike VELCADE® (Bortezomib), proteasome inhibition with KYPROLIS® is irreversible. Most of the recent phase III trials in Relapsed or Refractory Myeloma have used Progression Free Survival (PFS) as the Primary end point, with the exception of the phase III trial ENDEAVOR trial in which patients treated with KYPROLIS® and Dexamethasone achieved a statistically significant 7.6-month improvement in median Overall Survival (OS) compared to those patients treated with VELCADE® and Dexamethasone (HR=0.79; P=0.01). REVLIMID® (Lenalidomide) given along with weekly Dexamethasone, was associated with significantly improved Progression Free Survival (PFS) when administered until disease progression, in patients with newly diagnosed Multiple Myeloma. The combination of REVLIMID® and weekly Dexamethasone is considered a reference regimen for both newly diagnosed and relapsed Multiple Myeloma. VELCADE® in combination with REVLIMID® and Dexamethasone showed an overall response rate of 64% and a median PFS of 9.5 months in patients with Relapsed or Refractory Multiple Myeloma.

Based on this background, a randomized, open label, multicenter, phase III study (ASPIRE) was conducted, in which the safety and efficacy of a combination of KYPROLIS® (Carfilzomib), REVLIMID® and weekly Dexamethasone (KRd) was compared with a combination of REVLIMID® and weekly Dexamethasone (Rd), in patients with Relapsed or Refractory Multiple Myeloma. Seven hundred and ninety two (N=792) patients were randomly assigned in a 1:1 ratio to KRd (N=396) and Rd (N=396). Eligible patients included those with Multiple Myeloma who had received one to three prior treatments which included VELCADE® or REVLIMID® and Dexamethasone combination, provided that they did not have disease progression during treatment with these agents. The 28 day treatment cycle consisted of KYPROLIS® IV given on days 1, 2, 8, 9, 15, and 16 (starting dose, 20 mg/m2 on days 1 and 2 of cycle 1 with a target dose of 27 mg/m2 thereafter) during cycles 1 through 12 and on days 1, 2, 15, and 16 during cycles 13 through 18, following which KYPROLIS® was discontinued. REVLIMID® 25 mg PO was given on days 1 through 21 and Dexamethasone 40 mg PO was administered on days 1, 8, 15, and 22. Patients in both treatment groups received only REVLIMID® and Dexamethasone after cycle 18 until disease progression. Antiviral and antithrombotic prophylaxis was administered to patients in both treatment groups. The Primary end point was Progression Free Survival (PFS) and secondary end points included Overall Survival (OS), the rate of overall response (partial response or better), response duration, health-related quality of life, and safety.

The study met its Primary endpoint at the time of the pre-specified interim analysis with a significant improvement in the median PFS for those patients in the KRd group compared to the Rd (26.3 months versus 17.6 months; HR=0.69; P=0.0001). This benefit in the PFS was demonstrated across all predefined subgroups. The overall response rates (partial response or better) were 87.1% and 66.7% in the KYPROLIS® and control groups, respectively (P<0.001). Further, patients in the KYPROLIS® group reported superior health-related quality of life.

The authors in this prespecified analysis reported the final Overall Survival (OS) data and updated safety results. The median follow up was 67.1 months. The median OS was 48.3 months in the KRd group and 40.4 months in the Rd group (HR=0.79; P=0.0045). This represented a 7.9 month prolongation of OS and 21% decrease in the risk of death with KRd. Among patients who had received one prior line of therapy, KRd improved median OS by 11.4 months and among those who had received 2 or more prior lines of therapy, KRd improved median OS by 6.5 months, compared to Rd. Among patients who had received one prior line of VELCADE® based therapy, the median OS was improved by 12 months with KRd versus Rd, with a 18% reduction in the risk of death, and among patients with prior transplantation at first relapse, the median OS was improved by 18.6 months with KRd versus Rd, with a 29% reduction in the risk of death. The OS benefit with KRd was noted across all age, Creatinine Clearance (CrCL) and ECOG PS subgroups, including those 75 years or older, patients with impaired renal function (CrCL 30 to less than 60 mL/min), and patients with decreased Performance Status (ECOG PS, 2). The median time to next treatment from time of randomization was 39.0 months for patients who received KRd and 24.4 months for those who received Rd (HR=0.65; P<0.001).

An updated median PFS with longer follow up (median , 48.4 months) was 26.1 months in the KRd group versus 16.6 months in the Rd group (HR=0.66; P<0.001). Grade 3 or higher adverse events were reported in 87% and 83.3% of patients in the KRd and Rd groups, respectively.

It was concluded that treatment with KRd resulted in a statistically significant and clinically meaningful reduction in the risk of death, compared to Rd, among patients with Relapsed or Refractory Myeloma. This analysis supports the early use of KYPROLIS® at first relapse, regardless of prior treatment with VELCADE® or transplantation. Because each subsequent line of therapy can result in shorter response duration and increased treatment resistance, the authors suggested that early treatment with an effective regimen is important to maximize Overall Survival and KRd regimen should be considered a preferred treatment option in Relapsed or Refractory Multiple Myeloma. Improvement in Overall Survival With Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma. Siegel DS, Dimopoulos MA, Ludwig H, et al. J Clin Oncol. 2018;36:728-734

SUMMARY: Multiple Myeloma (MM) is a clonal disorder of plasma cells in the bone marrow. It evolves from a precursor stage called Monoclonal Gammopathy of Undetermined Significance (MGUS) to MM. Smoldering Multiple Myeloma (SMM) is an intermediate stage in this process of disease evolution. MGUS is defined as the presence of a serum monoclonal protein (M protein) at a concentration of 3 g/dl or less, urine with none or only modest amounts of monoclonal light chains, absence of CRAB features that are related to the M protein (Hypercalcemia, Renal insufficiency, Anemia, and Bone lesions) and 10% or fewer monoclonal plasma cells in the bone marrow. MGUS occurs in approximately 3% of individuals 50 years of age or older and in 5.3% of those 70 years of age or older.

MGUS is classified into two major subtypes, IgM and non-IgM. This is because the clonal cell that is involved and the nature of progression, differ between these two types. The origin of IgM MGUS is typically from a CD20 positive Lymphoplasmacytic cell that has not undergone Switch Recombination (Class-Switch Recombination or CSR, is a biological mechanism that changes a B cell production of immunoglobulin from one type to another, such as from the isotype IgM to the isotype IgG.), and this disease type is associated with a risk of progression to Lymphoma or Waldenström’s macroglobulinemia. In contrast, non-IgM MGUS typically arises from mature plasma cells that have undergone Switch Recombination and is associated with a risk of progression to Multiple Myeloma. Both disease types can progress to AL Amyloidosis.

There is limited information regarding malignant transformation of MGUS to Multiple Myeloma as well as Overall Survival, after diagnosis is made. Further, the risk of progression to Multiple Myeloma among the two major biologic subtypes of MGUS, IgM and non-IgM, is different, and data regarding the prognosis and risk stratification associated with these entities have not been well characterized. The authors in this publication, which is a longer follow up of previously reported findings, studied 1384 patients with MGUS, who were identified in a well-defined geographic area, from 1960-1994. The median follow up was 34.1 years. The Primary end point was progression to Multiple Myeloma or another Plasma-cell or Lymphoid disorder.

During 14,130 person-years of follow up, the rate of progression of MGUS to Multiple Myeloma was 6.5 times as high as the rate in the control population. The risk of progression to Multiple Myeloma was 10% at 10 years, 18% at 20 years, 28% at 30 years, 36% at 35 years, and 36% at 40 years. The risk of progression varied depending on the biologic subtypes of MGUS and other adverse risk factors. Among patients with IgM MGUS, the presence of two adverse risk factors – an abnormal serum free light chain ratio (ratio of kappa to lambda free light chains) and a high serum monoclonal protein level (1.5 g/dl or greater), was associated with a risk of progression at 20 years of 55%, as compared with 41% among patients who had one adverse risk factor and 19% among patients who had neither risk factor. Among patients with non-IgM MGUS, the risk of progression to Multiple Myeloma at 20 years was 30% among those who had the two risk factors, 20% among those who had one risk factor, and 7% among those who had neither risk factor. More importantly, patients with MGUS had shorter survival compared to age and sex matched control population (median 8.1 versus 12.4 years, P<0.001).

It was concluded that there were significant differences noted in the risk of progression between patients with IgM MGUS and those with non-IgM MGUS and Overall Survival was shorter among patients with MGUS than was expected in a matched control population. Long-Term Follow-up of Monoclonal Gammopathy of Undetermined Significance. Kyle RA, Larson DR, Therneau TM, et al. N Engl J Med 2018; 378:241-249

SUMMARY: The FDA on June 16, 2017 approved the use of DARZALEX® (Daratumumab) in combination with POMALYST® (Pomalidomide) and Dexamethasone for the treatment of patients with Multiple Myeloma who have received at least two prior therapies including REVLIMID® (Lenalidomide) and a Proteasome Inhibitor. Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, about 30,280 new cases will be diagnosed in 2017 and 12,590 patients will die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. With a record number of regulatory approvals for Myeloma treatment over the past 12 years, the median survival for patients with Myeloma is over 10 years.

DARZALEX® is a human IgG1 antibody that targets CD38, a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. DARZALEX® exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Mediated Cytotoxicity and direct apoptosis. Additionally, DARZALEX® may have a role in immunomodulation by depleting CD38-positive regulator Immune suppressor cells, and thereby expanding T cells, in patients responding to therapy. The FDA approved DARZALEX® in November 2015 as monotherapy for Myeloma patients who had received at least three prior lines of therapy including a Proteasome Inhibitor (PI) and an Immunomodulatory agent or who are double refractory to a PI and an Immunomodulatory agent. In November 2016, DARZALEX® was approved in combination with REVLIMID® and Dexamethasone, or VELCADE® (Bortezomib) and Dexamethasone, for the treatment of patients with Multiple Myeloma who have received at least one prior therapy. POMALYST® (Pomalidomide) is a novel, oral, immunomodulatory drug which is far more potent than THALOMID® (Thalidomide) and REVLIMID®, and has been shown to be active in REVLIMID® and VELCADE® refractory patients.

This new FDA approval was based on data from the phase Ib (MMY1001, EQUULEUS) study of DARZALEX® in combination with POMALYST® and Dexamethasone in relapsed or refractory Multiple Myeloma. This open-label study included 103 patients with Multiple Myeloma who had received prior treatment with a Proteasome Inhibitor and an Immunomodulatory agent. Treatment consisted of DARZALEX® 16 mg/kg IV on days 1, 8, 15, and 22 of a 28 day cycle for 8 weeks during cycles 1 and 2, every 2 weeks (on days 1 and 15) for 16 weeks (cycles 3 thru 6), and every 4 weeks thereafter until disease progression. POMALYST® 4 mg PO was administered daily for 21 days along with Dexamethasone 40 mg weekly (20 mg for patients over 75 years of age). The median patient age was 64 years and patients had received a median of 4 prior lines of therapy. About 75% of the patients had prior Autologous Stem Cell Transplant, 90% of patients were refractory to REVLIMID®, 70% were refractory to VELCADE®, and 64% were refractory to both agents.

The Overall Response Rate in this study was 59% with Very Good Partial Response (VGPR) noted in 28% of patients. Complete Response was achieved in 6% of patients and stringent Complete Response was achieved in 8% of patients. The median time to response was 1 month and the median duration of response was 13.6 months. The most common toxicities were infusion reactions, nausea, vomiting, diarrhea, fatigue, fever, upper respiratory tract infection, muscle spasms, cough and dyspnea. The most common grade 3/4 toxicities were cytopenias including lymphopenia.

It was concluded that DARZALEX® in combination with POMALYST® and Dexamethasone is a new combination therapy, with significant clinical benefit, for patients who relapse or become resistant to Proteasome Inhibitors and Immunomodulatory agents. This combination may be a viable option for patients who progress on a combination of REVLIMID®, VELCADE® and Dexamethasone (RVD) regimen, which is often given as first line therapy. A Study of JNJ-54767414 (HuMax CD38) (Anti-CD38 Monoclonal Antibody) in Combination With Backbone Treatments for the Treatment of Patients With Multiple Myeloma. ClinicalTrials.gov Identifier: NCT01998971 https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/761036orig1s005ltr.pdf.